Ultrasound Obstet Gynecol 2015; 45: 670–677 Published online 11 May 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.14736
Evaluation of right ventricular function in fetuses with hypoplastic left heart syndrome using tissue Doppler techniques R. AXT-FLIEDNER*, O. GRAUPNER*, A. KAWECKI*, J. DEGENHARDT*, J. HERRMANN†, A. TENZER*, A. DOELLE‡, A. WILLRUTH§, J. STEINHARD¶, U. GEMBRUCH*, F. BAHLMANN** and C. ENZENSBERGER*, on behalf of the Fetal Cardiac Imaging Research Group, Germany *Division of Prenatal Medicine, Department of Obstetrics & Gynecology, Justus-Liebig-University, Giessen, Germany; †IT Service Center, Statistical Consulting Service Unit, Justus-Liebig-University Giessen, Giessen, Germany; ‡Toshiba Medical Systems Europe BV, Zoetermeer, The Netherlands; §Department of Obstetrics and Prenatal Medicine, University of Bonn, Bonn, Germany; ¶Praxis Dr. Rosenberg, Dr. Steinhard und Kollegen, Munster, Germany; **Department of Obstetrics and Gynecology, Burgerhospital, Frankfurt, Germany ¨ ¨
K E Y W O R D S: cardiac function; fetus; hypoplastic left heart; TDI; tissue Doppler imaging
ABSTRACT Objective The outcome of patients with hypoplastic left heart syndrome (HLHS) is influenced by right ventricular function. This study aimed to investigate whether differences in right ventricular function of fetuses with HLHS are present during gestation. Methods This was a prospective study comprising 14 fetuses with HLHS (28 measurements obtained in total) and 28 normal control fetuses (31 measurements obtained in total). The two groups were matched for gestational age. Ultrasound M-mode was used to assess displacement of the tricuspid annulus. Spectral Doppler and myocardial tissue Doppler-derived inflow and outflow velocities were assessed. Tricuspid valve peak early wave to peak active wave (E/A) ratio, the early wave to early diastolic annular relaxation velocity (E/E ) ratio and the tissue Doppler-derived myocardial performance index (MPI ) were calculated. Results E-wave velocity was significantly higher in fetuses with HLHS than in control fetuses (mean, 40.14 cm/s vs 35.47 cm/s; P < 0.05, respectively), and A-wave velocity in fetuses with HLHS showed a tendency for higher values in the right ventricle compared with normal control fetuses, but this did not reach statistical significance (61.16 cm/s vs 54.64 cm/s; P = 0.08). The E/A ratio increased during gestation in controls, but this increase was not seen in HLHS fetuses. Peak annular velocity during atrial contraction (A ) and the E/E ratio were significantly lower in controls than in HLHS fetuses: 9.50 cm/s vs 10.39 cm/s (P < 0.05) and 5.77 vs 7.37 (P < 0.05), respectively. There
were no differences for right-ventricular MPI or tricuspid annular plane systolic excursion between HLHS fetuses and controls. Conclusion The results of this study show that altered right ventricular function in HLHS infants may develop antenatally. It is hoped that confirmation of these findings using Doppler-independent techniques will lead to further exploration of ventricular function in HLHS fetuses. Consequently, parental counseling and postnatal management strategies could be influenced. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
INTRODUCTION Hypoplastic left heart syndrome (HLHS), which is generally well tolerated in utero, is one of the most common forms of congenital heart disease (CHD) diagnosed in fetuses1,2 . Without postnatal treatment, this cardiac anomaly is almost certainly lethal because of the functionally hypoplastic left ventricle at birth, which is the hallmark of HLHS. Detection rates during fetal life may differ depending on the screening program established by healthcare providers. HLHS accounts for 4.8–9% of congenital heart anomalies among children3 – 6 . HLHS includes cardiac anomalies with hypoplasia or atresia of the mitral and/or aortic valve, leading to hypoplasia of the left ventricle7,8 . The consequence of this is the inability of the left ventricle to support the systemic circulation postnatally. Postnatal treatment strategies include compassionate care, hybrid procedure, single-ventricle palliation or heart
Correspondence to: Prof. R. Axt-Fliedner, Division of Prenatal Medicine, Department of Obstetrics & Gynecology, Justus-Liebig-University, Giessen, Germany (e-mail: [email protected]; [email protected]) Accepted: 17 November 2014
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
ORIGINAL PAPER
Right ventricular function in fetal HLHS transplantation. Increasing detection rates of CHD, along with earlier diagnosis and subsequent prenatal management, advances in perioperative care and surgical techniques, have led to a decrease in mortality rates of children with HLHS, such that the outlook for affected children has improved substantially9 – 12 . In a fetus with HLHS, the entire cardiac output depends on the right ventricle. In utero heart failure, hydrops fetalis and intrauterine fetal demise are rare findings in cases of HLHS and are found in some cases with severe tricuspid regurgitation13 . More recently, altered fetal cerebrovascular perfusion and developmental abnormalities of the central nervous system have been described in HLHS fetuses and it was postulated that, as a consequence, long-term neurological outcome would be impaired14 – 16 . In-utero investigation of right ventricular function in HLHS might offer new information on possible right ventricular myocardial alterations before postnatal circulatory changes or influences of surgical palliation are encountered. Recent data have shown that, in fetuses with HLHS, spectral Doppler-derived Tei indices from the right ventricle were elevated compared with fetuses with normal cardiac anatomy, reflecting right-ventricular dysfunction17,18 . Moreover cardiac output was reduced by 20% in fetuses with HLHS, and right ventricular ejection force was increased compared with fetuses with normal cardiac anatomy13 . These results point toward altered right ventricular performance in fetuses with HLHS. Calculation of myocardial velocities with low velocities and high amplitudes using tissue Doppler imaging (TDI) is based on frequency shifts of ultrasound waves, whereas conventional Doppler techniques are based on blood-flow analysis. TDI allows accurate and direct quantitative assessment of myocardial motion, and it has been postulated that TDI could constitute a more sensitive tool than standard methods to detect cardiac dysfunction19 – 21 . In this study, we used pulsed-wave (PW) Doppler interrogation to evaluate diastolic atrioventricular blood-flow velocities and PW-TDI to examine atrioventricular valve annulus displacement velocities for assessment of right ventricular myocardial function in fetuses with HLHS, compared with fetuses with normal cardiac anatomy.
METHODS This prospective study consisted of pregnant women referred for fetal echocardiography to the Fetal Heart Program at the Department of Fetal Diagnosis and Therapy, University of Giessen and Marburg, Germany, from 2011–2012. The study was approved by the Institutional Review Board (protocol number 209/11). The control group included fetuses with situs solitus, venoatrial, atrioventricular and ventriculoarterial concordance, normal-size ventricles and qualitatively normal cardiac function, normal fetoplacental function (defined as normal umbilical and uterine artery spectral Doppler waveforms according to gestational age) and absence of
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extracardiac abnormalities. The HLHS group included fetuses with severe mitral stenosis or atresia and/or severe aortic valve stenosis or atresia resulting in left-ventricular hypoplasia. All fetuses with HLHS demonstrated left-to-right shunting via the foramen ovale and retrograde aortic arch flow from the ductus arteriosus. Fetuses with further intracardiac abnormalities (venoatrial, atrioventricular or ventriculoarterial discordance, rhythm abnormalities, hydrops fetalis, evidence of atrial restriction or premature closure of the foramen ovale, as diagnosed by dilated pulmonary veins or pulsatile flow in the pulmonary veins on spectral Doppler and/or tricuspid valve regurgitation) were excluded. Exclusion criteria also included conditions with possible effects on fetal hemodynamics (e.g. maternal diabetes, pre-eclampsia, preterm labor or endocrinological disorders, such as thyroid disease). When available, fetuses with HLHS and normal controls were analyzed serially throughout gestation. For final analysis, a total of 14 HLHS fetuses and 28 control fetuses was included. Among the 14 HLHS fetuses, 28 examinations were performed, and, among the 28 controls, 31 examinations were performed. The two groups were matched for gestational age. In the HLHS group, six fetuses were examined once only, four underwent two examinations, two underwent three examinations and two underwent four examinations. Among the control group, three fetuses were examined twice and 25 underwent one examination only. According to Student’s t-test, both groups had a similar distribution of gestational age.
