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Right Ventricular Function in Fetal Hypoplastic Left Heart Syndrome
Right Ventricular Function in Fetal Hypoplastic Left Heart Syndrome Paul A. Brooks, MBBS, Nee S. Khoo, MBChB, Andrew S. Mackie, MD, SM, and Lisa K. Hornberger, MD, Edmonton, Alberta, Canada
Background: The systemic right ventricle in palliated hypoplastic left heart syndrome (HLHS) has relatively reduced longitudinal compared with circumferential deformation, a pattern of contraction more akin to the normal left ventricle, which presumably improves right ventricular (RV) pumping efficiency. The aim of this study was to test the hypothesis that these changes in the RV contraction pattern in infants with HLHS are present prenatally. Methods: Echocardiograms from 48 fetuses with HLHS were retrospectively compared with those from appropriately grown RV and left ventricular controls. Ventricular function was assessed using Velocity Vector Imaging velocity, tissue deformation, two-dimensional echocardiography, and Doppler flow parameters. Results: Fetuses with HLHS demonstrated reduced peak global RV longitudinal velocity (P < .01), strain (P < .001), and displacement (P < .05), while radial displacement was increased (P < .001) compared with the normal fetal right ventricle. Mean RV diameter was increased in HLHS (P < .001), but length was unchanged. The ratio of longitudinal to circumferential deformation was reduced in HLHS compared with the normal right ventricle (P < .001) and equivalent to the normal left ventricle. Tricuspid inflow peak A-wave velocity (P < .01), A-wave duration, A-wave inflow fraction, RV Tei index (P < .05 for all), and inferior vena cava A-wave reversal (P < .0001) were increased in HLHS. Conclusions: The fetal right ventricle in HLHS becomes more spherical because of increased RV diameter. It has relatively reduced longitudinal compared with circumferential deformation and an increased reliance on atrial contraction for ventricular filling. These findings are similar to postnatal changes observed in the systemic right ventricle in palliated congenital heart disease, suggesting that ventricular remodeling is initiated in fetal life. (J Am Soc Echocardiogr 2012;25:1068-74.) Keywords: Fetal development, Fetal echocardiography, Hypoplastic left heart syndrome, Myocardial contraction, Speckle tracking
The systemic right ventricle in long-term palliated congenital heart disease has relatively reduced longitudinal compared with circumferential contraction velocities and deformation.1 This change results in a pattern of contraction more similar to the normal left ventricle than right ventricle, with presumed improved ventricular efficiency. A recent study showed that similar changes also occur in the systemic right ventricle in infants with hypoplastic left heart syndrome (HLHS).2 In these infants, a more left ventricular (LV)–like pattern of contraction From the Fetal and Neonatal Cardiology Program, Division of Cardiology, Departments of Pediatrics (P.A.B., N.S.K., A.S.M., L.K.H.) and Obstetrics and Gynecology (L.K.H.), Women and Children’s Health Research and Mazankowski Alberta Heart Institutes, University of Alberta, Edmonton, Alberta, Canada. Dr Paul Brooks was supported by the RACP Foundation Eric Burnard Fellowship and Robert and Elizabeth Albert Study Grant. Reprint requests: Lisa K. Hornberger, MD, Fetal and Neonatal Cardiology Program, Pediatric Cardiology, Stollery Children’s Hospital, WCMC 4C2, 8440 112th Street, Edmonton, AB T6G 2B7, Canada (E-mail: lisa.hornberger@ albertahealthservices.ca). 0894-7317/$36.00 Copyright 2012 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2012.06.005
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was associated with improved mechanical synchrony, reduced right ventricular (RV) dilation, and hypertrophy. Although it has been assumed that this adaptation is a consequence of long-term exposure to both systemic pressure and increased volume load, differences in both RV morphology and function in HLHS are evident soon after birth.3,4 It remains unknown whether these changes begin antenatally. Fetal ventricular function can be evaluated noninvasively using twodimensional echocardiography, Doppler flow patterns, and more recently myocardial velocities and deformation. Two-dimensional speckle-tracking and feature-tracking techniques, such as Velocity Vector Imaging (VVI; Siemens Medical Solutions, Malvern, PA), have been used to assess normal fetal ventricular function,5-10 fetuses with twin-twin transfusion syndrome,11 and small groups with congenital heart disease.9,10 The advantages of these techniques for the assessment of fetal ventricular function are their angle independence and applicability to two-dimensional images, allowing retrospective review of relatively rare lesions in archived data. In this investigation, we compared systolic, diastolic, and global function using VVI and pulsed Doppler indices between fetuses with HLHS and healthy controls. We hypothesized that changes in the contraction pattern of the future systemic right ventricle in HLHS will be present during fetal life.
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METHODS
at end-diastole were measured from the same two-dimensional Digital Imaging and Communications in Medicine loops used for the VVI analysis (Figure 1). Sphericity index was calculated by dividing end-diastolic diameter by length (sphericity index = end-diastolic diameter/end-diastolic length). Ventricular fractional area change was calculated by the VVI software algorithm from the maximal and minimal areas enclosed by the manual endocardial border traces and expressed as a percentage. A single operator (P.A.B.) performed all Doppler measurements and calculations. Heart rate was calculated from Doppler flow assessment of atrioventricular valve inflow. Inferior vena cava (IVC), ductus venosus, umbilical artery, and venous Doppler flow patterns were also assessed in all fetuses. The percentage reversal of IVC Doppler flow during atrial systole was calculated by measuring the forward and backward velocity-time integrals (VTIs) (IVC Doppler A-wave VTI 100/IVC Doppler forward-flow VTI). The ratio between ductus venosus peak systolic (S-wave) velocity and minimum flow velocity during atrial contraction (A wave) was calculated (ductus venosus S-wave velocity/ductus venosus A-wave velocity), because there were no fetuses with A-wave reversal in the ductus venosus. The umbilical arterial pulsatility index was calculated using the formula ([peak systolic velocity end-diastolic velocity]/mean velocity).12 Doppler tricuspid valve inflow and pulmonary valve ejection were assessed for the HLHS and RV control fetuses. Ejection and inflow times were corrected for cardiac cycle duration. Ratios of systolic to diastolic duration for the right ventricle in both HLHS and control fetuses were calculated (systolic/diastolic duration ratio = [cardiac cycle duration tricuspid inflow duration]/tricuspid inflow duration). RV filling was assessed by the measurement of peak E-wave and A-wave inflow velocities and A-wave duration, and the E/A ratio was calculated. A-wave inflow fraction (A-wave inflow fraction = tricuspid inflow A-wave VTI/tricuspid inflow total VTI) was calculated, as was the RV Tei or myocardial performance index using standard technique.13 All Doppler measures were averaged over three cardiac cycles. Statistical analyses were performed using Prism version 5.3 (GraphPad Software, Inc., La Jolla, CA). Data are reported as mean 6 SD. Individual comparisons of both the general Doppler parameters and the RV Doppler measurements for the HLHS and normal control fetuses were performed using unpaired t tests. Comparisons among all three ventricles studied (the HLHS right ventricle, the normal control right ventricle, and the normal control left ventricle) were performed using one-way analysis of variance with Dunnett’s multiple comparison testing for post hoc comparisons of the HLHS right ventricle versus the normal right and left ventricles. Comparisons between HLHS and normal control right ventricles with advancing gestation were performed using analysis of covariance. Intraobserver (P.A.B.) and interobserver (N.S.K.) variability were assessed for RV VVI velocity, displacement, and strain. The absolute difference between reviewers divided by the mean of the measures was calculated in a randomly selected group of 10 fetuses with HLHS. The systematic bias of repeated measures was also calculated using Bland-Altman analysis.
