Right Ventricular Assessment in Adult Congenital Heart Disease Patients with Right Ventricle–to–Pulmonary Artery Conduits Miriam Wheeler, MBChB, Jonathon Leipsic, MD, Philip Trinh, Rekha Raju, MBChB, Shalan Alaamri, MBBS, Christopher R. Thompson, MD, Robert Moss, MBBS, Bradley Munt, MD, Marla Kiess, and Jasmine Grewal, MD, Vancouver, British Columbia, Canada; and Seattle, Washington

Background: There is little data on right ventricular (RV) remodeling patterns in complex congenital heart disease (CHD) patients with right ventricle to pulmonary artery (PA) conduits, and novel RV imaging modalities have not been explored in this population. Knowledge of the RV remodeling process is an important first step to future understanding and tracking of the RV response to pressure and volume overload in this diverse population. Three-dimensional knowledge-based reconstruction (3DKBR) derived from two-dimensional transthoracic echocardiography (TTE-3DKBR) is a novel approach to RV assessment. The aims of this study were twofold: (1) to assess the feasibility and accuracy of 3DKBR in patients with CHD with RV to PA conduits and (2) to characterize the three-dimensional shape of the RV across the spectrum of CHD with RV to PA conduits. Methods: Seventeen patients with tetralogy of Fallot, pulmonary atresia with ventricular septal defect, or truncus arteriosus (mean age, 29 6 8 years; 24% women) and a conduit referred for cardiac magnetic resonance imaging (CMR) were prospectively recruited and underwent TTE-3DKBR. TTE-3DKBR echocardiographic image acquisition was performed using a standard ultrasound scanner linked to a Ventripoint Medical Systems unit. The surface RV volumetric reconstruction was performed by transmitting two-dimensional data points to an online database and comparing these with a lesion-specific catalog to derive the RV reconstruction. Parameters analyzed were end-diastolic volume (EDV), end-systolic volume, and ejection fraction. Intertechnique agreement was assessed using Pearson’s correlation analysis, coefficients of variation, and BlandAltman analysis. Three-dimensional shape comparisons of RV surface reconstructions were performed via automated validation testing of CMRs from 43 patients (mean age, 30 6 8 years; 32% women) with RV to PA conduits (tetralogy of Fallot, n = 15; pulmonary atresia, n = 19; and truncus arteriosus, n = 9) distinct from patients in the 3DKBR comparison. Results: There was good correlation and agreement between the two modalities: EDV, R = 0.77, P = .0004; end-systolic volume, R = 0.93, P < .0001; ejection fraction, R = 0.75, P < .0005. On Bland-Altman analyses, CMR EDV was slightly larger TTE-3DKBR, while EF was slightly higher by 3DKBR. Qualitative and quantitative assessment both demonstrated RV shape diversity based on surface reconstructions. Conclusion: This study demonstrates that TTE-3DKBR is an alternative technology that can be used to assess the RV in patients with complex CHD with a conduit. A novel method was used to compare RV shapes in this important population, and our results draw specific attention to the fact that the RV both within and outside diagnostic groups has very different unpredictable shapes and should not be treated equally. Our findings should set into motion future work focused on indices of RV shape and their impact on overall RV function and clinical outcomes, hence defining optimal timing of conduit revision, which at the current time is very unclear. (J Am Soc Echocardiogr 2015;28:522-32.) Keywords: Right ventricle, Congenital heart disease, Conduit, Magnetic resonance imaging

From the Division of Cardiology, University of British Columbia Pacific Adult Congenital Heart Disease Clinic, St Paul’s Hospital, Vancouver, British Columbia, Canada (M.W., J.L., S.A., C.R.T., R.M., B.M., M.K., J.G.); Division of Radiology, University of British Columbia, St Paul’s Hospital, Vancouver, British Columbia, Canada (J.L., R.R.); and Ventripoint, Seattle, Washington (P.T.).

Reprint requests: Jasmine Grewal, MD, University of British Columbia, St Paul’s Hospital, Room 448, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2015 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2014.11.016