Fetal echocardiography Transabdominal echocardiograms were performed in a standardized manner, in transverse and longitudinal planes, using a Toshiba Aplio XG ultrasound system (Toshiba Medical Systems Corp., Otawara, Tochigi, Japan) with a 5-MHz transducer and equipped with tissue Doppler software. Sequential fetal echocardiography, as well as a complete fetal anomaly scan, using B-mode, color and spectral (pulsed and/or continuous wave) Doppler interrogation, were performed22 . The spatial peak temporal average power output for color and spectral Doppler was kept at < 100 mW/cm2 . All measurements were recorded digitally and stored as clips or stillframes on our archiving system (PIA fetal database). Doppler waveform analysis was performed offline with an average of three Doppler profiles of good quality to take into account beat-to-beat variation. All Doppler recordings were obtained at an insonation angle of < 10◦ and angle correction was not used. For PW Doppler of atrioventricular blood-flow velocities, the Doppler sample gate was located just below the tricuspid valve from an apical four-chamber view. PW-TDI was performed as described previously23 – 25 . From an apical or basal four-chamber view, the image was enlarged and the two-dimensional scan area reduced. A sample volume of 2–4 mm was placed just beneath the tricuspid valve annulus, into the right-ventricular free wall at a sweep speed of 100 mm/s. The insonation
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angle was < 10◦ and no angle correction was applied. The Nyquist limit was reduced to assess directly myocardial motion of low velocities, the wall filter was set to exclude high-frequency signals and the gain was reduced to depict a clear tissue signal with low background noise. M-mode was performed to assess displacement of the tricuspid annulus and the right ventricular free wall, from end diastole to end systole. The M-mode ultrasound beam was orientated perpendicular to the interventricular septum at the level of the tricuspid leaflets.
M-mode
Doppler-based tissue velocities and time intervals
For statistical analyses, SPSS for Mac OS 20.0 (IBM, Armonk, NY, USA) was used. To perform comparisons between groups, with adjustments for gestational age, either a general regression model or a random-intercept model was used. As some fetuses had multiple measurements, the independence of data was tested, performing a variance component analysis using the SPSS procedure MIXED (random-slopes model). Cardiac function parameters whose data were independent were analyzed using a general linear regression model (ANCOVA). If the analysis showed dependency of data, the parameters were analyzed using the SPSS procedure MIXED (random-intercept model). For both the linear regression model and the random-intercept model, gestational age was considered as a covariate. In addition, a linear regression analysis was performed to investigate possible changes of the Doppler-based tissue velocities and time intervals in the course of pregnancy in both the HLHS group and the control group. All values were considered significantly different at P < 0.05. Intraobserver and interobserver variability of the echocardiographic measurements were assessed in a subset of 20 echocardiograms from randomly selected control fetuses. Two operators analyzed the same images independently. The intraclass correlation coefficient (ICC) (two-way random, absolute agreement, single rater) was used to determine interobserver variability. Intraobserver variability was determined using Cronbach’s alpha. ICC or Cronbachs’s alpha values of 0.7–0.8 indicated
The averages of three cardiac cycles were analyzed offline. To evaluate the diastolic component of the cardiac cycle, inflow peak velocities and peak tissue diastolic annular relaxation velocities were assessed and ratios calculated. Tricuspid valve peak E (early or passive) wave and peak A (late or active) wave were measured and the E/A ratio was obtained. The peak myocardial velocities from the tricuspid valve annulus (peak E (early diastolic annular relaxation velocity), peak A (annular velocity during atrial contraction) and peak S (annular velocity during ventricular systole)) were assessed. Decreased peak S velocities are predictive of an increased afterload and decreased systolic performance26,27 . The E/E ratio, which corresponds to ventricular filling pressure, was calculated27 – 30 . The right-ventricular myocardial performance index (MPI), or Tei Index, is a marker of global, systolic and diastolic right myocardial function and provides information on the different time intervals during the systolic phase of the cardiac cycle. The MPI is calculated as the sum of the isovolumetric contraction time (ICT) and relaxation time (IRT), divided by the ejection time (ET), as described previously19 . We used PW-TDI to calculate the MPI (MPI ) because PW-TDI has a lower load dependency than do standard Doppler techniques21,31 . PW-TDI-based isovolumetric contraction time (ICT ), isovolumetric relaxation time (IRT ) and ejection time (ET ) were assessed. Controls: R2 Linear = 0.477 HLHS: R2 Linear = 0.025
(a) 60
Tricuspid annular plane systolic excursion (TAPSE) was obtained to quantify long-axis function of the right ventricle. This technique is suitable for examination of right-ventricular function because the deep right-ventricular muscle fibers are orientated longitudinally, as opposed to the predominantly circumferential orientation of the left-ventricular muscle fibers32 .
Statistical analysis
Controls: R2 Linear = 0.272 HLHS: R2 Linear = 0.025
(b)
1.25
40
30
PW-Doppler: E /A
PW-Doppler: A (cm/s)
PW-Doppler: E (cm/s)
100 50
Controls: R2 Linear = 0.191 HLHS: R2 Linear = 2.635E–4
(c)
80
60
1.00 0.75 0.50
40 0.25
20 20
25
30
35
Gestational age (weeks)
40
20
25
30
35
Gestational age (weeks)
40
20
25
30
35
40
Gestational age (weeks)
Figure 1 Impact of gestational age on right ventricular pulsed-wave (PW) Doppler evaluations of diastolic atrioventricular blood-flow velocities: early wave (E) (a), active wave (A) (b) and E/A ratio (c) in fetuses with hypoplastic left heart syndrome (HLHS; ) and in normal , controls) of individual measurements are shown. control fetuses ( ). Predicted 95% CI ( , HLHS fetuses;
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
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good agreement between measurements, and values > 0.8 indicated strong agreement. Finally, we tried to relate TDI indices to neonatal (umbilical cord arterial pH value and Apgar scores) and surgical (30-day postoperative survival) outcome of HLHS fetuses using Pearson’s correlation. All results are displayed in a descriptive manner because of the small number of cases.