Abbreviations
HLHS = Hypoplastic left heart syndrome
All pregnancies with fetal diagnoses of HLHS encountered in the Fetal and Neonatal Cardiology IVC = Inferior vena cava Program at the University of LV = Left ventricular Alberta between March 2006 and March 2011 were identified RV = Right ventricular through a review of our pediatric VTI = Velocity-time integral and fetal echocardiography database. Fetuses were excluded if VVI = Velocity Vector Imaging they had HLHS variants associated with discordant or double-outlet ventriculoarterial connections, a common atrioventricular valve, or ventricular septal defects. Suitable four-chamber images for analysis were identified in 48 of 49 eligible fetuses with HLHS. For those with more than one fetal echocardiogram, a single study (the earliest study with suitable four-chamber images) was analyzed. Forty-eight appropriately grown singleton controls without structural or functional heart disease from normal pregnancies were also identified for RV and LV assessments. The study was approved by the Health Research Ethics Board at the University of Alberta. Fetal echocardiograms were performed using Phillips iE33 (Philips Medical Systems, Bothell, WA), GE Voluson E8 (GE Medical Systems, Milwaukee, WI), or Siemens Acuson S2000 (Siemens Medical Solutions) cardiac ultrasound platforms. The Digital Imaging and Communications in Medicine images from the selected fetal echocardiograms were imported into Syngo US Workplace version 3.5 (Siemens Medical Solutions) for offline analysis. The VVI analysis frame rate of archived Digital Imaging and Communications in Medicine data was 30 frames/sec. A single operator (P.A.B.) used VVI version 2.0 software to assess global systolic longitudinal velocity, displacement, and strain, as well as global radial displacement for the right ventricle in HLHS and both the right and left ventricles in normal control fetuses. The peak of the mean modal velocities calculated by the software was measured. The onset of each cardiac cycle was determined using anatomic M-mode assessment of the earliest inward motion of the ventricular free wall. The ventricular endocardial border was traced from the lateral atrioventricular valve annulus to the apex and back to the septal atrioventricular valve annulus for each of the ventricles examined. Manual adjustments were made as required to ensure that all segments appropriately tracked myocardial motion after processing by the software algorithm. Because this was a retrospective study, specific images to allow direct measurement of circumferential deformation were not available. However, a surrogate for circumferential deformation was calculated by indexing the peak global radial displacement to end-diastolic diameter (global radial shortening index = [global peak radial displacement/end-diastolic diameter]; Figure 1). This index represents the fractional change in diameter during systolic contraction which is proportional to circumferential deformation through the relationship diameter = circumference/p. It was given a negative value to represent muscle shortening, as is the convention for both longitudinal and circumferential deformation. The global radial shortening index was then used in the calculation of a ratio of longitudinal to circumferential deformation (deformation ratio = peak global longitudinal strain/global radial shortening index). Ventricular length (plane of atrioventricular valve annulus to ventricular apex) and diameter (perpendicular to the midpoint of length)
RESULTS The 96 fetal echocardiograms reviewed (48 cases, 48 controls) were performed between 19 and 39 weeks of gestation. There was no difference in gestational age between the fetuses with HLHS and
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Figure 1 (A) Example Velocity Vector Imaging still frame from a fetus at 27-week gestation with HLHS showing velocity vectors (yellow arrows indicating relative velocity and direction of myocardial motion) during diastole. (B) Diagram illustrating end-diastolic diameter (EDD) measurement perpendicular to the midpoint of length used in calculating radial shortening index. LV, Left ventricle; RV, right ventricle.
controls at the time of fetal echocardiography (27.9 6 6.2 vs 28.1 6 6.4 weeks, respectively, P = .90). Of the HLHS fetuses, 35 had aortic and mitral atresia, eight had aortic atresia with mitral stenosis, and five had both aortic and mitral stenosis with forward flow through the hypoplastic left ventricle. One pregnancy ended in spontaneous intrauterine fetal demise, and there were 12 elective terminations. Two neonates died, one with an intact atrial septum who was managed with comfort care and another after an intracerebral hemorrhage while awaiting transplantation after bilateral branch pulmonary artery bands and a stent in the ductus arteriosus. Thirty-three neonates went on to the first stage of surgical palliation with the Norwood procedure. RV Contraction Patterns and Morphology in Fetal HLHS Compared with the Normal Right Ventricle Fetuses with HLHS had reduced peak global RV longitudinal velocity, displacement, and strain compared with the normal right ventricle, while peak global radial displacement was increased (Table 1). The global radial shortening index was no different when comparing right ventricles between fetuses with HLHS and normal controls, but the ratio of longitudinal to circumferential deformation was reduced for the right ventricle in HLHS compared with the normal fetal right ventricle as a consequence of reduced longitudinal strain. RV end-diastolic diameter was increased in fetuses with HLHS compared with the right ventricles of controls, while RV length was unchanged (Table 2). The sphericity index was therefore increased in fetuses with HLHS compared with the normal right ventricle. Fetuses with HLHS and normal controls showed no difference in RV fractional area change. Linear regressions over gestation showed that RV peak global longitudinal velocity, radial displacement, and end-diastolic diameter in fetuses with HLHS significantly differed from normal fetuses (comparisons by analysis of covariance; Figure 2). RV Contraction Patterns and Morphology in Fetal HLHS Compared with the Normal Left Ventricle When comparing the right ventricles in fetuses with HLHS to the normal fetal left ventricle, peak global longitudinal velocity and
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displacement were no different, while strain was reduced in fetuses with HLHS (Table 1). Peak global radial displacement also showed no difference between the right ventricle in HLHS and the normal fetal left ventricle. The global radial shortening index was lower in the right ventricles of fetuses with HLHS compared with the normal left ventricle, which produced comparable ratios of longitudinal to circumferential deformation for the right ventricles in HLHS and the normal fetal left ventricle. RV end-diastolic diameter was increased in fetuses with HLHS compared with the normal left ventricle, while there was no difference in ventricular length (Table 2). The sphericity index was therefore greater for the right ventricle in fetuses with HLHS compared with the normal left ventricle (Figure 3). There was no difference in fractional area change. Heart Rate and Doppler Indices of Function and Loading Fetuses with HLHS had a slightly lower mean heart rate than controls (Table 3). There was an increase in the percentage reversal in IVC flow during atrial contraction in fetuses with HLHS in comparison with normal controls, but the ductus venosus showed only a trend toward deeper A-wave reversal, and umbilical venous Doppler flow revealed no evidence of venous pulsations in fetuses with HLHS. There was also a trend toward increased umbilical artery pulsatility index in fetuses with HLHS compared with normal controls. When comparing RV Doppler parameters (Table 4), tricuspid valve inflow revealed no difference in the peak E-wave velocity or the E/A ratio, but peak A-wave velocity was increased in the fetuses with HLHS. A-wave duration and A-wave inflow fraction were also increased. There was no difference in the ratio of systolic to diastolic duration of tricuspid valve inflow, but there was a reduction in normalized RV ejection time in the HLHS right ventricle compared with the normal fetal right ventricle. Fetuses with HLHS had increased isovolumic times and RV Tei indices compared with controls. Intraobserver and Interobserver Variability The respective intraobserver and interobserver variability values for peak global systolic VVI parameters were 0.18 and 0.14 for longitudinal velocity, 0.16 and 0.19 for longitudinal displacement, 0.16 and 0.14 for longitudinal strain, and 0.18 and 0.12 for radial displacement. Bias and confidence intervals are presented in Table 5.
DISCUSSION This study demonstrates that the fetal right ventricle in HLHS became more spherical with reduced ratio of longitudinal to circumferential deformation. Fetuses with HLHS also had Doppler changes that suggest a greater reliance on atrial contraction for RV filling and altered diastolic properties. These findings suggest that the changes in RV morphology, contraction, and filling pattern in infants with HLHS2 appear to begin during fetal life. Ventricular Contraction Patterns in the Systemic Right Ventricle The adult systemic right ventricle in transposition of the great arteries after palliative atrial redirection surgery (a Senning operation) demonstrates relatively reduced longitudinal compared with circumferential velocities and deformation, a pattern of contraction more akin to the normal left ventricle than right ventricle.1 Reduced RV longitudinal
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Table 1 Myocardial velocities and deformation Parameter
Peak global systolic Longitudinal velocity (cm/sec) Longitudinal displacement (cm) Longitudinal strain (%) Radial displacement (cm) Global radial shortening index Deformation ratio
HLHS right ventricle
1.03 6 0.42 1.33 6 0.59 14.8 6 4.0 0.82 6 0.29 0.067 6 0.027 259 6 124
Normal right ventricle
1.39 6 0.53† 1.70 6 0.61* 17.9 6 3.1‡ 0.52 6 0.19‡ 0.057 6 0.026 359 6 170‡
Normal left ventricle
P value by analysis of variance
1.18 6 0.69 1.36 6 0.79 16.7 6 3.2* 0.72 6 0.26 0.087 6 0.026‡ 211 6 85
<.01 <.05 <.0001 <.0001 <.0001 <.0001
Data are expressed as mean 6 SD. *P < .05. † P < .01. ‡ P < .001 versus HLHS right ventricle (Dunnett’s multiple comparisons).