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Surgical placement of a right ventricle (RV)–to–pulmonary AVT = Automated validation artery (PA) conduit plays an testing important role in the repair of complex congenital heart CHD = Congenital heart disease (CHD), specifically in disease conotruncal abnormalities, in CMR = Cardiac magnetic which there is abnormal resonance imaging development of the right venEDV = End-diastolic volume tricular outflow tract (RVOT).1 Insertion of a RV-PA conduit EF = Ejection fraction has improved pulmonary blood ESV = End-systolic volume flow in defects such as pulmonary atresia with ventricular PA = Pulmonary artery septal defect (VSD), tetralogy RV = Right ventricular/ of Fallot (TOF) and allows for a ventricle biventricular repair in truncus arteriosus (TA). The critical limiRVOT = Right ventricular tation of RV-PA conduits is the outflow tract high failure rate over time, TA = Truncus arteriosus leading to symptoms and 3D = Three-dimensional progressive RV dilatation and dysfunction.2-5 RV assessment 3DKBR = Three-dimensional is thought to be important to knowledge-based timing of reintervention, reconstruction although there are little data to TOF = Tetralogy of Fallot support this notion or to define optimal timing of intervention TTE = Transthoracic based on RV parameters. echocardiography Furthermore, the RV has been TTE-3DKBR = Threeassumed to be the same dimensional knowledgein patients with conduits based reconstruction derived regardless of the underlying from two-dimensional CHD diagnosis. Knowledge of transthoracic the RV remodeling process is echocardiography an important first step to future 2D = Two-dimensional understanding and tracking the VMS = Ventripoint Medical RV response to pressure and Systems volume overload in this diverse population. This line of VSD = Ventricular septal investigation has been pursued defect in patients with TOF without conduits.6,7 This work has led to many novel studies, including the investigation of surgical techniques that address RV shape abnormalities to optimize RV function post-surgery.8 The RV in the complex conduit population has not been studied to date. Two-dimensional (2D) transthoracic echocardiography (TTE) is limited in providing a quantitative assessment of RV volumes or ejection fraction (EF), as a result, cardiac magnetic resonance imaging (CMR) has become the reference standard. Quantitative threedimensional (3D) echocardiography has been evaluated as a more economical and facile alternative to CMR. However, several limitations have been observed, including poor endocardial definition and consistent underestimation of RV volumes related to severe enlargement and abnormal remodeling such that the RV extends to outside the transducer imaging volume.9,10 Generation of a 3D RV model from 2D TTE images is possible with 3D knowledge-based reconstruction (TTE-3DKBR). This method has been validated in vitro and against CMR in patients with TOF, transposition of the great arteries, and in pulmonary hypertension.6,11,12 Specific anatomic landmarks are identified, and the proprietary Abbreviations

reconstruction algorithm uses these landmarks to fit specific regions of the RV to various hearts in a catalog of patients with similar pathology. The algorithm then generates a 3D model based on all the subregions. The aims of this study were twofold: (1) to assess the feasibility and accuracy of TTE-3DKBR in CHD patients with RV to PA conduits and (2) to characterize the 3D shape of the RV across the spectrum of patients with CHD with RV-PA conduits.

METHODS Study Design and Population This was a single-center, prospective, observational study. The study was approved by the institutional research ethics board. Written informed consent was obtained from all patients prior to study enrollment. All patients were $18 years of age, had an RV-PA conduit, and had an underlying diagnosis of TOF, pulmonary atresia with VSD, or TA. Patients who were scheduled to undergo CMR for a clinical indication were eligible for inclusion. Exclusion criteria were any contraindication to CMR, including pacemaker or defibrillator, inability to comply with breath-hold instructions, and claustrophobia. Patients with a surgical history of a Rastelli procedure were excluded as the RV-PA conduit 3DKBR catalog did not extend to include this group. Patients were not screened for 2D transthoracic image quality prior to enrollment. Just before or after the CMR, an echocardiographic study was performed, including image acquisition for TTE-3DKBR. A total of 17 patients were prospectively enrolled for this TTE-3DKBR comparison. To determine if RV shape among patients with RV-PA conduit varied by underlying diagnosis, 3D CMR shape comparisons were performed. CMR studies of patients from our program were used for this purpose, for a total of 43 studies from patients with a conduit (TOF, n = 15; pulmonary atresia with VSD, n = 19; and TA, n = 9). These were patients who had a CMR and were not clinically eligible for another CMR and hence were not eligible for enrollment into the TTE-3DKBR comparison as described above. Details pertaining to conduit type, implantation approach, and conduit location were obtained and recorded from operative notes. 3D Knowledge-Based Reconstruction Method Image Acquisition. Two-dimensional TTE images were acquired with standard ultrasound equipment (iE33 system and S5 transducer; Philips Medical Imaging, Andover, MA). This was connected to a specialized console and used with a magnetic field generator, located underneath the patient bed (Ventripoint Diagnostics Ltd, Seattle, WA). A standard 2D probe was used, with the addition of the magnetic field localizing system (Ascension Technology Corporation, Andover, MA) to track the transducer movements and position relative to the magnetic field transmitter located under the examination bed. The position and orientation of the receiver and thus the plane of the 2D picture can be computed and placed within the volume created by the magnetic transmitter. Images were recorded from the parasternal long-axis, RV inflow and outflow views, parasternal short-axis at both the papillary muscle and apical level apical fourchamber and focused RV apical views, with a focus on endocardial definition of the RV. Additional views were performed to demonstrate the RV-PA conduit. Each image was obtained at endexpiration with the patient in a fixed position throughout the study. The ultrasound scanner is linked to a computer (Ventripoint Medical Systems [VMS]; Ventripoint, Inc, Seattle, WA) through the

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Figure 1 Minimum point placements required for 3DKBR as demonstrated on 2D imaging. (A) Posterior tricuspid annulus; (B) RV endocardium, tricuspid annulus, and septum; (C) RV conal septum and endocardium; (D) pulmonary annulus; and (E) apex. 2D, Two-dimensional; 3DKBR, three-dimensional knowledge-based reconstruction; RV, right ventricular. video output, and every clip is digitized at 30 frames/sec. The magnetic field data are entered at the same time, and 3D localizing data are linked in the computer online. All images were acquired by two sonographers (M.L. and L.J.) trained in equipment use and image analysis. The entire acquisition protocol takes approximately 10 min. Image Reconstruction. The images and spatial information recorded are stored on the VMS computer, which has an Internet connection to the centralized database. Offline analysis is performed by placing anatomic points using the VMS software. RV end-diastolic volume (EDV), end-systolic volume (ESV), and EF were calculated. End-diastole was selected manually on an apical four-chamber view, by visual determination of the time point at which RV area was largest immediately at or prior to tricuspid valve closure. Endsystole was selected as the smallest area on the same apical fourchamber view. The same end-diastole–to–end-systole interval was automatically applied to all other acquisitions. Points corresponding to several anatomic landmarks were placed on TTE images at enddiastole and end-systole. For full 3DKBR, a minimum of nine key points need to be identified on the 2D images for a reconstruction to be possible (Figure 1, Table 1). However, we placed many more points; on average, 23 points were placed for reconstruction of the RV volumes in this study. Better endocardial definition allows a