(b)
9.0
PW-TDI: A' (cm/s)
PW-TDI: E' (cm/s)
8.0 7.0 6.0 5.0 4.0 3.0
Controls: R2 Linear = 0.115 HLHS: R2 Linear = 0.091
(c)
16.0 14.0 12.0 10.0 8.0
Controls: R2 Linear = 0.355 HLHS: R2 Linear = 0.301
10.0
8.0
6.0
4.0
6.0 20
(d)
Of the fetuses enrolled in the study between August 2012 and August 2013, 28 measurements of fetuses with HLHS and 31 measurements of healthy control fetuses were included. There was no significant difference in gestational age between the HLHS group and the control group. According to linear regression, PW-Doppler-based peak E- and A-wave velocities (R2 = 0.48 (P < 0.001) and
PW-TDI: S' (cm/s)
(a)
Controls: R2 Linear = 0.274 HLHS: R2 Linear = 0.011
RESULTS
35 25 30 Gestational age (weeks)
20
40
Controls: R2 Linear = 0.044 HLHS: R2 Linear = 4.409E–4
25 30 35 Gestational age (weeks)
40
20
Controls: R2 Linear = 0.004 HLHS: R2 Linear = 0.029
40
Controls: R2 Linear = 0.017 HLHS: R2 Linear = 0.035
(e)
20.0
35 25 30 Gestational age (weeks)
(f) 0.250
PW-TDI: ICT' (s)
PW-TDI: E/E'
15.0
10.0
5.0
PW-TDI: ET' (s)
0.08
0.06
0.04
0.225 0.200 0.175 0.150 0.125
0.02
0.0 20
25
30
35
20
40
Gestational age (weeks) (g) 0.12
25
Controls: R2 Linear = 1.142E– 4 HLHS: R2 Linear = 0.061
(h)
0.10
40
20
25
30
35
40
Gestational age (weeks)
Controls: R2 Linear = 1.649E– 6 HLHS: R2 Linear = 6.960E– 4
1.2 1.0
PW-TDI: MPI'
PW-TDI: IRT' (s)
35
30
Gestational age (weeks)
0.08 0.06 0.04
0.8 0.6 0.4
0.02
0.2
0.00
0.0 20
25
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35
Gestational age (weeks)
40
20
25
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35
40
Gestational age (weeks)
Figure 2 Impact of gestational age on right ventricular (RV) pulsed-wave tissue Doppler imaging (PW-TDI) evaluation of atrioventricular valve annulus displacement velocities: peak early diastolic annular relaxation velocity (E ) (a), peak annular velocity during atrial contraction (A ) (b) and ventricular systole (S ) (c), peak early wave (E) to E ratio (d), cardiac cycle time intervals: isovolumetric contraction time (ICT ) (e), ejection time (ET ) (f) and isovolumetric relaxation time (IRT ) (g) and myocardial performance index (MPI ) (h) for fetuses with , controls) of individual measurements hypoplastic left heart syndrome (HLHS; ) and controls ( ). Predicted 95% CI ( , HLHS fetuses; are shown.
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
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relationship of TDI indices to neonatal and surgical outcome are described in Table 3. In HLHS fetuses, ET was negatively correlated with pH values (r = −0.466; n = 11). A greater PW-TDI-acquired peak E velocity was positively correlated with pH value and Apgar scores. A higher E/E ratio was positively correlated with adverse surgical outcome (r = 0.247; n = 9). A lower PW-TDI-acquired peak A velocity correlated with positive surgical outcome (r = −0.378; n = 9).
Controls: R2 Linear = 0.299 HLHS: R2 Linear = 0.014 15.0
TAPSE (mm)
12.5
10.0
DISCUSSION
7.5
5.0
2.5 20
25
30
35
40
Gestational age (weeks)
Figure 3 Impact of gestational age on M-mode-derived tricuspid annular plane systolic excursion (TAPSE) in fetuses with hypoplastic left heart syndrome (HLHS) ( ) and controls ( ). , controls) of individual Predicted 95% CI ( , HLHS fetuses; measurements are shown. Predicted lower 95% CI for HLHS fetuses not shown.
R2 = 0.27 (P < 0.01), respectively) and PW-TDI-based S and E velocities (R2 = 0.36 (P < 0.01) and R2 = 0.27 (P < 0.01), respectively) increased over gestation in the control group (Figures 1 and 2); however, only PW-TDI S velocity increased over gestation in HLHS fetuses (R2 = 0.3; P < 0.01). The PW-Doppler E/A ratio increased over gestation in controls but this was not seen in HLHS fetuses (R2 = 0.19 (P < 0.05) and R2 = 0 (P = 0.94), respectively). No significant changes over gestation were observed for the right ventricular E/E ratio and MPI in both controls and HLHS fetuses (Figures 1 and 2). Values for TAPSE increased over gestation in controls but not in HLHS fetuses (R2 = 0.3 (P < 0.01) and R2 = 0.01 (P = 0.55), respectively; Figure 3). The PW-Doppler-obtained peak E-wave velocity was significantly lower in controls than in HLHS fetuses (P = 0.02; Table 1). PW-Doppler-obtained peak A-wave velocity and E/A ratio did not differ between the groups. PW-TDI-acquired peak A velocity was significantly lower in controls than in HLHS fetuses (P = 0.04; Table 1). There were no significant differences between controls and HLHS fetuses for peak S and E velocities, but the E/E ratio was significantly lower in controls than in HLHS fetuses (P = 0.04). The PW-TDI right-ventricular MPI and TAPSE values showed no significant differences between controls and HLHS fetuses. ICT (0.047 s vs 0.056 s), IRT (0.057 s vs 0.059 s) and ET (0.168 s vs 0.175 s) did not differ significantly between controls and HLHS fetuses. All echocardiographic measurements showed good interobserver and intraobserver reliability (Table 2). The
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
This study demonstrates that right ventricular diastolic function may be altered during gestation in fetuses with HLHS compared with controls. First, altered right ventricular diastolic function in HLHS fetuses might be reflected by the finding of higher spectral Doppler-derived tricuspid valve peak E-wave compared with that of normal controls. Spectral Doppler-derived tricuspid valve peak A-wave showed a tendency for higher values in the right ventricle of HLHS fetuses compared with normal controls, but this did not reach statistical significance. It may suggest a strong reliance of right ventricular filling on atrial contraction in HLHS fetuses. Second, neither tricuspid valve peak velocities nor the E/A ratio increased in HLHS fetuses with ongoing gestation, as observed in our study in normal controls and reported in the literature33,34 . The result of a fixed E/A ratio over gestation in HLHS fetuses in our study might be suggestive of impaired maturation of ventricular relaxation, which can be observed in normal fetuses. Data on changes in the E/A ratio in pathological fetal conditions are not consistent. A reduction of mitral and tricuspid E/A ratios has been shown in recipient twins in twin–twin transfusion syndrome (TTTS)35 . However, other studies have shown an increase in the E/A ratio in cardiovascular-compromised fetuses (e.g. intrauterine growth restriction (IUGR) and intrathoracic malformations with hydrops fetalis36,37 ). Third, this study demonstrates different tissue Doppler velocities in the right-ventricular free wall of normal controls and fetuses with HLHS, suggesting altered right-ventricular mechanics in fetuses with HLHS. A higher peak A velocity has been reported to be sensitive in the detection of atrial mechanical dysfunction38 . The E/E ratio has been evaluated in measuring atrial pressure and diastolic ventricular filling pressures in adulthood, and a higher E/E ratio was suggested to be a sensitive measure of diastolic dysfunction in fetuses with hydrops fetalis27,39 . In our study, the E/E ratio was elevated in HLHS fetuses, suggesting higher atrial filling pressures compared with controls. Over gestation, peak E velocities of the tricuspid valve annulus increased in controls but not in HLHS fetuses, suggesting altered maturation of diastolic function in fetuses with HLHS. The myocardial right-ventricular peak S velocity increased over gestation in both controls and HLHS fetuses, and the mean values for S velocities were not significantly different between the groups, presuming preserved systolic function of the right ventricle in fetuses with HLHS in our study.