Table 2 Two-dimensional measurements Parameter
HLHS right ventricle
Normal right ventricle
Normal left ventricle
P value by analysis of variance
Ventricular end-diastolic diameter (mm) Ventricular end-diastolic length (mm) Sphericity index Ventricular fractional area change (%)
13.7 6 5.9 18.9 6 5.4 0.72 6 0.20 40.8 6 8.3
9.9 6 3.5* 19.4 6 5.3 0.51 6 0.09* 39.7 6 8.5
8.5 6 3.0* 19.6 6 5.2 0.43 6 0.08* 43.7 6 6.8
<.0001 .79 <.0001 <.05
Data are expressed as mean 6 SD. *P < .001 versus HLHS right ventricle (Dunnett’s multiple comparisons).
deformation in HLHS has recently been demonstrated before and after Norwood palliation by several groups.2,4 In a longitudinal study, Khoo et al.2 demonstrated that these RV functional changes occur progressively in infants with HLHS and are associated with improved mechanical synchrony and smaller RVend-diastolic volume and mass. Until now, it has always been assumed that this adaptation was a result of chronic postnatal exposure of the right ventricle to systemic pressure and increased volume load. The present study is the first to suggest that these changes in contraction patterns are evident before birth in HLHS and may be associated with altered intrauterine loading conditions encountered by the future systemic right ventricle. The pattern of RV contraction in fetal HLHS demonstrated by our results is clearly different from the normal right ventricle, despite the frame rate limitations of the VVI technique in the fetus. When comparing fetuses with HLHS with those with normal right ventricles, a greater systolic radial myocardial displacement concurrent with greater RV diameter in HLHS maintains an equivalent global radial shortening index and by implication circumferential shortening. As a consequence of reduced longitudinal strain, the ratio of longitudinal to circumferential deformation for the right ventricle in HLHS was reduced compared with the normal right ventricle and did not differ from the normal fetal left ventricle. Ventricular Contraction Patterns, Morphology, and Altered Ventricular Load The alteration of contraction pattern toward relatively greater circumferential deformation theoretically improves mechanical efficiency postnatally in a ventricle required to generate high pressure. Maintenance of deformation along the plane of smallest curvature of the RV free wall, the circumferential plane of the ventricle, provides the most effective generation of inward or radial force during ejection
according to Laplace’s law.14 It therefore seems logical that adaptation could begin during fetal life given the altered loading conditions to which the right ventricle is exposed in HLHS, particularly greater wall tension as a consequence of increasing diameter. In the long term, myocyte hypertrophy increases RV wall thickness, thus reducing wall tension.15 The idea that contraction patterns and morphology can be altered by loading conditions in the developing heart is supported by experimental animal models. It has previously been demonstrated that maturational patterns of myocardial architecture and strain are altered in both the left and right ventricles of chick embryos in a model of HLHS secondary to left atrial ligation.16 Chick embryos normally develop a dominance of RV circumferential over longitudinal contraction; however, in the HLHS model, this develops significantly earlier in the more spherical right ventricles of fetuses with altered loading secondary to left atrial ligation. The maturational course of myofiber architecture in chick embryos has also been altered after the placement of a conotruncal band17 and by disruption of the left vitelline vein,18 further evidence of the link between altered hemodynamics and histologic and morphologic changes. In addition to the modified patterns of ventricular contraction, we have also demonstrated morphologic changes, which are logically initiated by the altered volume work faced by the fetal right ventricle in HLHS. Although not measured in this study because of inconsistent alignment of stored pulsed-wave Doppler with the RV outflow tract, increased RVoutput in fetal HLHS attempts to maintain normal combined ventricular output.19 This increased volume work must be due to increased RV stroke volume, because heart rate does not increase. The demonstrated increase in RV diameter with normal length results in a larger end-diastolic volume, with an equivalent fractional area change to the normal right ventricle, confirming increased stroke volume.
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Figure 3 (A) Illustrative example of the greater right ventricular end-diastolic short-axis dimension relative to length resulting in increased sphericity index in (A) HLHS compared with (B) the normal fetal right ventricle (RV). LA, Left atrium; LV, left ventricle; RA, right atrium. afterload.20 Systolic function was maintained during progressive pulmonary artery banding by adaptive RV hypertrophy, but increased right atrial systolic contractility also developed to compensate for the altered diastolic properties of the right ventricle. This pattern of ventricular filling with increased reliance on active atrial filling has also been observed in children with pulmonary stenosis21 and functionally single right ventricles.22 It is therefore plausible that changes in the fetal right ventricle to altered intrauterine ventricular load may also be associated with the loss of diastolic efficiency. Our observation that the RV Tei index is significantly increased in fetal HLHS is consistent with the previous work of Szwast et al.19 Abnormalities of diastolic function and further increases in the RV Tei index have also been observed in patients with HLHS after birth3 and after surgical palliation.23 Interestingly, however, we found the ratio of systolic to diastolic duration not to be increased in fetal HLHS, a finding that is in contrast to observations by Friedberg and Silverman24 in children after all three stages of surgical palliation in HLHS after birth. However, it is likely that postnatal increases in this ratio are contributed to by normal increases in both postnatal preload, which prolongs the duration of systole,25,26 and afterload, which lengthens the duration of isovolumic relaxation in fetal and neonatal animals27 and mature human hearts.28 RV isovolumic contraction and relaxation times in HLHS are prolonged postnatally,3 but the relative changes in isovolumic contraction and relaxation times remain to be determined, because our pulsed Doppler data did not allow them to be individually measured. Figure 2 RV longitudinal velocity, radial displacement, and enddiastolic diameter versus gestation in HLHS and normal fetuses. All linear regressions in HLHS were significantly different from normal fetuses. (A) Peak global longitudinal velocity (P < .01), (B) peak global radial displacement (P < .05), (C) end-diastolic diameter (P < .001).
Doppler Flow Patterns and Diastolic Properties Fetal HLHS tricuspid Doppler inflow patterns revealed a greater reliance on atrial contraction for ventricular filling with increased A-wave velocity, A-wave duration, and A-wave inflow fraction. Furthermore, changes in IVC Doppler suggested the presence of higher atrial filling pressures in fetal HLHS, although not so elevated as to significantly alter ductus venosus and umbilical venous flow patterns. A similar change in ventricular filling has been observed in a canine model investigating right heart adaptation to chronically increased
Intraobserver and Interobserver Variability Our results demonstrate similar findings for reproducibility using VVI analysis for deformation assessment to previously published normal fetal values8,10 and pediatric patients with and without congenital heart disease.29 They highlight that this technique produces significant variability even in the research study setting. Limitations The main limitations of this study were a consequence of its retrospective nature. First, given that we reviewed archived two-dimensional images from multiple echocardiographic platforms, we chose to use VVI for speckle and tissue tracking. We acknowledge that this introduces the possibility of systematic differences in measurements obtained from different vendors’ data29 and that there is significant intraobserver and interobserver variability in measurements. The
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Table 3 Doppler-derived systemic measurements Parameter
Heart rate (beats/min) Reversal of IVC Doppler flow during atrial systole (%) Ductus venosus S/A ratio Umbilical artery pulsatility index
Table 5 Intraobserver and interobserver variability (n = 10)
Control fetuses
P
135 6 9 11.3 6 4.8
140 6 9 6.2 6 4.5
<.01 <.0001
2.3 6 0.9 1.25 6 0.31
2.0 6 0.6 1.14 6 0.28
.06 .09
HLHS
Data are expressed as mean 6 SD. P values were calculated using unpaired t tests.