greater number of points to be placed. No additional anatomic tracing or border detection is required. RV endocardial points were placed at the base of trabeculations to the endocardial surface. Once the anatomic points on the 2D TTE images have been marked and localized in the magnetic 3D space, the surface RV volumetric reconstruction is performed by transmitting the data to the online database. The catalog CMR database consists of fully traced RV volumes of patients with RV-PA conduits with a wide spectrum of RV volumes and function. The points identified on the 2D images and relative 3D location is matched to the catalog database, and the best fit is computed using a proprietary algorithm. Once the minimum number of points has been placed, the first reconstruction can be performed. The reconstructed RV volume is projected on the 2D data set (Figure 2A), and point placement can be adjusted and/or more points can be added to refine the RV reconstruction and improve border alignment (Figure 2B). On TTE images with clear border misalignment giving rise to a very abnormal shape, suggesting a shift in patient position, images recorded after the patient had moved were excluded if all essential points were already placed, or the study was no longer able to be used if patient movement was not detected at the time of acquisition. All TTE studies were analyzed by a single observer (M.W.) with formal training in software use, who was blinded to CMR results. All analyses were performed offline after

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Table 1 Minimum point placement required in systole and diastole for 3DKBR Site

No. of points*

RV endocardium

2

RV septum

1

Pulmonic annulus

1

Conal septum

1

Tricuspid annulus

3

Basal bulge

0

Apex

1

RV septal edge

0

Subtricuspid

0

3DKBR, Three-dimensional knowledge-based reconstruction; RV, right ventricular. *Optional sites are denoted by zeros.

completion of acquisition. Five studies were performed for primary analysis before enrollment commenced. Analyses were also performed on all studies by two observers experienced with 3DKBR in assessment of interobserver variability. CMR Image Acquisition and Analysis. Cardiac magnetic resonance images were acquired using a 1.5-T scanner (GE Signa Twin Speed; GE Healthcare, Waukesha, WI). Retrospectively gated cine images were obtained with a steady-state free precession sequence (fast imaging employing steady-state acquisition). A stack of short-axis slices (1.3 msec TE; 3–4.5 msec TR; 45 Flip Angle; 10 mm thick; 0 interslice gap; 32–35 cm field of view; 224  224 matrix [phase, frequency]) from base to apex of the entire heart was acquired, from the tricuspid annulus to the level of the pulmonary valve. Short-axis cine slices were analyzed using volumetric analysis software (ReportCard 4; Neosoft LLC, New York, NY) to measure ventricular volumes and EFs using the Simpson method of disks using the standard technique of tracing the contours of the ventricular borders to the base of the endocardium, excluding trabeculations. The images with the largest and smallest ventricular volumes were selected as the end-diastolic and end-systolic images, respectively. RV Shape Variation Assessment To determine if RV shape among patients with RV-PA conduits varied by underlying diagnosis, 3D CMR shape comparisons were performed using the automated validation testing (AVT) algorithm. CMR studies of patients from our program were used for this purpose, for a total of 43 studies from patients with a conduit (TOF, n = 15; pulmonary atresia with VSD, n = 19; and TA, n = 9). None of these CMRs were from the 17 prospectively enrolled patients for 3DKBR comparison. All shapes used in the quantitative AVT comparison were produced from CMR manual FullFit end-diastole tracings using VentriPoint’s piecewise smooth subdivision surface method.6 No 2D TTE images were utilized in this process. In order to compare shapes, the AVT program was fed (1) a test shape (i.e., one of the 43 CMR manual FullFit shapes) and (2) a hearts ‘‘catalog’’ for comparison (the remaining 42 CMR manual FullFit shapes). By analyzing which and how many of the 42 hearts the KBR used