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Table 1 Findings of tricuspid valve pulsed-wave (PW) Doppler and PW tissue Doppler imaging (TDI) examinations in fetuses with hypoplastic left heart syndrome (HLHS) and in healthy controls Parameter Gestational age (weeks) PW Doppler E (cm/s) A (cm/s) E/A ratio PW-TDI S (cm/s) E (cm/s) A (cm/s) ICT (s) ET (s) IRT (s) E/E ratio MPI M-mode TAPSE (mm)
HLHS
Control
P
31.6 ± 4.6 (28)
29.8 ± 4.6 (31)
0.15
40.14 ± 1.25 (24) 61.16 ± 2.75 (26) 0.69 ± 0.04 (24)
35.47 ± 1.36 (28) 54.64 ± 2.32 (28) 0.65 ± 0.02 (28)
0.02* 0.08 0.26
6.20 ± 0.2 (25) 5.98 ± 0.23 (26) 10.39 ± 0.31 (27) 0.056 ± 0.003 (28) 0.175 ± 0.005 (28) 0.059 ± 0.004 (27) 7.37 ± 0.71 (23) 0.69 ± 0.04 (26)
6.53 ± 0.19 (28) 6.09 ± 0.22 (29) 9.50 ± 0.29 (29) 0.047 ± 0.003 (27) 0.168 ± 0.005 (27) 0.057 ± 0.004 (27) 5.77 ± 0.25 (27) 0.63 ± 0.04 (27)
0.23 0.73 0.04* 0.053 0.32 0.73 0.04* 0.30
7.65 ± 0.58 (28)
7.88 ± 0.47 (30)
0.76
Data are given as mean ± SD (n) for gestational age and mean ± standard error (n) for all cardiac function parameters. Comparison of gestational age was performed using the Student’s t-test and cardiac function parameters using ANCOVA or MIXED random intercept model. *P < 0.05 was considered statistically significant. A, peak active (late) wave; A , peak annular velocity during atrial contraction; E, peak early (passive) wave; ET , ejection time; E , early diastolic annular relaxation velocity; ICT , isovolumetric contraction time; IRT , isovolumetric relaxation time; MPI , myocardial performance index; S , peak annular velocity during ventricular systole; TAPSE, tricuspid annular plane systolic excursion. Table 2 Interobserver and intraobserver variability of tricuspid valve echocardiographic measurements using pulsed-wave (PW) Doppler or PW tissue Doppler imaging (TDI) Agreement Echocardiographic parameter PW Doppler E A PW-TDI E A S ICT ET IRT
Interobserver*
Intraobserver†
0.979 0.979
0.995 0.962
0.994 0.981 0.999 0.822 0.740 0.775
0.998 0.994 0.997 0.778 0.830 0.824
*Intraclass correlation coefficient (ICC) (two-way-random, absolute agreement, single rater). †Cronbach’s alpha. ICC and Cronbach’s alpha values between 0.7 and 0.8 indicate good agreement between measurements and values > 0.8 indicate strong agreement. A, peak active (late) wave; A , peak annular velocity during atrial contraction; E, peak early (passive) wave; ET , ejection time; E , early diastolic annular relaxation velocity; ICT , isovolumetric contraction time; IRT , isovolumetric relaxation time; S , peak annular velocity during ventricular systole.
This is in line with the results of Brooks et al. but in contrast to the results of Natarjan et al., who found lower systolic myocardial velocities in the right ventricle of HLHS fetuses17,18 . Elevated MPI values have been reported in HLHS fetuses compared with controls and in other pathologic fetal conditions (e.g. TTTS, IUGR, inflammation, diabetes mellitus and hydrops fetalis40 – 42 ). The main parameter of the MPI that is altered in such conditions is the IRT. In our study, the MPI in HLHS fetuses showed a tendency for higher values in
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
the right ventricle compared with controls; however, this did not reach statistical significance. Similarly to other studies, we observed stable, slightly varying, MPI values over gestation, in both HLHS fetuses and controls40,43 . Natarajan et al. and Brooks et al. reported higher PW-Doppler-derived MPI values in HLHS fetuses compared with normal fetuses17,18 . Measuring MPI using this approach might be cumbersome for the right ventricle, requiring measurements in two different locations44 . We used the PW-TDI method for MPI measurement in the right ventricle, which can be performed within the same cardiac cycle, and there is a debate whether PW-TDI and PW-Doppler evaluation of MPI give the same results45 . No significant changes over gestation were found in ICT , IRT and ET among HLHS and control fetuses. It has been shown postnatally that the duration of systole is prolonged in HLHS patients46 . However, the physiological increase in postnatal preload, which increases the duration of systole, and in afterload, which prolongs IRT, might, in part, account for the difference seen among prenatal and postnatal findings47 . Values for TAPSE in HLHS did not increase over gestation compared with the increase seen in controls, further suggesting an altered long-axis function of the right ventricle in HLHS fetuses. In addition, altered tricuspid valve inflow velocities and right-ventricular myocardial tissue velocities, and the lack of increase in tricuspid inflow and myocardial velocities over gestation, point toward altered myocardial function in HLHS fetuses in the present study. Our relatively small sample size precluded subgroup analysis of ventricular function. Natarajan et al. showed
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Table 3 Correlation of right ventricular tissue Doppler imaging indices with neonatal and surgical outcomes of fetuses with hypoplastic left heart syndrome Outcome Umbilical cord blood pH value 1-min Apgar score 5-min Apgar score 10-min Apgar score Surgical outcome
ICT
ET
−0.209 (11) −0.466 (11) −0.151 (11) −0.208 (11) −0.182 (11) −0.438 (9)
0.053 (11) 0.110 (11) 0.241 (11) 0.369 (9)
IRT
E
0.429 (11)
0.456 (11)
0.076 (11) 0.003 (11) −0.161 (11) −0.464 (9)
0.280 (11) 0.301 (11) 0.235 (11) −0.072 (9)
A
S
MPI
E/E ratio
0.152 (10)
0.338 (11) −0.363 (10)
−0.041 (11) 0.143 (10) −0.096 (11) 0.258 (10) −0.275 (11) 0.403 (10) −0.378 (9) −0.307 (9)
−0.056 (11) −0.041 (10) −0.151 (11) −0.082 (10) −0.289 (11) −0.116 (10) −0.653 (9) 0.247 (9)
0.176 (11)
Data are given as point-biserial (Pearson’s) correlation coefficient (r) and number of cases (n). For surgical outcome, r = 1 indicates postoperative death and r = 0 indicates 30-day postoperative survival. A , peak annular velocity during atrial contraction; E, peak early (passive) wave; E , early diastolic annular relaxation velocity; ET , ejection time; ICT , isovolumetric contraction time; IRT , isovolumetric relaxation time; MPI , myocardial performance index; S , peak annular velocity during ventricular systole.
that HLHS with endocardial fibroelastosis, of the left ventricle in particular, negatively affects right ventricular myocardial function17 . Fetal cardiac function in HLHS has further been evaluated by two-dimensional speckle-tracking techniques, such as velocity vector imaging (VVI)18 . However, VVI techniques allow for endocardial or epicardial wall motion tracking only and not the whole myocardium, which might result in limited information on the whole myocardial mass18,45,46 . Another technical limitation of VVI is that, in the absence of fetal electrocardiography gating, data transfer is often only possible in standard archived digital imaging and communications in medicine (DICOM) format with 25–30 frames/s, which limits image frequencies that can be transferred from the ultrasound system to the storage system47,48 . There were limitations to our study. PW-TDI is a Doppler-based technique, displaying frequency shifts of low velocity and high intensity. Therefore, one main limitation is that PW-TDI does not allow multiple myocardial regions to be studied simultaneously. The relatively small sample size increased the risk for a Type 1 statistical error. Furthermore, there was substantial overlap of the examined parameter values among HLHS and normal fetuses, calling into question the clinical usefulness of the techniques applied. In conclusion, this study demonstrates that fetuses with HLHS present echocardiographic evidence of altered right ventricular diastolic properties compared with normal gestational-age-matched fetuses. Further investigation of fetal cardiac function using more sophisticated techniques (e.g. two-dimensional or three-dimensional speckle tracking49 ) might allow more precise assessment of functional outcome in single-ventricle hearts.