Table 4 Doppler-derived RV measurements Parameter
HLHS right ventricle
Atrioventricular valve inflow peak E-wave velocity (cm/sec) 0.39 6 0.09 A-wave velocity (cm/sec) 0.58 6 0.14 E/A ratio 0.68 6 0.12 A-wave duration 101 6 18 A-wave inflow fraction 0.68 6 0.10 Systolic/diastolic duration 1.51 6 0.24 Ejection time (normalized 0.40 6 0.06 for RR interval) Inflow duration (normalized 0.39 6 0.07 for RR interval) Tei index 0.50 6 0.13
Normal right ventricle
P
0.36 6 0.09 0.51 6 0.10 0.71 6 0.13 92 6 12 0.63 6 0.10 1.51 6 0.35 0.42 6 0.03
.13 <.01 .23 <.05 <.05 .99 <.05
0.41 6 0.06
.39
0.42 6 0.16
<.05
Data are expressed as mean 6 SD. P values were calculated using unpaired t tests. Measurements derived from Doppler flow patterns.
archived images stored at 30 frames/sec resulted in a significant loss of temporal detail. Peak velocity and derived deformation measures are therefore of reduced magnitude, with separation of early and late myocardial diastolic velocities not possible. Although this limits the utility of derived measures, it does not discount the obvious differences in the HLHS right ventricle compared with controls and therefore the inferences made regarding RV contraction patterns. Prospectively acquired data using a higher frame rate for speckle tracking or Doppler tissue imaging will overcome this limitation and allow confirmation of our findings. Second, we used peak global radial displacement divided by enddiastolic diameter as a surrogate for global circumferential deformation given that our archived data did not reliably include short-axis loops. This makes the assumption that radial shortening is proportional to circumferential deformation. Ventricular morphology that deviates significantly from a spherical cross-section invalidates this assumption. Future investigation should measure circumferential deformation prospectively to confirm the findings of this study. Finally, the use of multiple comparisons with the relatively small sample size of 48 cases of fetal HLHS increases the risk for a type 1 statistical error despite the use of Dunnett’s test for post hoc comparisons within the analysis of variance. Despite this potential, all of the parameters that could logically be grouped to represent similar functional consequences (e.g., diastolic Doppler parameters related to atrial contraction) were shown to be significant without unexplained outliers.
Intraobserver variability Peak RV Global Systolic
Longitudinal velocity Longitudinal displacement Longitudinal strain Radial displacement
Bias
0.08 0.06 0.81 0.04
95% CI
0.7 to 0.6 0.7 to 0.6 4.0 to 5.6 0.3 to 0.3
Interobserver variability Bias
0.04 0.40 0.6 0.04
95% CI
0.4 to 0.3 0.8 to 1.6 5.9 to 4.7 0.2 to 0.3
CI, Confidence interval.
Clinical Significance Currently, there are few proven functional criteria, other than pulmonary venous flow patterns in the setting of a restrictive or intact atrial septum in HLHS,30 to guide antenatal counseling and postnatal management in single-ventricle circulations. This study confirms that intrauterine changes in RV function occur in HLHS, which may have important consequences for systolic and diastolic function in the future single right ventricle. Postnatal ventricular dysfunction remains an important risk factor in HLHS survival during staged palliation as well as for long-term morbidity and mortality.31 Confirmation of the findings in this study with tools not reliant on surrogate markers will be important. This will allow further exploration of fetal ventricular assessment as a prognostic tool for the functional outcome in single-ventricle hearts. Development of such indicators could influence counseling and early postnatal management strategies, for example, in consideration of prenatal listing for cardiac transplantation versus palliative surgery where available. CONCLUSIONS Fetuses with HLHS show RV remodeling with increased ventricular sphericity accompanied by relatively reduced longitudinal compared with circumferential deformation, more akin to the normal LV contraction pattern. Doppler flow indices also suggest altered ventricular filling and a greater reliance on atrial contraction. These findings suggest that the long-term changes observed in the contraction pattern of the systemic right ventricle in congenital heart disease begin during fetal life. REFERENCES 1. Pettersen E, Helle-Valle T, Edvardsen T, Lindberg H, Smith HJ, Smevik B, et al. Contraction pattern of the systemic right ventricle shift from longitudinal to circumferential shortening and absent global ventricular torsion. J Am Coll Cardiol 2007;49:2450-6. 2. Khoo NS, Smallhorn JF, Kaneko S, Myers K, Kutty S, Tham EB. Novel insights into RV adaptation and function in hypoplastic left heart syndrome between the first 2 stages of surgical palliation. JACC Cardiovasc Imaging 2011;4:128-37. 3. Frommelt PC, Sheridan DC, Mussatto KA, Hoffman GM, Ghanayem NS, Frommelt MA, et al. Effect of shunt type on echocardiographic indices after initial palliations for hypoplastic left heart syndrome: Blalock-Taussig shunt versus right ventricle-pulmonary artery conduit. J Am Soc Echocardiogr 2007;20:1364-73. 4. Petko C, Uebing A, Furck A, Rickers C, Scheewe J, Kramer HH. Changes of right ventricular function and longitudinal deformation in children with hypoplastic left heart syndrome before and after the Norwood operation. J Am Soc Echocardiogr 2011;24:1226-32.
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5. Di Salvo G, Russo MG, Paladini D, Felicetti M, Castaldi B, Tartaglione A, et al. Two-dimensional strain to assess regional left and right ventricular longitudinal function in 100 normal foetuses. Eur J Echocardiogr 2008;9:754-6. 6. Peng QH, Zhou QC, Zeng S, Tian LQ, Zhang M, Tan Y, et al. Evaluation of regional left ventricular longitudinal function in 151 normal fetuses using Velocity Vector Imaging. Prenat Diagn 2009;29:1149-55. 7. Ta-Shma A, Perles Z, Gavri S, Golender J, Tarshansky S, Shlichter C, et al. Analysis of segmental and global function of the fetal heart using novel automatic functional imaging. J Am Soc Echocardiogr 2008;21:146-50. 8. Younoszai AK, Saudek DE, Emery SP, Thomas JD. Evaluation of myocardial mechanics in the fetus by Velocity Vector Imaging. J Am Soc Echocardiogr 2008;21:470-4. 9. Barker PC, Houle H, Li JS, Miller S, Herlong JR, Camitta MG. Global longitudinal cardiac strain and strain rate for assessment of fetal cardiac function: novel experience with Velocity Vector Imaging. Echocardiography 2009;26:28-36. 10. Ishii T, McElhinney DB, Harrild DM, Marcus EN, Sahn DJ, Truong U, et al. Circumferential and longitudinal ventricular strain in the normal human fetus. J Am Soc Echocardiogr 2012;25:105-11. 11. Van Mieghem T, Giusca S, DeKoninck P, Gucciardo L, Done E, Hindryckx A, et al. Prospective assessment of fetal cardiac function with speckle tracking in healthy fetuses and recipient fetuses of twin-to-twin transfusion syndrome. J Am Soc Echocardiogr 2010;23:301-8. 12. Adamson SL. Arterial pressure, vascular input impedance, and resistance as determinants of pulsatile blood flow in the umbilical artery. Eur J Obstet Gynecol Reprod Biol 1999;84:119-25. 13. Tei C, Nishimura RA, Seward JB, Tajik AJ. Noninvasive Doppler-derived myocardial performance index: correlation with simultaneous measurements of cardiac catheterization measurements. J Am Soc Echocardiogr 1997;10:169-78. 14. Ingels NB Jr. Myocardial fiber architecture and left ventricular function. Technol Health Care 1997;5:45-52. 15. Norton JM. Toward consistent definitions for preload and afterload. Adv Physiol Educ 2001;25:53-61. 16. Tobita K, Keller BB. Right and left ventricular wall deformation patterns in normal and left heart hypoplasia chick embryos. Am J Physiol Heart Circ Physiol 2000;279:H959-69. 17. Tobita K, Garrison JB, Liu LJ, Tinney JP, Keller BB. Three-dimensional myofiber architecture of the embryonic left ventricle during normal development and altered mechanical loads. Anat Rec A Discov Mol Cell Evol Biol 2005;283:193-201. 18. Icardo JM. Endocardial cell arrangement: role of hemodynamics. Anat Rec 1989;225:150-5.