to reconstruct the test shape, the AVT program allows shape variability assessment. The AVT program samples several 3D anatomical points from the FullFit surface of the test shape. These points are inputted into the catalog of shapes and used to identify shapes with similar segmental or global shape, the combination of identified shapes is used to form a preliminary reconstruction. The resultant KBR reconstruction is quantitatively compared with the original FullFit phantom to find regions with discrepancies. To achieve the best possible match, the AVT then analyzes these discrepancies and adds additional points and incorporates additional corresponding shapes from the catalog, fine-tuning the reconstruction to more closely match the FullFit shape. This process is repeated until four reconstructions are ran in total, ensuring that the final fourth-round resultant VMS reconstruction is an almost perfect match to the test shape. This process was repeated for each of the 43 CMR studies included in this study. The similarity between hearts was assessed qualitatively and by quantitative analyses. Shape comparisons were made from the CMR piecewise smooth subdivision surface FullFit images. It is important to note that all of the comparison hearts are scaled and normalized before being compared, so that two hearts with the exact same shape but different volume will match perfectly. Similarity is determined by how much any given ‘‘catalog’’ shape contributes to reconstruction of the ‘‘test’’ shape. This is a percentage that reflects how weighted the ‘‘catalog’’ shape is to provide the closest match to the ‘‘test’’ shape, as compared with other hearts in the ‘‘catalog.’’ In the case of ‘‘unique’’ hearts, many catalog shapes may be used to contribute to the reconstruction, none of which contribute a significant percentage to the final reconstruction. In the case of similar hearts, one or two hearts may contribute to the final reconstruction. A final check is performed to ensure that the test shape is truly unique by looking at the hearts contributing to the reconstruction, specifically to ensure that it is not that several similar heart shapes are contributing to an equally similar test shape. Another quantitative check is to look at maximum point distance discrepancies. This is done by orienting all hearts in the same plane as determined by the valve planes and apex. The meshes of the test shape and catalog hearts contributing to the single reconstruction are overlaid and compared. Differences in the distances orthogonal to each mesh surface at the reconstruction points are determined. A maximum mesh difference (maximum surface gap) of >1 cm implies that the shape reconstruction does not match the test shape well. Difference in volume calculated as percent volume difference (volume of test shape volume of reconstruction/volume of test shape) was also determined. The volume difference is attributable to differences in shape given that the hearts are all scaled and normalized before the AVT algorithm is applied. Statistical Analysis Categorical variables were summarized using frequencies and percentages. Continuous variables were summarized using mean 6 SD. The relationship between TTE-3DKBR- and CMRderived RV volumes and EFs was evaluated using linear regression analysis with Pearson’s correlation coefficient. Bland-Altman analysis was performed to assess agreement between the two imaging modalities. Intraobserver (M.W.) agreement was assessed with repeated 3DKBR analysis 4 weeks after the initial analysis. Interobserver agreement was assessed for all study patients by two observers experienced with 3DKBR. Inter- and intraobserver agreement was quantified with intraclass correlation and coefficients of variation, the latter being the

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Figure 2 (A) Two-dimensional echocardiogram, parasternal short-axis view. Images analyzed offline for placement of points using the VMS. Red point denotes RV endocardium, blue point denotes RV septum in this plane. The yellow borders show where the best fit created by the 3DKBR analysis intersects the parasternal short-axis plane. The yellow lines fall off the short-axis plane as they represent the entire 3DKBR, taking into account all cardiac planes and not just the single plane shown in the figure. (B) Additional points placed at the RV septal edge to improve border alignment. Green points denote RV septal edge. 3DKBR, Three-dimensional knowledge-based reconstruction; RV, right ventricular; VMS, ventripoint medical systems.

Table 2 Patient characteristics

Characteristic

TTE-3DKBR comparison (n = 17)

RV shape assessment (n = 43)

Age (yrs)

29 6 8

30 6 8

Women

4 (24%)

14 (32%)

Underlying diagnosis TOF

9 (53%)

15 (35%)

Pulmonary atresia with VSD

6 (35%)

19 (44%)

TA BSA (m2)

2 (12%)

9 (21%)

1.8 6 0.2

1.7 6 0.3

Heart rate (beats/min)

69 6 14

73 6 15

Conduit stenosis > mild

13 (76%)

36 (84%)

Conduit regurgitation > mild

6 (35%)

17 (39%)

Previous RVOT patch

3 (18%)

9 (21%)

Tricuspid valve annuloplasty

1 (6%)

5 (12%)

3DKBR, Three-dimensional knowledge-based reconstruction; BSA, body surface area; RV, right ventricular; RVOT, right ventricular outflow tract; TA, truncus arteriosus; TOF, tetralogy of fallot; TTE3DKBR, three-dimensional knowledge-based reconstruction derived from two-dimensional transthoracic echocardiography; VMS, ventripoint medical systems. Data are expressed as mean 6 SD or as number (percentage).

standard deviation of the difference of paired samples divided by the average of the paired samples. A P value < .05 has been considered statistically significant. Statistical analysis was performed using SPSS version 21.0 for Windows (SPSS, Chicago, IL).

RESULTS A total of 37 patients were approached, and 17 were enrolled for the TTE-3DKBR and CMR comparison (Table 2). Eight patients were excluded due to CMR contraindications, eight patients had