ACKNOWLEDGMENT This research study was funded in part by a grant from the German Society of Ultrasound in Medicine ¨ Ultraschall in der Medizin, (Deutsche Gesellschaft fur DEGUM) and technical support was provided by Toshiba Medical Systems Corporation, Otawara, Tochigi, Japan.
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
REFERENCES 1. Allan LD, Sharland GK, Milburn A, Lockhart SM, Groves AM, Anderson RH, Cokk AC, Nuala LK. Prospective diagnosis of 1,006 consecutive cases of congenital heart disease in the fetus. J Am Coll Cardiol 1994; 23: 1452–1458. 2. Hoffman JIE. Incidence of congenital heart disease: II. Prenatal incidence. Pediatr Cardiol 1995; 16: 155–165. 3. Hoffman JIE, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol 2002; 39: 1890–1900. 4. Ferencz C, Rubin JD, McCarter RJ, Brenner JI, Neill CA, Perry LW, Hepner SI, Downing JW. Congenital heart disease: prevalence at livebirth. The Baltimore-Washington infant study. Am J Epidemiol 1985; 121: 31–36. 5. Fyler DC, Buckley LP, Hellenbrand WE, Cohn HE. Report of the New England Regional Infant Cardiac Care Program. Pediatrics 1980; 65: 375–461. 6. Freedom RM. Atresia or hypoplasia of the left atrioventricular and/or ventriculoarterial junction. In Paediatric Cardiology, vol. 2, Anderson RH, McCartney FJ, Shinebourne EA, Tynan M (eds). Churchill Livingstone: Edinburgh, London, Melbourne, New York, 1987; 737–765. 7. Allan LD, Anderson RH, Cook AC. Atresia or absence of the left-sided atrioventricular connection in the fetus: echocardiographic diagnosis and outcome. Ultrasound Obstet Gynecol 1996; 8: 295–302. 8. Axt-Fliedner R, Enzensberger C, Fass N, Vogel M, Kawecki A, Weichert J, Kohl T, Gembruch U, Germer U, Krapp M, Degenhardt J. Fetal diagnosis of hypoplastic left heart, associations and outcomes in the current era. Ultraschall Med 2012; 33: E51–6. 9. Axt-Fliedner R, Kreiselmaier P, Schwarze A, Krapp M, Gembruch U. Development of hypoplastic left heart syndrome after diagnosis of aortic stenosis in the first trimester by early echocardiography. Ultrasound Obstet Gynecol 2006; 28: 106–109. 10. Enzensberger C, Vogel M, Degenhardt J, Fass N, Kawecki A, Kohl T, Widriani E, Axt-Fliedner R. Fetal pulmonary venous flow and restrictive foramen ovale in hypoplastic left heart. Ultraschall Med 2012; 33: E38–45. 11. Hartge DR, Weichert J, Krapp M, Germer U, Gembruch U, Axt-Fliedner R. Results of early foetal echocardiography and cumulative detection rate of congenital heart disease. Cardiol Young 2011; 21: 505–517. 12. Furck AK, Uebing A, Hansen JH, Scheewe J, Jung O, Fischer G, Rickers C, Holland-Letz T, Kramer HH. Outcome of the norwood operation in patients with hypoplastic left heart syndrome: a 12 year single-center survey. J Thorac Cardiovasc Surg 2010; 139: 359–365. 13. 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: 1214–1219. 14. Kaltman JR, Di H, Tian Z, Rychik J. Impact of congenital heart disease on cerebrovascular blood flow dynamics in the fetus. Ultrasound Obstet Gynecol 2005; 25: 32–36. 15. Donofrio MT, Bremer YA, Schieken RM, Gennings C, Morton LD, Eidem BW, Cetta F, Falkensammer CB, Huhta JC, Kleinman CS. Autoregulation of cerebral blood flow in the fetus with congential heart disease: the brain sparing effect. Pediatr Cardiol 2003; 24: 436–443. 16. Miller SP, McQuillen PS, Hamrick S, Xu D, Glidden DV, Charlton N, Karl T, Azakie A, Ferriero DM, Barkovich AJ, Vigneron DB. Abnormal brain development in newborns with congenital heart disease. N Engl J Med 2007; 357: 1928–1938. 17. Natarjan S, Szwast A, Tian Z, McCann M, Soffer D, Rychik J. Right ventricular mechanics in the fetus with hypoplastic left heart syndrome. J Am Soc Echocardiogr 2013; 26: 515–520. 18. Brooks PA, Khoo NS, Mackie AS, Hornberger LK. Right ventricular function in fetal hypoplastic left heart syndrome. J Am Soc Echocardiogr 2012; 25: 1068–1074. 19. 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: 169–178. 20. Comas M, Crispi F. Assessment of fetal cardiac function using tissue Doppler techniques. Fetal Diagn Ther 2012; 32: 30–38. 21. Godfrey ME, Messing B, Cohen SM, Valsky DV, Yagel S. Functional assessment of the fetal heart: a review. Ultrasound Obstet Gynecol 2012; 39: 131–144. 22. ISUOG Practice Guidelines (updated): sonographic screening examination of the fetal heart. International Society of Ultrasound in Obstetrics and Gynecology, Carvalho JS, Allan LD, Chaoui R, Copel JA, DeVore GR, Hecher K, Lee W, Munoz H, Paladini D, Tutschek B, Yagel S. Ultrasound Obstet Gynecol 2013; 41: 348–359.
Ultrasound Obstet Gynecol 2015; 45: 670–677.
Right ventricular function in fetal HLHS 23. Tutschek B, Zimmermann T, Buck T, Bender HG. Fetal tissue Doppler echocardiography: detection rates of cardiac structures and quantitative assessment of the fetal heart. Ultrasound Obstet Gynecol 2003; 21: 26–32. 24. Naujorks AA, Zielinsky P, Beltrame PA, Castagna RC, Petracco R, Busato A, Nicoloso AL, Piccoli A, Manica JL. Myocardial tissue Doppler assessment of diastolic function in the growth-restricted fetus. Ultrasound Obstet Gynecol 2009; 34: 68–73. 25. Comas M, Crispi F, Gomez O, Puerto B, Figueras F, Gratacos E. Gestational age- and estimated fetal weight-adjusted reference ranges for myocardial tissue Doppler indices at 24–41 weeks’ gestation. Ultrasound Obstet Gynecol 2011; 37: 57–64. 26. Park YS, Park JH, Ahn KT, Jang WI, Park HS, Kim JH, Lee JH, Choi SW, Jeong JO, Seong IW. Usefulness of mitral annular systolic velocity in the detection of left ventricular systolic dysfunction: comparison with three dimensional echocardiographic data. J Cardiovasc Ultrasound 2010; 18: 1–5. 27. Watanabe S, Hashimoto I, Saito K, Watanabe K, Hirono K, Uese K, Ichida F, Saito S, Miyawaki T, Niemann P, Sahn DJ. Characterization of ventricular myocardial performance in the fetus by tissue Doppler imaging. Circ J 2009; 73: 943–947. 28. Nagueh SF, Middleton KJ, Kopelen HA, Zoghbi WA, Quinones MA. Doppler tissue imaging: a non invasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol 1997; 30: 1527–1533. 29. Sohn DW, Chai IH, Lee DJ, Kim HC, Kim HS, Oh BH, Lee MM, Park YB, Choi YS, Seo JD, Lee YW. Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997; 30: 474–480. 30. Ommen SR, Nishimura RA, Appleton CP, Miller FA, Oh JK, Redfield MM, Tajik AJ. Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: a comparative simultaneous Doppler-cathererization study. Circulation 2000; 102: 1788–1794. 31. Comas M, Crispi F, Cruz-Martinez R, Martinez JM, Figueras F, Gratacos E. Usefulness of myocardial tissue Doppler vs conventional echocardiography in the evaluation of cardiac dysfunction in early-onset intrauterine growth restriction. Am J Obstet Gynecol 2010; 203: 45e41–47. 32. Carvalho JS, O´Sullivan C, Shinebourne EA, Henein MY. Right and left ventricular long-axis function in the fetus using angular M-Mode. Ultrasound Obstet Gynecol 2001; 18: 619–622. 33. Tulzer G, Khowsathit P, Gudmundsson S, Wood DC, Tian ZY, Schmitt K, Huhta JC. Diastolic function of the fetal heart during second and third trimester: a prospective longitudinal Doppler-echocardiographic study. Eur J Pediatr 1994; 153: 151–154. 34. Rizzo G, Arduini D, Romanini C. Doppler echocardiographic assessment of fetal cardiac function. Ultrasound Obstet Gynecol 1992; 2: 434–445. 35. Stirnemann JJ, Mougeot M, Proulx F, Nasr B, Essaoui M, Fouron JC, Ville Y. Profiling fetal cardiac function in twin-twin transfusion syndrome. Ultrasound Obstet Gynecol 2010; 35: 19–27.