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19. Szwast A, Tian Z, McCann M, Donaghue D, Rychik J. Right ventricular performance in the fetus with hypoplastic left heart syndrome. Ann Thorac Surg 2009;87:1214-9. 20. Gaynor SL, Maniar HS, Bloch JB, Steendijk P, Moon MR. Right atrial and ventricular adaptation to chronic right ventricular pressure overload. Circulation 2005;112:I212-8. 21. Vermilion RP, Snider AR, Bengur AR, Meliones JN. Long-term assessment of right ventricular diastolic filling in patients with pulmonic valve stenosis successfully treated in childhood. Am J Cardiol 1991;68:648-52. 22. Mahle WT, Silverman NH, Marx GR, Anderson RH. Echo-morphological correlates concerning the functionally univentricular heart in the setting of isomeric atrial appendages. Cardiol Young 2006;16(suppl):35-42. 23. Mahle WT, Coon PD, Wernovsky G, Rychik J. Quantitative echocardiographic assessment of the performance of the functionally single right ventricle after the Fontan operation. Cardiol Young 2001;11: 399-406. 24. Friedberg MK, Silverman NH. The systolic to diastolic duration ratio in children with hypoplastic left heart syndrome: a novel Doppler index of right ventricular function. J Am Soc Echocardiogr 2007;20:749-55. 25. Goodlin RC, Girard J, Hollmen A. Systolic time intervals in the fetus and neonate. Obstet Gynecol 1972;39:295-303. 26. Wiggers CJ. Studies on the consecutive phases of the cardiac cycle (ii) the laws governing the relative durations of ventricular systole and diastole. Am J Physiol 1921;56:439. 27. Hoerter JA, Lecarpentier Y. Load sensitivity of relaxation in the foetal and newborn rabbit heart. Cardiovasc Res 1984;18:523-7. 28. Thomas JD, Flachskampf FA, Chen C, Guererro JL, Picard MH, Levine RA, et al. Isovolumic relaxation time varies predictably with its time constant and aortic and left atrial pressures: implications for the noninvasive evaluation of ventricular relaxation. Am Heart J 1992;124: 1305-13. 29. Koopman LP, Slorach C, Manlhiot C, McCrindle BW, Jaeggi ET, Mertens L, et al. Assessment of myocardial deformation in children using Digital Imaging and Communications in Medicine (DICOM) data and vendor independent speckle tracking software. J Am Soc Echocardiogr 2011;24:37-44. 30. Taketazu M, Barrea C, Smallhorn JF, Wilson GJ, Hornberger LK. Intrauterine pulmonary venous flow and restrictive foramen ovale in fetal hypoplastic left heart syndrome. J Am Coll Cardiol 2004;43:1902-7. 31. Altmann K, Printz BF, Solowiejczky DE, Gersony WM, Quaegebeur J, Apfel HD. Two-dimensional echocardiographic assessment of right ventricular function as a predictor of outcome in hypoplastic left heart syndrome. Am J Cardiol 2000;86:964-8.
Background: The systemic right ventricle in palliated hypoplastic left heart syndrome (HLHS) has relatively reduced longitudinal compared with circumferential deformation, a pattern of contraction more akin to the normal left ventricle, which presumably improves right ventricular (RV) pumping efficiency. The aim of this study was to test the hypothesis that these changes in the RV contraction pattern in infants with HLHS are present prenatally. Methods: Echocardiograms from 48 fetuses with HLHS were retrospectively compared with those from appropriately grown RV and left ventricular controls. Ventricular function was assessed using Velocity Vector Imaging velocity, tissue deformation, two-dimensional echocardiography, and Doppler flow parameters. Results: Fetuses with HLHS demonstrated reduced peak global RV longitudinal velocity (P < .01), strain (P < .001), and displacement (P < .05), while radial displacement was increased (P < .001) compared with the normal fetal right ventricle. Mean RV diameter was increased in HLHS (P < .001), but length was unchanged. The ratio of longitudinal to circumferential deformation was reduced in HLHS compared with the normal right ventricle (P < .001) and equivalent to the normal left ventricle. Tricuspid inflow peak A-wave velocity (P < .01), A-wave duration, A-wave inflow fraction, RV Tei index (P < .05 for all), and inferior vena cava A-wave reversal (P < .0001) were increased in HLHS. Conclusions: The fetal right ventricle in HLHS becomes more spherical because of increased RV diameter. It has relatively reduced longitudinal compared with circumferential deformation and an increased reliance on atrial contraction for ventricular filling. These findings are similar to postnatal changes observed in the systemic right ventricle in palliated congenital heart disease, suggesting that ventricular remodeling is initiated in fetal life. (J Am Soc Echocardiogr 2012;25:1068-74.) Keywords: Fetal development, Fetal echocardiography, Hypoplastic left heart syndrome, Myocardial contraction, Speckle tracking
The systemic right ventricle in long-term palliated congenital heart disease has relatively reduced longitudinal compared with circumferential contraction velocities and deformation.1 This change results in a pattern of contraction more similar to the normal left ventricle than right ventricle, with presumed improved ventricular efficiency. A recent study showed that similar changes also occur in the systemic right ventricle in infants with hypoplastic left heart syndrome (HLHS).2 In these infants, a more left ventricular (LV)–like pattern of contraction From the Fetal and Neonatal Cardiology Program, Division of Cardiology, Departments of Pediatrics (P.A.B., N.S.K., A.S.M., L.K.H.) and Obstetrics and Gynecology (L.K.H.), Women and Children’s Health Research and Mazankowski Alberta Heart Institutes, University of Alberta, Edmonton, Alberta, Canada. Dr Paul Brooks was supported by the RACP Foundation Eric Burnard Fellowship and Robert and Elizabeth Albert Study Grant. Reprint requests: Lisa K. Hornberger, MD, Fetal and Neonatal Cardiology Program, Pediatric Cardiology, Stollery Children’s Hospital, WCMC 4C2, 8440 112th Street, Edmonton, AB T6G 2B7, Canada (E-mail: lisa.hornberger@ albertahealthservices.ca). 0894-7317/$36.00 Copyright 2012 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2012.06.005
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was associated with improved mechanical synchrony, reduced right ventricular (RV) dilation, and hypertrophy. Although it has been assumed that this adaptation is a consequence of long-term exposure to both systemic pressure and increased volume load, differences in both RV morphology and function in HLHS are evident soon after birth.3,4 It remains unknown whether these changes begin antenatally. Fetal ventricular function can be evaluated noninvasively using twodimensional echocardiography, Doppler flow patterns, and more recently myocardial velocities and deformation. Two-dimensional speckle-tracking and feature-tracking techniques, such as Velocity Vector Imaging (VVI; Siemens Medical Solutions, Malvern, PA), have been used to assess normal fetal ventricular function,5-10 fetuses with twin-twin transfusion syndrome,11 and small groups with congenital heart disease.9,10 The advantages of these techniques for the assessment of fetal ventricular function are their angle independence and applicability to two-dimensional images, allowing retrospective review of relatively rare lesions in archived data. In this investigation, we compared systolic, diastolic, and global function using VVI and pulsed Doppler indices between fetuses with HLHS and healthy controls. We hypothesized that changes in the contraction pattern of the future systemic right ventricle in HLHS will be present during fetal life.