behavioral issues or claustrophobia and were/would be unable to tolerate CMR, and four patients did not consent to the study. The CMR RV EDV and ESV were 114 6 32 and 76 6 33 mL/ m2, respectively. TTE-3DKBR volumes and EFs correlated well with CMR values: for EDV, R = 0.77; for ESV, R = 0.93; and for EF, R = 0.75 (Figure 3). On Bland-Altman analyses, CMR EDV volumes were slightly larger than those obtained by TTE3DKBR (DEDV CMR-TTE, 2.5 6 19 mL; DESV CMR-TTE, 0.6 6 10 mL), whereas EF tended to be slightly lower by CMR (DEF CMR-TTE, 2 6 8%) (Figure 3). Inter- and intraobserver analyses revealed relatively close agreement for volumes, with slightly larger variability for EF. For interobserver variability, intraclass correlation coefficients were 0.91 for EDV, 0.83 for ESV, and 0.80 for EF, and coefficients of variation were as follows: EDV, 8.8 6 6.4%; ESV, 10.5 6 8.3%; and EF, 16.2 6 12.7%. For intraobserver analyses, intraclass correlation coefficients was 0.93 for EDV, 0.87 for ESV, and 0.80 for EF, and coefficients of variation were as follows: EDV, 7.4 6 4.3%; ESV, 9.2 6 7.4%; and EF, 12.3 6 9.1%. The RV shape assessment was performed with the CMR studies of 43 patients not included in the TTE-3DKBR comparison studies (Table 2). The CMR-determined RV EDV, ESV, and EF were 212 6 75 mL, 147 6 73 mL, and 33 6 10%, respectively. A large variation in RV shape was noted among this RV-PA conduit group. The three conduit subgroups could not be reliably discerned qualitatively looking at the 3D shapes. While all right RVs were dilated, a specific region of dilation could not be identified, with the exception of the apex. Specifically, the free wall, inferior, superior, and septal regions did not consistently show a shape pattern. TA hearts tended to have a smaller basal bulge, but it was not a reliable distinction, as we also found pulmonary atresia with VSD and TOF hearts with less pronounced basal bulge. Inflow and outflow annuli were in various orientations, and the conus region was not always dilated. Figure 4 illustrates the RV shape variability in this RV-PA conduit group. Quantitative assessment also demonstrated RV shape diversity, as several catalog hearts were needed to closely approximate any given test shape, as shown in Table 3. These hearts were not similar, and all contributed a small

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Figure 3 Correlations (top row) represented by regression analysis and intertechnique agreement (bottom row) represented by Bland-Altman plots between TTE-3DKBR and CMR measurements for RV EDV (A, B), ESV (C, D), and EF (E, F). CMR, Cardiac magnetic resonance; EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; RV, right ventricular; TTE-3DKBR, threedimensional knowledge-based reconstruction derived from two-dimensional transthoracic echocardiography.

percentage to the final reconstruction. Moreover, for any given diagnosis, the reconstruction used hearts with from all three diagnostic groups, indicating that there was minimal similarity within diagnostic groups. Eight hearts had a maximum surface gap > 1 cm (TOF, n = 4; pulmonary atresia with VSD, n = 2; TA, n = 2). Overall, the maximum surface gap was 8 6 2 mm (TOF, 8.4 6 3.2 mm; pulmonary atresia with VSD, 7.7 6 2.1 mm; TA, 8.0 6 2.5 mm; P = .72). The number of hearts used in the reconstruction was 7.1 6 2.1 (range, 4–12). The number of hearts used in the reconstruction was similar regardless of the underlying diagnosis (TOF, 7.3 6 2.0; pulmonary atresia with VSD, 7.1 6 2.3; TA, 7.1 6 1.8; P = .97). The number of hearts used in reconstructions that yielded a maximum surface gap $ 1 cm was significantly less than in those with a gap < 1 cm (5.5 6 2.2 vs 7.5 6 1.9, P = .01). This suggests that these eight hearts were particularly unique, such that few catalog hearts were similar in shape and hence able to be used in the reconstruction. The conduit details of a randomly selected subset of 20 of the 43 patients who underwent RV shape assessment are shown in Table 4. All three groups were similar with respect to the number of conduit revisions, type of conduit implanted, and history of a ventriculotomy. Three or more conduit revisions were performed in six of 15 patients with TOF (40%), seven of 19 with pulmonary atresia with VSD (37%), and five of nine with TA (55%). No qualitative or quantitative relationship between number of conduit revisions and RV shape was found. The choice of conduit was similar across diagnostic groups, with approximately half being homografts, and almost all patients had a ventriculotomy. The conduit location for patients with TOF and those with pulmonary atresia with VSD was mostly in the RVOT at the level of the infundibulum. In patients with TA, it was in the region of the RVOT but noted to be located slightly more anterior. There was no additional variation in conduit location noted between patients. Exact details about conduit location/angle, and so on, were generally not available from the intraoperative notes.

DISCUSSION This is an important study to validate the use of TTE-3DKBR and to perform 3D shape analysis of the RV in patients with a RV-PA conduit. We found the assessment of RV volumes and function using TTE3DKBR to be feasible, accurate, and in good agreement with CMR. In a larger group of patients, we also demonstrated the unique and diverse nature of RV shapes that occur in the adult CHD population with previous conduit surgery. The use of TTE-3DKBR for RV volume and function assessment has been validated in TOF, transposition of the great arteries, and pulmonary arterial hypertension.6,11-15 The absence of a true RVOT with lack of movement or change in shape from diastole to systole separates the RV-PA conduit shapes from other diagnoses. Moreover, the underlying heterogeneity in the diagnoses of patients with RV-PA conduit appears to result in significant variations in shape patterns so that each RV is different from its counterparts. As a result, these studies can be the most difficult to reconstruct, often requiring placement of more points for VMS mapping for accurate reconstruction of RV shape compared with other catalog groups. Despite this, there was good correlation and agreement between the TTE-3DKBR and CMR seen in this study. We did not screen the patients for image quality, so that a ‘‘real-life’’ scenario would likely lead to better agreement between the two modalities. The use of TTE3DKBR in the regular assessment of RV volumes and function over time may provide a reasonable adjunct to intermittent imaging with CMR and prove to be particularly helpful in cases when CMR is contraindicated or not tolerated. Although 3D TTE is becoming an accurate and reproducible tool to quantify RV volumes and function, it can prove to be difficult in a population with complex RV geometry. Limitations include the inability to capture the entire enlarged RV within the 3D imaging sector and the compounding detrimental effects of suboptimal image quality. TTE-3DKBR offers the opportunity to image the RV using different 2D imaging planes so that the RV is visualized in its entirety.

