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.
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.
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.
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.
The systemic right ventricle in long-term palliated congenital heart disease has relatively reduced longitudinal compared with circumferential contraction velocities and deformation. 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). In these infants, a more left ventricular (LV)–like pattern of contraction 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. It remains unknown whether these changes begin antenatally.
Fetal ventricular function can be evaluated noninvasively using two-dimensional 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, fetuses with twin-twin transfusion syndrome, and small groups with congenital heart disease. 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.
All pregnancies with fetal diagnoses of HLHS encountered in the Fetal and Neonatal Cardiology Program at the University of Alberta between March 2006 and March 2011 were identified through a review of our pediatric and fetal echocardiography database. Fetuses were excluded if 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/π. 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) 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).
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. 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 ± 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.
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 controls at the time of fetal echocardiography (27.9 ± 6.2 vs 28.1 ± 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.
|HLHS right ventricle
|Normal right ventricle
|Normal left ventricle
|P value by analysis of variance
|Peak global systolic
|Longitudinal velocity (cm/sec)
|1.03 ± 0.42
|1.39 ± 0.53 †
|1.18 ± 0.69
|Longitudinal displacement (cm)
|1.33 ± 0.59
|1.70 ± 0.61 ∗
|1.36 ± 0.79
|Longitudinal strain (%)
|−14.8 ± 4.0
|−17.9 ± 3.1 ‡
|−16.7 ± 3.2 ∗
|Radial displacement (cm)
|0.82 ± 0.29
|0.52 ± 0.19 ‡
|0.72 ± 0.26
|Global radial shortening index
|−0.067 ± 0.027
|−0.057 ± 0.026
|−0.087 ± 0.026 ‡
|259 ± 124
|359 ± 170 ‡
|211 ± 85
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.
|HLHS right ventricle
|Normal right ventricle
|Normal left ventricle
|P value by analysis of variance
|Ventricular end-diastolic diameter (mm)
|13.7 ± 5.9
|9.9 ± 3.5 ∗
|8.5 ± 3.0 ∗
|Ventricular end-diastolic length (mm)
|18.9 ± 5.4
|19.4 ± 5.3
|19.6 ± 5.2
|0.72 ± 0.20
|0.51 ± 0.09 ∗
|0.43 ± 0.08 ∗
|Ventricular fractional area change (%)
|40.8 ± 8.3
|39.7 ± 8.5
|43.7 ± 6.8
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 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.
|Heart rate (beats/min)
|135 ± 9
|140 ± 9
|Reversal of IVC Doppler flow during atrial systole (%)
|11.3 ± 4.8
|6.2 ± 4.5
|Ductus venosus S/A ratio
|2.3 ± 0.9
|2.0 ± 0.6
|Umbilical artery pulsatility index
|1.25 ± 0.31
|1.14 ± 0.28
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.