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METHODS
at end-diastole were measured from the same two-dimensional Digital Imaging and Communications in Medicine loops used for the VVI analysis (Figure 1). Sphericity index was calculated by dividing end-diastolic diameter by length (sphericity index = end-diastolic diameter/end-diastolic length). Ventricular fractional area change was calculated by the VVI software algorithm from the maximal and minimal areas enclosed by the manual endocardial border traces and expressed as a percentage. A single operator (P.A.B.) performed all Doppler measurements and calculations. Heart rate was calculated from Doppler flow assessment of atrioventricular valve inflow. Inferior vena cava (IVC), ductus venosus, umbilical artery, and venous Doppler flow patterns were also assessed in all fetuses. The percentage reversal of IVC Doppler flow during atrial systole was calculated by measuring the forward and backward velocity-time integrals (VTIs) (IVC Doppler A-wave VTI 100/IVC Doppler forward-flow VTI). The ratio between ductus venosus peak systolic (S-wave) velocity and minimum flow velocity during atrial contraction (A wave) was calculated (ductus venosus S-wave velocity/ductus venosus A-wave velocity), because there were no fetuses with A-wave reversal in the ductus venosus. The umbilical arterial pulsatility index was calculated using the formula ([peak systolic velocity end-diastolic velocity]/mean velocity).12 Doppler tricuspid valve inflow and pulmonary valve ejection were assessed for the HLHS and RV control fetuses. Ejection and inflow times were corrected for cardiac cycle duration. Ratios of systolic to diastolic duration for the right ventricle in both HLHS and control fetuses were calculated (systolic/diastolic duration ratio = [cardiac cycle duration tricuspid inflow duration]/tricuspid inflow duration). RV filling was assessed by the measurement of peak E-wave and A-wave inflow velocities and A-wave duration, and the E/A ratio was calculated. A-wave inflow fraction (A-wave inflow fraction = tricuspid inflow A-wave VTI/tricuspid inflow total VTI) was calculated, as was the RV Tei or myocardial performance index using standard technique.13 All Doppler measures were averaged over three cardiac cycles. Statistical analyses were performed using Prism version 5.3 (GraphPad Software, Inc., La Jolla, CA). Data are reported as mean 6 SD. Individual comparisons of both the general Doppler parameters and the RV Doppler measurements for the HLHS and normal control fetuses were performed using unpaired t tests. Comparisons among all three ventricles studied (the HLHS right ventricle, the normal control right ventricle, and the normal control left ventricle) were performed using one-way analysis of variance with Dunnett’s multiple comparison testing for post hoc comparisons of the HLHS right ventricle versus the normal right and left ventricles. Comparisons between HLHS and normal control right ventricles with advancing gestation were performed using analysis of covariance. Intraobserver (P.A.B.) and interobserver (N.S.K.) variability were assessed for RV VVI velocity, displacement, and strain. The absolute difference between reviewers divided by the mean of the measures was calculated in a randomly selected group of 10 fetuses with HLHS. The systematic bias of repeated measures was also calculated using Bland-Altman analysis.
Abbreviations
HLHS = Hypoplastic left heart syndrome
All pregnancies with fetal diagnoses of HLHS encountered in the Fetal and Neonatal Cardiology IVC = Inferior vena cava Program at the University of LV = Left ventricular Alberta between March 2006 and March 2011 were identified RV = Right ventricular through a review of our pediatric VTI = Velocity-time integral and fetal echocardiography database. Fetuses were excluded if VVI = Velocity Vector Imaging they had HLHS variants associated with discordant or double-outlet ventriculoarterial connections, a common atrioventricular valve, or ventricular septal defects. Suitable four-chamber images for analysis were identified in 48 of 49 eligible fetuses with HLHS. For those with more than one fetal echocardiogram, a single study (the earliest study with suitable four-chamber images) was analyzed. Forty-eight appropriately grown singleton controls without structural or functional heart disease from normal pregnancies were also identified for RV and LV assessments. The study was approved by the Health Research Ethics Board at the University of Alberta. Fetal echocardiograms were performed using Phillips iE33 (Philips Medical Systems, Bothell, WA), GE Voluson E8 (GE Medical Systems, Milwaukee, WI), or Siemens Acuson S2000 (Siemens Medical Solutions) cardiac ultrasound platforms. The Digital Imaging and Communications in Medicine images from the selected fetal echocardiograms were imported into Syngo US Workplace version 3.5 (Siemens Medical Solutions) for offline analysis. The VVI analysis frame rate of archived Digital Imaging and Communications in Medicine data was 30 frames/sec. A single operator (P.A.B.) used VVI version 2.0 software to assess global systolic longitudinal velocity, displacement, and strain, as well as global radial displacement for the right ventricle in HLHS and both the right and left ventricles in normal control fetuses. The peak of the mean modal velocities calculated by the software was measured. The onset of each cardiac cycle was determined using anatomic M-mode assessment of the earliest inward motion of the ventricular free wall. The ventricular endocardial border was traced from the lateral atrioventricular valve annulus to the apex and back to the septal atrioventricular valve annulus for each of the ventricles examined. Manual adjustments were made as required to ensure that all segments appropriately tracked myocardial motion after processing by the software algorithm. Because this was a retrospective study, specific images to allow direct measurement of circumferential deformation were not available. However, a surrogate for circumferential deformation was calculated by indexing the peak global radial displacement to end-diastolic diameter (global radial shortening index = [global peak radial displacement/end-diastolic diameter]; Figure 1). This index represents the fractional change in diameter during systolic contraction which is proportional to circumferential deformation through the relationship diameter = circumference/p. It was given a negative value to represent muscle shortening, as is the convention for both longitudinal and circumferential deformation. The global radial shortening index was then used in the calculation of a ratio of longitudinal to circumferential deformation (deformation ratio = peak global longitudinal strain/global radial shortening index). Ventricular length (plane of atrioventricular valve annulus to ventricular apex) and diameter (perpendicular to the midpoint of length)
RESULTS The 96 fetal echocardiograms reviewed (48 cases, 48 controls) were performed between 19 and 39 weeks of gestation. There was no difference in gestational age between the fetuses with HLHS and
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Figure 1 (A) Example Velocity Vector Imaging still frame from a fetus at 27-week gestation with HLHS showing velocity vectors (yellow arrows indicating relative velocity and direction of myocardial motion) during diastole. (B) Diagram illustrating end-diastolic diameter (EDD) measurement perpendicular to the midpoint of length used in calculating radial shortening index. LV, Left ventricle; RV, right ventricle.
controls at the time of fetal echocardiography (27.9 6 6.2 vs 28.1 6 6.4 weeks, respectively, P = .90). Of the HLHS fetuses, 35 had aortic and mitral atresia, eight had aortic atresia with mitral stenosis, and five had both aortic and mitral stenosis with forward flow through the hypoplastic left ventricle. One pregnancy ended in spontaneous intrauterine fetal demise, and there were 12 elective terminations. Two neonates died, one with an intact atrial septum who was managed with comfort care and another after an intracerebral hemorrhage while awaiting transplantation after bilateral branch pulmonary artery bands and a stent in the ductus arteriosus. Thirty-three neonates went on to the first stage of surgical palliation with the Norwood procedure. RV Contraction Patterns and Morphology in Fetal HLHS Compared with the Normal Right Ventricle Fetuses with HLHS had reduced peak global RV longitudinal velocity, displacement, and strain compared with the normal right ventricle, while peak global radial displacement was increased (Table 1). The global radial shortening index was no different when comparing right ventricles between fetuses with HLHS and normal controls, but the ratio of longitudinal to circumferential deformation was reduced for the right ventricle in HLHS compared with the normal fetal right ventricle as a consequence of reduced longitudinal strain. RV end-diastolic diameter was increased in fetuses with HLHS compared with the right ventricles of controls, while RV length was unchanged (Table 2). The sphericity index was therefore increased in fetuses with HLHS compared with the normal right ventricle. Fetuses with HLHS and normal controls showed no difference in RV fractional area change. Linear regressions over gestation showed that RV peak global longitudinal velocity, radial displacement, and end-diastolic diameter in fetuses with HLHS significantly differed from normal fetuses (comparisons by analysis of covariance; Figure 2). RV Contraction Patterns and Morphology in Fetal HLHS Compared with the Normal Left Ventricle When comparing the right ventricles in fetuses with HLHS to the normal fetal left ventricle, peak global longitudinal velocity and
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displacement were no different, while strain was reduced in fetuses with HLHS (Table 1). Peak global radial displacement also showed no difference between the right ventricle in HLHS and the normal fetal left ventricle. The global radial shortening index was lower in the right ventricles of fetuses with HLHS compared with the normal left ventricle, which produced comparable ratios of longitudinal to circumferential deformation for the right ventricles in HLHS and the normal fetal left ventricle. RV end-diastolic diameter was increased in fetuses with HLHS compared with the normal left ventricle, while there was no difference in ventricular length (Table 2). The sphericity index was therefore greater for the right ventricle in fetuses with HLHS compared with the normal left ventricle (Figure 3). There was no difference in fractional area change. Heart Rate and Doppler Indices of Function and Loading Fetuses with HLHS had a slightly lower mean heart rate than controls (Table 3). There was an increase in the percentage reversal in IVC flow during atrial contraction in fetuses with HLHS in comparison with normal controls, but the ductus venosus showed only a trend toward deeper A-wave reversal, and umbilical venous Doppler flow revealed no evidence of venous pulsations in fetuses with HLHS. There was also a trend toward increased umbilical artery pulsatility index in fetuses with HLHS compared with normal controls. When comparing RV Doppler parameters (Table 4), tricuspid valve inflow revealed no difference in the peak E-wave velocity or the E/A ratio, but peak A-wave velocity was increased in the fetuses with HLHS. A-wave duration and A-wave inflow fraction were also increased. There was no difference in the ratio of systolic to diastolic duration of tricuspid valve inflow, but there was a reduction in normalized RV ejection time in the HLHS right ventricle compared with the normal fetal right ventricle. Fetuses with HLHS had increased isovolumic times and RV Tei indices compared with controls. Intraobserver and Interobserver Variability The respective intraobserver and interobserver variability values for peak global systolic VVI parameters were 0.18 and 0.14 for longitudinal velocity, 0.16 and 0.19 for longitudinal displacement, 0.16 and 0.14 for longitudinal strain, and 0.18 and 0.12 for radial displacement. Bias and confidence intervals are presented in Table 5.