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Figure 4 Three-dimensional knowledge-based reconstructions of the RV illustrating diversity in shapes across and within diagnostic groups: (A) TA, (B) TOF, and (C) pulmonary atresia with VSD.

We used the piecewise smooth subdivision surface reconstruction method to examine the RV from complete surface reconstructions in a large complex CHD group. This method has been validated for accuracy in representing the 3D RV shape.16,17 We demonstrated that the RV can assume an unpredictable shape both within and across diagnostic groups. Conduit type, size, and number of revisions were similar across diagnostic groups, and no relationship with RV shape was discernable. Conduit implant location was similar, and a ventriculotomy had been performed in almost all patients, so that these conduit factors also do not explain variations in RV shape. We believe that there is likely a complex interplay between multiple factors, with varying effects on RV shape in different patients that are difficult to account for in a simple way. These factors likely include the underlying congenital lesion, associated often multiple other cardiac lesions, repeat and prolonged exposure to cardiopulmonary bypass. RV exposure to prolonged excess loading and then unloading conditions inherent to chronic conduit dysfunction and subsequent revision likely affect RV parameters to a greater extent than the presence and location of the conduit alone. Over the past decade, there has been an increasing interest and awareness of RV complexity, mostly focusing on the normal ventricle. Most recently, Saremi et al.18 highlighted RVOT complexity in normal and pathologic groups. Several studies have also shown differences in the response to an increase in afterload on the inflow and outflow regions.19,20 Animal studies have provided observational data

on regional responses to increasing RV afterload,20 where an increase in end-diastolic fiber length, but no change in systolic shortening, was seen in the RV inlet portion following an acute increase in afterload. In contrast, decreased systolic shortening of the outflow tract region was seen. We could not find any RV shape characteristics unique to a given diagnosis or the presence of a conduit. A larger basal bulge was more commonly seen in patients with pulmonary atresia with VSD and those with TOF compared with TA, however this was not a reliable distinguishing factor. It has been suggested that predominance of the basal bulge in the TOF population may be related to loss of tethering from the medial papillary muscle, which is usually absent in this group. A basal bulge may also occur as a result of the lower pressure of the adjacent right atrium, whereas the remaining RV base is constrained by the crista supraventricularis and overlying aorta, which would not be the case in TA. This basal bulge has been previously described in TOF with volume overload and primary pulmonary hypertension with tricuspid regurgitation.21 Enlargement of the RV free wall and apical broadening commonly occur so that the RV assumes a less crescentic and a more squarelike shape. Loss of the acute angle seen at the RV apex has been described in both conditions of RV dilatation secondary to pressure or volume overload with systolic dysfunction.22 Across underlying diagnoses, in addition to the variation in outflow tract orientation, the inflow annulus also showed variation in location. Variation in the outflow tract orientation may be

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Table 3 Quantitative assessment of RV shape diversity in patients with CHD with RV-PA conduit* Reconstruction composition for each test shape*

Maximal surface gap (mm)

TOF1

PA1 21%, TOF2 21%, PA18 19%, TA5 12%, TOF14 9%, PA9 10%, TA2 8%

6

1.9

TOF2

TOF15 20%, TA9 19%, PA19 16%, TA8 12%, TOF14 11%, PA18 8%, PA1 7%, TOF5 4%, TA6 3%

11.8

0.7

TOF3

TOF4 35%, TOF5 29%, PA15 19%, PA4 17%

TOF4

TOF9 48%, TOF7 21%, TA3 12%, TOF10 10%, TOF3 9%

TOF5

Test shape

FullFit volume difference (%)