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
677 36. Mahle WT, Rychik J, Tian ZY, Cohen MS, Howell LJ, Crombleholem TM, Flake AW, Adzick NS. Echocardiographic evaluation of the fetus with congenital cystic adenomatoid malformation. Ultasound Obstet Gynecol 2000; 16: 620–624. 37. Crispi F, Hernandez-Andrade E, Pelsers MM, Plasencia W, Benavives-Serralde JA, Eixarch E, LeNoble F, Ahmed A, Glatz JF, Nicolaides KH, Gratacos E. Cardiac dysfunction and cell damage across clinical stages of severity in growth-restricted fetuses. Am J Obstet Gynecol 2008; 199: 254.e1–8. 38. Yu CM, Fung JW, Zhang Q, Kum LC, Lin H, Yip GW, Wang M, Sanderson JE. Tissue Doppler echocardiographic evidence of atrial mechanical dysfunction in coronary artery disease. Int J Cardiol 2005; 105: 178–185. 39. Aoki M, Harada K, Ogawa M, Tanaka T. Quantitative assessment of right ventricular function using Doppler tissue imaging in fetuses with and without heart failure. J Am Soc Echocardiogr 2004; 17: 28–35. 40. Eidem BW, Edwards JM, Cetta F. Quantitative assessement of fetal ventricular function: establishing normal values of the myocardial perfromance index in the fetus. Echocardiography 2001; 18: 9–13. 41. Letti Muller AL, Barrios Pde M, Kliemann LM, Valerio EG, Gasnier R, Magalhaes JA. Tei Index to assess fetal cardiac performance in fetuses at risk for fetal inflammatory response syndrome. Ultrasound Obstet Gynecol 2010; 36: 26–31. 42. Szwast A, Tian Z, McCann M, Donaghue D, Bebbington M, Johnson M, Wislon RD, Rychik J. Impact of altered loading conditions on ventricular performance in fetuses with congential cystic adenomatoid malformation and twin-twin transfusion syndrome. Ultrasound Obstet Gynecol 2007; 30: 40–46. 43. Friedman D, Buyon J, Kim M, Glickstein JS. Fetal cardiac function assessed by Doppler myocardial performance index (Tei index). Ultrasound Obstet Gynecol 2003; 21: 33–36. 44. Hernandez-Andrade E, Benavides-Serralde JA, Cruz-Martinez R, Welsh A, Mancilla-Ramirez J. Evaluation of conventional Doppler fetal cardiac funtion parameters: E/A ratios, out flow tracts and myocardial performance index. Fetal Diagn Ther 2012; 32: 22–29. 45. Rojo EC, Rodrigo JL, Perez de Isla L, Almeria C, Gonzalo N, Aubele A, Cinza R, Zamorano J, Macaya C. Disagreement between tissue Doppler imaging and conventional pulsed wave Doppler in the measurement of myocardial performance index. Eur J Echocardiogr 2006; 7: 356–364. 46. 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: 749–755. 47. Goodlin RC, Girard J, Hollmann A. Systolic time intervals in the fetus and neonate. Obstet Gynecol 1972; 39: 295–303. 48. Germanakis I, Gardiner H. Assessment of fetal myocardial deformation using speckle tracking techniques. Fetal Diagn Ther 2012; 32: 39–46. 49. Enzensberger C, Degenhardt J, Tenzer A, Doelle A, Axt-Fliedner R. First experience with three-dimensional speckle tracking (3D Wall Motion Tracking) in fetal echocardiography. Ultraschall Med 2014; 35: 566–572.
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Evaluation of right ventricular function in fetuses with hypoplastic left heart syndrome using tissue Doppler techniques R. AXT-FLIEDNER*, O. GRAUPNER*, A. KAWECKI*, J. DEGENHARDT*, J. HERRMANN†, A. TENZER*, A. DOELLE‡, A. WILLRUTH§, J. STEINHARD¶, U. GEMBRUCH*, F. BAHLMANN** and C. ENZENSBERGER*, on behalf of the Fetal Cardiac Imaging Research Group, Germany *Division of Prenatal Medicine, Department of Obstetrics & Gynecology, Justus-Liebig-University, Giessen, Germany; †IT Service Center, Statistical Consulting Service Unit, Justus-Liebig-University Giessen, Giessen, Germany; ‡Toshiba Medical Systems Europe BV, Zoetermeer, The Netherlands; §Department of Obstetrics and Prenatal Medicine, University of Bonn, Bonn, Germany; ¶Praxis Dr. Rosenberg, Dr. Steinhard und Kollegen, Munster, Germany; **Department of Obstetrics and Gynecology, Burgerhospital, Frankfurt, Germany ¨ ¨
K E Y W O R D S: cardiac function; fetus; hypoplastic left heart; TDI; tissue Doppler imaging
ABSTRACT Objective The outcome of patients with hypoplastic left heart syndrome (HLHS) is influenced by right ventricular function. This study aimed to investigate whether differences in right ventricular function of fetuses with HLHS are present during gestation. Methods This was a prospective study comprising 14 fetuses with HLHS (28 measurements obtained in total) and 28 normal control fetuses (31 measurements obtained in total). The two groups were matched for gestational age. Ultrasound M-mode was used to assess displacement of the tricuspid annulus. Spectral Doppler and myocardial tissue Doppler-derived inflow and outflow velocities were assessed. Tricuspid valve peak early wave to peak active wave (E/A) ratio, the early wave to early diastolic annular relaxation velocity (E/E ) ratio and the tissue Doppler-derived myocardial performance index (MPI ) were calculated. Results E-wave velocity was significantly higher in fetuses with HLHS than in control fetuses (mean, 40.14 cm/s vs 35.47 cm/s; P < 0.05, respectively), and A-wave velocity in fetuses with HLHS showed a tendency for higher values in the right ventricle compared with normal control fetuses, but this did not reach statistical significance (61.16 cm/s vs 54.64 cm/s; P = 0.08). The E/A ratio increased during gestation in controls, but this increase was not seen in HLHS fetuses. Peak annular velocity during atrial contraction (A ) and the E/E ratio were significantly lower in controls than in HLHS fetuses: 9.50 cm/s vs 10.39 cm/s (P < 0.05) and 5.77 vs 7.37 (P < 0.05), respectively. There
were no differences for right-ventricular MPI or tricuspid annular plane systolic excursion between HLHS fetuses and controls. Conclusion The results of this study show that altered right ventricular function in HLHS infants may develop antenatally. It is hoped that confirmation of these findings using Doppler-independent techniques will lead to further exploration of ventricular function in HLHS fetuses. Consequently, parental counseling and postnatal management strategies could be influenced. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
INTRODUCTION Hypoplastic left heart syndrome (HLHS), which is generally well tolerated in utero, is one of the most common forms of congenital heart disease (CHD) diagnosed in fetuses1,2 . Without postnatal treatment, this cardiac anomaly is almost certainly lethal because of the functionally hypoplastic left ventricle at birth, which is the hallmark of HLHS. Detection rates during fetal life may differ depending on the screening program established by healthcare providers. HLHS accounts for 4.8–9% of congenital heart anomalies among children3 – 6 . HLHS includes cardiac anomalies with hypoplasia or atresia of the mitral and/or aortic valve, leading to hypoplasia of the left ventricle7,8 . The consequence of this is the inability of the left ventricle to support the systemic circulation postnatally. Postnatal treatment strategies include compassionate care, hybrid procedure, single-ventricle palliation or heart