DISCUSSION This study demonstrates that the fetal right ventricle in HLHS became more spherical with reduced ratio of longitudinal to circumferential deformation. Fetuses with HLHS also had Doppler changes that suggest a greater reliance on atrial contraction for RV filling and altered diastolic properties. These findings suggest that the changes in RV morphology, contraction, and filling pattern in infants with HLHS2 appear to begin during fetal life. Ventricular Contraction Patterns in the Systemic Right Ventricle The adult systemic right ventricle in transposition of the great arteries after palliative atrial redirection surgery (a Senning operation) demonstrates relatively reduced longitudinal compared with circumferential velocities and deformation, a pattern of contraction more akin to the normal left ventricle than right ventricle.1 Reduced RV longitudinal
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Table 1 Myocardial velocities and deformation Parameter
Peak global systolic Longitudinal velocity (cm/sec) Longitudinal displacement (cm) Longitudinal strain (%) Radial displacement (cm) Global radial shortening index Deformation ratio
HLHS right ventricle
1.03 6 0.42 1.33 6 0.59 14.8 6 4.0 0.82 6 0.29 0.067 6 0.027 259 6 124
Normal right ventricle
1.39 6 0.53† 1.70 6 0.61* 17.9 6 3.1‡ 0.52 6 0.19‡ 0.057 6 0.026 359 6 170‡
Normal left ventricle
P value by analysis of variance
1.18 6 0.69 1.36 6 0.79 16.7 6 3.2* 0.72 6 0.26 0.087 6 0.026‡ 211 6 85
<.01 <.05 <.0001 <.0001 <.0001 <.0001
Data are expressed as mean 6 SD. *P < .05. † P < .01. ‡ P < .001 versus HLHS right ventricle (Dunnett’s multiple comparisons).
Table 2 Two-dimensional measurements Parameter
HLHS right ventricle
Normal right ventricle
Normal left ventricle
P value by analysis of variance
Ventricular end-diastolic diameter (mm) Ventricular end-diastolic length (mm) Sphericity index Ventricular fractional area change (%)
13.7 6 5.9 18.9 6 5.4 0.72 6 0.20 40.8 6 8.3
9.9 6 3.5* 19.4 6 5.3 0.51 6 0.09* 39.7 6 8.5
8.5 6 3.0* 19.6 6 5.2 0.43 6 0.08* 43.7 6 6.8
<.0001 .79 <.0001 <.05
Data are expressed as mean 6 SD. *P < .001 versus HLHS right ventricle (Dunnett’s multiple comparisons).
deformation in HLHS has recently been demonstrated before and after Norwood palliation by several groups.2,4 In a longitudinal study, Khoo et al.2 demonstrated that these RV functional changes occur progressively in infants with HLHS and are associated with improved mechanical synchrony and smaller RVend-diastolic volume and mass. Until now, it has always been assumed that this adaptation was a result of chronic postnatal exposure of the right ventricle to systemic pressure and increased volume load. The present study is the first to suggest that these changes in contraction patterns are evident before birth in HLHS and may be associated with altered intrauterine loading conditions encountered by the future systemic right ventricle. The pattern of RV contraction in fetal HLHS demonstrated by our results is clearly different from the normal right ventricle, despite the frame rate limitations of the VVI technique in the fetus. When comparing fetuses with HLHS with those with normal right ventricles, a greater systolic radial myocardial displacement concurrent with greater RV diameter in HLHS maintains an equivalent global radial shortening index and by implication circumferential shortening. As a consequence of reduced longitudinal strain, the ratio of longitudinal to circumferential deformation for the right ventricle in HLHS was reduced compared with the normal right ventricle and did not differ from the normal fetal left ventricle. Ventricular Contraction Patterns, Morphology, and Altered Ventricular Load The alteration of contraction pattern toward relatively greater circumferential deformation theoretically improves mechanical efficiency postnatally in a ventricle required to generate high pressure. Maintenance of deformation along the plane of smallest curvature of the RV free wall, the circumferential plane of the ventricle, provides the most effective generation of inward or radial force during ejection
according to Laplace’s law.14 It therefore seems logical that adaptation could begin during fetal life given the altered loading conditions to which the right ventricle is exposed in HLHS, particularly greater wall tension as a consequence of increasing diameter. In the long term, myocyte hypertrophy increases RV wall thickness, thus reducing wall tension.15 The idea that contraction patterns and morphology can be altered by loading conditions in the developing heart is supported by experimental animal models. It has previously been demonstrated that maturational patterns of myocardial architecture and strain are altered in both the left and right ventricles of chick embryos in a model of HLHS secondary to left atrial ligation.16 Chick embryos normally develop a dominance of RV circumferential over longitudinal contraction; however, in the HLHS model, this develops significantly earlier in the more spherical right ventricles of fetuses with altered loading secondary to left atrial ligation. The maturational course of myofiber architecture in chick embryos has also been altered after the placement of a conotruncal band17 and by disruption of the left vitelline vein,18 further evidence of the link between altered hemodynamics and histologic and morphologic changes. In addition to the modified patterns of ventricular contraction, we have also demonstrated morphologic changes, which are logically initiated by the altered volume work faced by the fetal right ventricle in HLHS. Although not measured in this study because of inconsistent alignment of stored pulsed-wave Doppler with the RV outflow tract, increased RVoutput in fetal HLHS attempts to maintain normal combined ventricular output.19 This increased volume work must be due to increased RV stroke volume, because heart rate does not increase. The demonstrated increase in RV diameter with normal length results in a larger end-diastolic volume, with an equivalent fractional area change to the normal right ventricle, confirming increased stroke volume.