TOF

7.8

8.6

12.8

33.2

TOF3 27%, TOF2 21%, PA12 13%, PA13 11%, TA8 10%, TOF15 10%, TOF6 9%

8.9

2.8

TOF6

TOF1 24%, TOF9 19%, TOF3 15%, TOF12 13%, PA15 9%, TOF4 7%, TOF3 6%, TOF8 3%, PA13 3%, PA7 1%

7.5

5.4

TOF7

TOF1 24%, TOF13 23%, TOF4 16%, PA13 14%, PA1 10%, TOF14 7%, TOF10 6%

8.7

6.6

TOF8

PA14 43%, PA12 23%, PA15 10%, TA6 8%, TOF15 7%, TA6 6%, PA11 3%

2.7

0.1

TOF9

TA7 37%, PA4 27%, TOF10 9%, TOF3 8%, PA13 6%, TOF6 3%, TOF12 3%, TOF7 4%, TOF4 3%

6.2

0.1

TOF10

PA7 24%, TOF4 15%, PA3 15%, PA17 14%, PA13 13%, TOF13 6%, PA11 4%, PA4 3%, TOF7 3%, TA1 3%

8.4

10.8

TOF11

TA1 39%, PA13 25%, TA8 13%, PA3 10%, TOF15 4%, PA1 4%, PA11 3%, PA3 1%, TOF13 1%

4.5

1.8

TOF12

PA5 37%, PA17 35%, TOF5 26%, PA6 2%

14.8

9.4

TOF13

TOF7 40%, TOF10 11%, TOF5 11%, TOF14 10%, PA11 10%, PA12 7%, PA3 5%, TA6 4%, PA13 2%

6.9

5.5

TOF14

TOF8 36%, TOF4 28%, TA6 17%, TOF10 10%, TOF3 9%

11.2

26.3

TOF15

PA12 39%, PA3 26%, PA5 11%, TOF6 8%, TA6 8%, TA8 7%, PA13 1%

7.9

9.3 1.9

Pulmonary atresia with VSD PA1

PA18 62%, TA8 16%, TOF14 11%, TA6 8%, PA19 3%

7.9

PA2

PA18 32%, TOF14 25%, PA19 21%, TOF12 12%, TA8 10%

6.8

0.9

PA3

TOF11 37%, TOF7 19%, PA13 19%, TOF3 15%, PA19 6%, PA5 2%

7.6

7.5

PA4

TOF8 31%, PA8 17%, TA9 15%, TOF9 15%, TA3 10%, TOF12 5%, PA17 4%, TOF13 3%

9.1

12.1

PA5

PA1 34%, TOF9 28%, TOF7 17%, TOF9 11%, PA1 8%, TOF3 4%

7.9

4.1

PA6

TA5 18%, PA13 18%, PA8 16%, PA19 15%, TOF12 11%, TOF14 8%, PA16 8%, TOF15 3%, TOF3 3%

8.9

2.9

PA7

TOF7 21%, TOF13 16%, TOF6 14%, PA17 12%, TOF3 8%, TOF4 7%, TA3 6%, PA5 5%, TA6 4%, PA4 4%, TOF9 3%

5.3

4.3

PA8

PA17 19%, PA6 18%, PA19 15%, PA4 15%, TA7 12%, PA18 10%, TOF8 4%, TA3 4%, PA9 3%

6.4

4.8

PA9

PA18 23%, PA12 20%, TOF2 17%, TA3 11%, TOF3 11%, TA6 6%, TOF8 6%, TA5 4%, PA18 2%

8.8

5.5

PA10

PA19 27%, PA5 20%, TOF15 14%, TOF3 11%, TA6 6%, PA9 5%, TA5 5%, PA14 4%, PA12 3%, PA1 2%, PA2 2%, TA5 1%

4.2

2.2

PA11

TOF15 53%, PA4 22%, PA8 16%, PA17 9%

12.9

12.4

PA12

TOF14 32%, TOF8 27%, PA1 16%, PA10 10%, TOF4 8%, TA4 7%

7.7

7

PA13

TOF7 29%, PA3 27%, TOF5 16%, PA16 14%, PA6 10%, TA1 4%

7.4

2.2

PA14

TOF8 54%, TOF13 15%, PA17 9%, TOF5 5%, TA8 5%, PA11 5%, TOF11 4%, TOF7 3%

4.4

2.8

PA15

PA19 43%, TOF3 15%, PA18 13%, PA8 12%, TA6 10%, PA14 7%

7

7.8

PA16

TOF15 28%, TOF7 13%, TOF9 12%, TOF5 10%, PA6 7%, PA13 7%, PA17 6%, PA19 6%, TA7 6%, TA1 5%

7.7

0.7

PA17

PA8 30%, TOF12 21%, PA13 20%, TOF10 15%, PA11 9%, TOF3 5%

6.7

9.5

PA18

PA16 30%, TOF6 28%, PA9 21%, TOF11 11%, TA4 10%

7.3

0.9 (Continued )

530 Wheeler et al

Journal of the American Society of Echocardiography May 2015

Table 3 (Continued ) Test shape

PA19

Reconstruction composition for each test shape*

TOF8 48%, PA1 28%, PA6 15%, TOF3 9%

Maximal surface gap (mm)

FullFit volume difference (%)

11.8

14.6 3

TA TA1

PA6 21%, PA16 18%, TOF11 18%, TA4 13%, TA5 13%, PA3 8%, TOF7 5%, PA12 4%

7.4

TA2

TOF5 32%, PA14 25%, TOF13 20%, TA7 13%, PA12 5%, PA16 5%

5.8

8

TA3

PA14 39%, PA5 22%, TOF4 20%, PA9 14%, TA4 5%

6.1

2.4

TA4

PA18 37%, PA16 16%, TOF11 11%, TA4 10%, TA8 9%, PA2 6%, PA12 5%, PA13 3%, TOF2 2%

8.5

13.3

TA5

TA7 33%, PA11 28%, TA6 14%,TOF15 8%,TA4 8%,PA9 5%,PA1 3%

TA6

TOF8 42%, PA1 28%, PA12 16%, TOF15 14%

TA7

6.1

4.6

11.6

22.7

TA5 42%, TA8 23%, PA14 10%, TA9 9%, PA16 5%, PA1 4%, TA6 4%, TA3 3%

6.3

6.3

TA8

PA1 31%, TA7 20%, TOF11 18%, PA14 13%, PA18 7%, TOF10 6%, TOF14 3%, PA9 2%

7.9

4.8

TA9

PA16 30%, TOF2 26%, TOF3 11%, TA8 10%, TOF5 8%, TOF12 6%, TOF15 5%, PA17 2%, TOF2 2%

12.6

14.7

CHD, Congenital heart disease; PA, pulmonary artery; RV-PA, right ventricular to pulmonary artery; TA, truncus arteriosus; TOF, tetralogy of fallot; VSD, ventricular septal defect. *Catalog hearts that contributed to the final reconstruction of the ‘‘test’’ shape and percentage contribution of each.