Correspondence to: Prof. R. Axt-Fliedner, Division of Prenatal Medicine, Department of Obstetrics & Gynecology, Justus-Liebig-University, Giessen, Germany (e-mail: [email protected]; [email protected]) Accepted: 17 November 2014
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
ORIGINAL PAPER
Right ventricular function in fetal HLHS transplantation. Increasing detection rates of CHD, along with earlier diagnosis and subsequent prenatal management, advances in perioperative care and surgical techniques, have led to a decrease in mortality rates of children with HLHS, such that the outlook for affected children has improved substantially9 – 12 . In a fetus with HLHS, the entire cardiac output depends on the right ventricle. In utero heart failure, hydrops fetalis and intrauterine fetal demise are rare findings in cases of HLHS and are found in some cases with severe tricuspid regurgitation13 . More recently, altered fetal cerebrovascular perfusion and developmental abnormalities of the central nervous system have been described in HLHS fetuses and it was postulated that, as a consequence, long-term neurological outcome would be impaired14 – 16 . In-utero investigation of right ventricular function in HLHS might offer new information on possible right ventricular myocardial alterations before postnatal circulatory changes or influences of surgical palliation are encountered. Recent data have shown that, in fetuses with HLHS, spectral Doppler-derived Tei indices from the right ventricle were elevated compared with fetuses with normal cardiac anatomy, reflecting right-ventricular dysfunction17,18 . Moreover cardiac output was reduced by 20% in fetuses with HLHS, and right ventricular ejection force was increased compared with fetuses with normal cardiac anatomy13 . These results point toward altered right ventricular performance in fetuses with HLHS. Calculation of myocardial velocities with low velocities and high amplitudes using tissue Doppler imaging (TDI) is based on frequency shifts of ultrasound waves, whereas conventional Doppler techniques are based on blood-flow analysis. TDI allows accurate and direct quantitative assessment of myocardial motion, and it has been postulated that TDI could constitute a more sensitive tool than standard methods to detect cardiac dysfunction19 – 21 . In this study, we used pulsed-wave (PW) Doppler interrogation to evaluate diastolic atrioventricular blood-flow velocities and PW-TDI to examine atrioventricular valve annulus displacement velocities for assessment of right ventricular myocardial function in fetuses with HLHS, compared with fetuses with normal cardiac anatomy.
METHODS This prospective study consisted of pregnant women referred for fetal echocardiography to the Fetal Heart Program at the Department of Fetal Diagnosis and Therapy, University of Giessen and Marburg, Germany, from 2011–2012. The study was approved by the Institutional Review Board (protocol number 209/11). The control group included fetuses with situs solitus, venoatrial, atrioventricular and ventriculoarterial concordance, normal-size ventricles and qualitatively normal cardiac function, normal fetoplacental function (defined as normal umbilical and uterine artery spectral Doppler waveforms according to gestational age) and absence of
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extracardiac abnormalities. The HLHS group included fetuses with severe mitral stenosis or atresia and/or severe aortic valve stenosis or atresia resulting in left-ventricular hypoplasia. All fetuses with HLHS demonstrated left-to-right shunting via the foramen ovale and retrograde aortic arch flow from the ductus arteriosus. Fetuses with further intracardiac abnormalities (venoatrial, atrioventricular or ventriculoarterial discordance, rhythm abnormalities, hydrops fetalis, evidence of atrial restriction or premature closure of the foramen ovale, as diagnosed by dilated pulmonary veins or pulsatile flow in the pulmonary veins on spectral Doppler and/or tricuspid valve regurgitation) were excluded. Exclusion criteria also included conditions with possible effects on fetal hemodynamics (e.g. maternal diabetes, pre-eclampsia, preterm labor or endocrinological disorders, such as thyroid disease). When available, fetuses with HLHS and normal controls were analyzed serially throughout gestation. For final analysis, a total of 14 HLHS fetuses and 28 control fetuses was included. Among the 14 HLHS fetuses, 28 examinations were performed, and, among the 28 controls, 31 examinations were performed. The two groups were matched for gestational age. In the HLHS group, six fetuses were examined once only, four underwent two examinations, two underwent three examinations and two underwent four examinations. Among the control group, three fetuses were examined twice and 25 underwent one examination only. According to Student’s t-test, both groups had a similar distribution of gestational age.
Fetal echocardiography Transabdominal echocardiograms were performed in a standardized manner, in transverse and longitudinal planes, using a Toshiba Aplio XG ultrasound system (Toshiba Medical Systems Corp., Otawara, Tochigi, Japan) with a 5-MHz transducer and equipped with tissue Doppler software. Sequential fetal echocardiography, as well as a complete fetal anomaly scan, using B-mode, color and spectral (pulsed and/or continuous wave) Doppler interrogation, were performed22 . The spatial peak temporal average power output for color and spectral Doppler was kept at < 100 mW/cm2 . All measurements were recorded digitally and stored as clips or stillframes on our archiving system (PIA fetal database). Doppler waveform analysis was performed offline with an average of three Doppler profiles of good quality to take into account beat-to-beat variation. All Doppler recordings were obtained at an insonation angle of < 10◦ and angle correction was not used. For PW Doppler of atrioventricular blood-flow velocities, the Doppler sample gate was located just below the tricuspid valve from an apical four-chamber view. PW-TDI was performed as described previously23 – 25 . From an apical or basal four-chamber view, the image was enlarged and the two-dimensional scan area reduced. A sample volume of 2–4 mm was placed just beneath the tricuspid valve annulus, into the right-ventricular free wall at a sweep speed of 100 mm/s. The insonation
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angle was < 10◦ and no angle correction was applied. The Nyquist limit was reduced to assess directly myocardial motion of low velocities, the wall filter was set to exclude high-frequency signals and the gain was reduced to depict a clear tissue signal with low background noise. M-mode was performed to assess displacement of the tricuspid annulus and the right ventricular free wall, from end diastole to end systole. The M-mode ultrasound beam was orientated perpendicular to the interventricular septum at the level of the tricuspid leaflets.