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Figure 3 (A) Illustrative example of the greater right ventricular end-diastolic short-axis dimension relative to length resulting in increased sphericity index in (A) HLHS compared with (B) the normal fetal right ventricle (RV). LA, Left atrium; LV, left ventricle; RA, right atrium. afterload.20 Systolic function was maintained during progressive pulmonary artery banding by adaptive RV hypertrophy, but increased right atrial systolic contractility also developed to compensate for the altered diastolic properties of the right ventricle. This pattern of ventricular filling with increased reliance on active atrial filling has also been observed in children with pulmonary stenosis21 and functionally single right ventricles.22 It is therefore plausible that changes in the fetal right ventricle to altered intrauterine ventricular load may also be associated with the loss of diastolic efficiency. Our observation that the RV Tei index is significantly increased in fetal HLHS is consistent with the previous work of Szwast et al.19 Abnormalities of diastolic function and further increases in the RV Tei index have also been observed in patients with HLHS after birth3 and after surgical palliation.23 Interestingly, however, we found the ratio of systolic to diastolic duration not to be increased in fetal HLHS, a finding that is in contrast to observations by Friedberg and Silverman24 in children after all three stages of surgical palliation in HLHS after birth. However, it is likely that postnatal increases in this ratio are contributed to by normal increases in both postnatal preload, which prolongs the duration of systole,25,26 and afterload, which lengthens the duration of isovolumic relaxation in fetal and neonatal animals27 and mature human hearts.28 RV isovolumic contraction and relaxation times in HLHS are prolonged postnatally,3 but the relative changes in isovolumic contraction and relaxation times remain to be determined, because our pulsed Doppler data did not allow them to be individually measured. Figure 2 RV longitudinal velocity, radial displacement, and enddiastolic diameter versus gestation in HLHS and normal fetuses. All linear regressions in HLHS were significantly different from normal fetuses. (A) Peak global longitudinal velocity (P < .01), (B) peak global radial displacement (P < .05), (C) end-diastolic diameter (P < .001).
Doppler Flow Patterns and Diastolic Properties Fetal HLHS tricuspid Doppler inflow patterns revealed a greater reliance on atrial contraction for ventricular filling with increased A-wave velocity, A-wave duration, and A-wave inflow fraction. Furthermore, changes in IVC Doppler suggested the presence of higher atrial filling pressures in fetal HLHS, although not so elevated as to significantly alter ductus venosus and umbilical venous flow patterns. A similar change in ventricular filling has been observed in a canine model investigating right heart adaptation to chronically increased
Intraobserver and Interobserver Variability Our results demonstrate similar findings for reproducibility using VVI analysis for deformation assessment to previously published normal fetal values8,10 and pediatric patients with and without congenital heart disease.29 They highlight that this technique produces significant variability even in the research study setting. Limitations The main limitations of this study were a consequence of its retrospective nature. First, given that we reviewed archived two-dimensional images from multiple echocardiographic platforms, we chose to use VVI for speckle and tissue tracking. We acknowledge that this introduces the possibility of systematic differences in measurements obtained from different vendors’ data29 and that there is significant intraobserver and interobserver variability in measurements. The
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Table 3 Doppler-derived systemic measurements Parameter
Heart rate (beats/min) Reversal of IVC Doppler flow during atrial systole (%) Ductus venosus S/A ratio Umbilical artery pulsatility index
Table 5 Intraobserver and interobserver variability (n = 10)
Control fetuses
P
135 6 9 11.3 6 4.8
140 6 9 6.2 6 4.5
<.01 <.0001
2.3 6 0.9 1.25 6 0.31
2.0 6 0.6 1.14 6 0.28
.06 .09
HLHS
Data are expressed as mean 6 SD. P values were calculated using unpaired t tests.
Table 4 Doppler-derived RV measurements Parameter
HLHS right ventricle
Atrioventricular valve inflow peak E-wave velocity (cm/sec) 0.39 6 0.09 A-wave velocity (cm/sec) 0.58 6 0.14 E/A ratio 0.68 6 0.12 A-wave duration 101 6 18 A-wave inflow fraction 0.68 6 0.10 Systolic/diastolic duration 1.51 6 0.24 Ejection time (normalized 0.40 6 0.06 for RR interval) Inflow duration (normalized 0.39 6 0.07 for RR interval) Tei index 0.50 6 0.13
Normal right ventricle
P
0.36 6 0.09 0.51 6 0.10 0.71 6 0.13 92 6 12 0.63 6 0.10 1.51 6 0.35 0.42 6 0.03
.13 <.01 .23 <.05 <.05 .99 <.05
0.41 6 0.06
.39
0.42 6 0.16
<.05
Data are expressed as mean 6 SD. P values were calculated using unpaired t tests. Measurements derived from Doppler flow patterns.
archived images stored at 30 frames/sec resulted in a significant loss of temporal detail. Peak velocity and derived deformation measures are therefore of reduced magnitude, with separation of early and late myocardial diastolic velocities not possible. Although this limits the utility of derived measures, it does not discount the obvious differences in the HLHS right ventricle compared with controls and therefore the inferences made regarding RV contraction patterns. Prospectively acquired data using a higher frame rate for speckle tracking or Doppler tissue imaging will overcome this limitation and allow confirmation of our findings. Second, we used peak global radial displacement divided by enddiastolic diameter as a surrogate for global circumferential deformation given that our archived data did not reliably include short-axis loops. This makes the assumption that radial shortening is proportional to circumferential deformation. Ventricular morphology that deviates significantly from a spherical cross-section invalidates this assumption. Future investigation should measure circumferential deformation prospectively to confirm the findings of this study. Finally, the use of multiple comparisons with the relatively small sample size of 48 cases of fetal HLHS increases the risk for a type 1 statistical error despite the use of Dunnett’s test for post hoc comparisons within the analysis of variance. Despite this potential, all of the parameters that could logically be grouped to represent similar functional consequences (e.g., diastolic Doppler parameters related to atrial contraction) were shown to be significant without unexplained outliers.
Intraobserver variability Peak RV Global Systolic
Longitudinal velocity Longitudinal displacement Longitudinal strain Radial displacement
Bias
0.08 0.06 0.81 0.04
95% CI
0.7 to 0.6 0.7 to 0.6 4.0 to 5.6 0.3 to 0.3
Interobserver variability Bias
0.04 0.40 0.6 0.04
95% CI
0.4 to 0.3 0.8 to 1.6 5.9 to 4.7 0.2 to 0.3
CI, Confidence interval.
Clinical Significance Currently, there are few proven functional criteria, other than pulmonary venous flow patterns in the setting of a restrictive or intact atrial septum in HLHS,30 to guide antenatal counseling and postnatal management in single-ventricle circulations. This study confirms that intrauterine changes in RV function occur in HLHS, which may have important consequences for systolic and diastolic function in the future single right ventricle. Postnatal ventricular dysfunction remains an important risk factor in HLHS survival during staged palliation as well as for long-term morbidity and mortality.31 Confirmation of the findings in this study with tools not reliant on surrogate markers will be important. This will allow further exploration of fetal ventricular assessment as a prognostic tool for the functional outcome in single-ventricle hearts. Development of such indicators could influence counseling and early postnatal management strategies, for example, in consideration of prenatal listing for cardiac transplantation versus palliative surgery where available. CONCLUSIONS Fetuses with HLHS show RV remodeling with increased ventricular sphericity accompanied by relatively reduced longitudinal compared with circumferential deformation, more akin to the normal LV contraction pattern. Doppler flow indices also suggest altered ventricular filling and a greater reliance on atrial contraction. These findings suggest that the long-term changes observed in the contraction pattern of the systemic right ventricle in congenital heart disease begin during fetal life. REFERENCES 1. Pettersen E, Helle-Valle T, Edvardsen T, Lindberg H, Smith HJ, Smevik B, et al. Contraction pattern of the systemic right ventricle shift from longitudinal to circumferential shortening and absent global ventricular torsion. J Am Coll Cardiol 2007;49:2450-6. 2. Khoo NS, Smallhorn JF, Kaneko S, Myers K, Kutty S, Tham EB. Novel insights into RV adaptation and function in hypoplastic left heart syndrome between the first 2 stages of surgical palliation. JACC Cardiovasc Imaging 2011;4:128-37. 3. Frommelt PC, Sheridan DC, Mussatto KA, Hoffman GM, Ghanayem NS, Frommelt MA, et al. Effect of shunt type on echocardiographic indices after initial palliations for hypoplastic left heart syndrome: Blalock-Taussig shunt versus right ventricle-pulmonary artery conduit. J Am Soc Echocardiogr 2007;20:1364-73. 4. Petko C, Uebing A, Furck A, Rickers C, Scheewe J, Kramer HH. Changes of right ventricular function and longitudinal deformation in children with hypoplastic left heart syndrome before and after the Norwood operation. J Am Soc Echocardiogr 2011;24:1226-32.
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