expected given the variability of where conduits are placed at the time of surgery. We used a novel method of comparing RV shapes in this important population, and our results draw specific attention to the fact that the RV both within and outside of diagnostic groups should not be treated equally. This is in direct contrast to the TOF (without conduit) population, where the RV assumes a predictable ‘‘TOF’’ shape, and all RVs can be and are treated as equal. These pronounced alterations in RV shape would make any 2D imaging assessment inaccurate and misleading, although this remains the standard of care.17 The RV in this complex conduit population goes largely ignored in research studies, although it comprises a not insignificant proportion of the patients seen at an adult CHD clinic. Our results would be the first to objectively show the marked differences in RV shape and that a standard approach is likely not ideal. Yet these patients continue to be treated very equally with respect to follow-up, assessment, and interventions. This population is continuing to grow and requires repeat conduit interventions, yet our understanding of the RV in these patients remains limited. We believe that this is an important step to improving our understanding of the RV in this population and provides a springboard for future work. To date, data addressing patterns of RV remodeling and evidence to recommend the optimal timing for intervention in the setting of conduit dysfunction have been lacking. The American College of Cardiology and American Heart Association 2008 guidelines for the management of adults with CHD and the European Society of Cardiology 2010 guidelines for the management of grown-up CHD lack specifics for timing of reintervention on the basis of RV parameters in this population due to the lack of data to inform clinical decision making.23,24 Our findings of significant RV remodeling heterogeneity should set into motion future work focused on serial observations to define whether there is a temporal progression in RV remodeling in patients with RV-PA conduit. Indices of RV shape would need to be identified and the prognostic role of these in predicting impact on

overall RV function, clinical heart failure and/or arrhythmias, patient symptoms, and prognosis evaluated. This would help define the optimal timing of intervention for conduit dysfunction with well-defined lesion-specific RV cutoffs forming part of the algorithm. Also, the RV shape may have a prognostic impact on how the RV responds to conduit revision. Study Limitations This was a small single-center study, however, we felt the sample size to be reasonable given the complex nature of the population. TTE-3DKBR has its limitations, including (1) requirement for specialized equipment and training, making this technology impractical in smaller echocardiography laboratories; (2) patient cooperation with breath holding is crucial to image acquisition; (3) steady heart rate required, so any arrhythmias preclude good image acquisition; (4) in practice, more than nine minimum points are required to generate an RV model with good adherence to endocardial borders; and (5) TTE-3DKBR is more labor intensive than standard 2D or 3D TTE.

CONCLUSIONS This study to demonstrates that TTE-3DKBR is an alternative technology that can be used to assess the RV in patients with very complex CHD with RV-PA conduit. We also used a novel method of comparing RV shapes in this important population, and our results draw specific attention to the fact that the RV both within and outside of diagnostic groups have very different unpredictable shapes and should not be treated equally. This further underscores the great limits to traditional approaches such as 2D echocardiography to RV assessment, especially in this population. Our findings should set into motion future work focused on indices of RV shape and their impact

Wheeler et al 531

Journal of the American Society of Echocardiography Volume 28 Number 5

Table 4 Conduit details by diagnostic group Conduit type

Conduit size (mm)

No. of conduits

RV

TOF Pulmonary homograft

28

3

Yes

Hancock Dacron porcine valved

27

3

Yes

Hancock Dacron porcine valved

30

2

Yes

Pulmonary homograft

23

2

Yes

Pulmonary homograft

26

4

Yes

Hancock Dacron porcine valved

27

2

Yes Yes

Pulmonary homograft

27

2

Carpentier-Edwards valved

27

2

No

Pulmonary homograft

28

3

Yes

Pulmonary homograft

23

3

Yes

Contegra

22

2

Yes

Hancock Dacron porcine valved

27

2

Yes

Pulmonary homograft

27

3

Yes

Aortic homograft

18

1

Yes

Pulmonary homograft

27

3

Yes

Pulmonary homograft

23

2

Yes

Carpentier-Edwards valved

25

2

Yes

Pulmonary homograft

26

3

Yes

Pulmonary homograft

27

4

Yes

Aortic homograft

23

3

Yes

Pulmonary atresia with VSD

TA

RV, Right ventricular; TA, truncus arteriosus; TOF, tetralogy of fallot.

on overall RV function and clinical outcomes, hence defining the optimal timing of conduit revision, which at the current time is very unclear.

ACKNOWLEDGMENTS The authors would like to acknowledge and thank Mehmooda Lakhani and Lynn Jones for their assistance with this study, specifically with image acquisition.

6.

7.

8.

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