M-mode
Doppler-based tissue velocities and time intervals
For statistical analyses, SPSS for Mac OS 20.0 (IBM, Armonk, NY, USA) was used. To perform comparisons between groups, with adjustments for gestational age, either a general regression model or a random-intercept model was used. As some fetuses had multiple measurements, the independence of data was tested, performing a variance component analysis using the SPSS procedure MIXED (random-slopes model). Cardiac function parameters whose data were independent were analyzed using a general linear regression model (ANCOVA). If the analysis showed dependency of data, the parameters were analyzed using the SPSS procedure MIXED (random-intercept model). For both the linear regression model and the random-intercept model, gestational age was considered as a covariate. In addition, a linear regression analysis was performed to investigate possible changes of the Doppler-based tissue velocities and time intervals in the course of pregnancy in both the HLHS group and the control group. All values were considered significantly different at P < 0.05. Intraobserver and interobserver variability of the echocardiographic measurements were assessed in a subset of 20 echocardiograms from randomly selected control fetuses. Two operators analyzed the same images independently. The intraclass correlation coefficient (ICC) (two-way random, absolute agreement, single rater) was used to determine interobserver variability. Intraobserver variability was determined using Cronbach’s alpha. ICC or Cronbachs’s alpha values of 0.7–0.8 indicated
The averages of three cardiac cycles were analyzed offline. To evaluate the diastolic component of the cardiac cycle, inflow peak velocities and peak tissue diastolic annular relaxation velocities were assessed and ratios calculated. Tricuspid valve peak E (early or passive) wave and peak A (late or active) wave were measured and the E/A ratio was obtained. The peak myocardial velocities from the tricuspid valve annulus (peak E (early diastolic annular relaxation velocity), peak A (annular velocity during atrial contraction) and peak S (annular velocity during ventricular systole)) were assessed. Decreased peak S velocities are predictive of an increased afterload and decreased systolic performance26,27 . The E/E ratio, which corresponds to ventricular filling pressure, was calculated27 – 30 . The right-ventricular myocardial performance index (MPI), or Tei Index, is a marker of global, systolic and diastolic right myocardial function and provides information on the different time intervals during the systolic phase of the cardiac cycle. The MPI is calculated as the sum of the isovolumetric contraction time (ICT) and relaxation time (IRT), divided by the ejection time (ET), as described previously19 . We used PW-TDI to calculate the MPI (MPI ) because PW-TDI has a lower load dependency than do standard Doppler techniques21,31 . PW-TDI-based isovolumetric contraction time (ICT ), isovolumetric relaxation time (IRT ) and ejection time (ET ) were assessed. Controls: R2 Linear = 0.477 HLHS: R2 Linear = 0.025
(a) 60
Tricuspid annular plane systolic excursion (TAPSE) was obtained to quantify long-axis function of the right ventricle. This technique is suitable for examination of right-ventricular function because the deep right-ventricular muscle fibers are orientated longitudinally, as opposed to the predominantly circumferential orientation of the left-ventricular muscle fibers32 .
Statistical analysis
Controls: R2 Linear = 0.272 HLHS: R2 Linear = 0.025
(b)
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Figure 1 Impact of gestational age on right ventricular pulsed-wave (PW) Doppler evaluations of diastolic atrioventricular blood-flow velocities: early wave (E) (a), active wave (A) (b) and E/A ratio (c) in fetuses with hypoplastic left heart syndrome (HLHS; ) and in normal , controls) of individual measurements are shown. control fetuses ( ). Predicted 95% CI ( , HLHS fetuses;
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
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good agreement between measurements, and values > 0.8 indicated strong agreement. Finally, we tried to relate TDI indices to neonatal (umbilical cord arterial pH value and Apgar scores) and surgical (30-day postoperative survival) outcome of HLHS fetuses using Pearson’s correlation. All results are displayed in a descriptive manner because of the small number of cases.
(b)
9.0
PW-TDI: A' (cm/s)
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8.0 7.0 6.0 5.0 4.0 3.0
Controls: R2 Linear = 0.115 HLHS: R2 Linear = 0.091
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Controls: R2 Linear = 0.355 HLHS: R2 Linear = 0.301
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Of the fetuses enrolled in the study between August 2012 and August 2013, 28 measurements of fetuses with HLHS and 31 measurements of healthy control fetuses were included. There was no significant difference in gestational age between the HLHS group and the control group. According to linear regression, PW-Doppler-based peak E- and A-wave velocities (R2 = 0.48 (P < 0.001) and
PW-TDI: S' (cm/s)
(a)
Controls: R2 Linear = 0.274 HLHS: R2 Linear = 0.011
RESULTS
35 25 30 Gestational age (weeks)
20
40
Controls: R2 Linear = 0.044 HLHS: R2 Linear = 4.409E–4
25 30 35 Gestational age (weeks)
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Controls: R2 Linear = 0.004 HLHS: R2 Linear = 0.029
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Controls: R2 Linear = 0.017 HLHS: R2 Linear = 0.035
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Controls: R2 Linear = 1.142E– 4 HLHS: R2 Linear = 0.061
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Controls: R2 Linear = 1.649E– 6 HLHS: R2 Linear = 6.960E– 4
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40
Gestational age (weeks)
Figure 2 Impact of gestational age on right ventricular (RV) pulsed-wave tissue Doppler imaging (PW-TDI) evaluation of atrioventricular valve annulus displacement velocities: peak early diastolic annular relaxation velocity (E ) (a), peak annular velocity during atrial contraction (A ) (b) and ventricular systole (S ) (c), peak early wave (E) to E ratio (d), cardiac cycle time intervals: isovolumetric contraction time (ICT ) (e), ejection time (ET ) (f) and isovolumetric relaxation time (IRT ) (g) and myocardial performance index (MPI ) (h) for fetuses with , controls) of individual measurements hypoplastic left heart syndrome (HLHS; ) and controls ( ). Predicted 95% CI ( , HLHS fetuses; are shown.
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relationship of TDI indices to neonatal and surgical outcome are described in Table 3. In HLHS fetuses, ET was negatively correlated with pH values (r = −0.466; n = 11). A greater PW-TDI-acquired peak E velocity was positively correlated with pH value and Apgar scores. A higher E/E ratio was positively correlated with adverse surgical outcome (r = 0.247; n = 9). A lower PW-TDI-acquired peak A velocity correlated with positive surgical outcome (r = −0.378; n = 9).
Controls: R2 Linear = 0.299 HLHS: R2 Linear = 0.014 15.0
TAPSE (mm)
12.5
10.0
DISCUSSION
7.5
5.0
2.5 20
25
30
35
40
Gestational age (weeks)
Figure 3 Impact of gestational age on M-mode-derived tricuspid annular plane systolic excursion (TAPSE) in fetuses with hypoplastic left heart syndrome (HLHS) ( ) and controls ( ). , controls) of individual Predicted 95% CI ( , HLHS fetuses; measurements are shown. Predicted lower 95% CI for HLHS fetuses not shown.
R2 = 0.27 (P < 0.01), respectively) and PW-TDI-based S and E velocities (R2 = 0.36 (P < 0.01) and R2 = 0.27 (P < 0.01), respectively) increased over gestation in the control group (Figures 1 and 2); however, only PW-TDI S velocity increased over gestation in HLHS fetuses (R2 = 0.3; P < 0.01). The PW-Doppler E/A ratio increased over gestation in controls but this was not seen in HLHS fetuses (R2 = 0.19 (P < 0.05) and R2 = 0 (P = 0.94), respectively). No significant changes over gestation were observed for the right ventricular E/E ratio and MPI in both controls and HLHS fetuses (Figures 1 and 2). Values for TAPSE increased over gestation in controls but not in HLHS fetuses (R2 = 0.3 (P < 0.01) and R2 = 0.01 (P = 0.55), respectively; Figure 3). The PW-Doppler-obtained peak E-wave velocity was significantly lower in controls than in HLHS fetuses (P = 0.02; Table 1). PW-Doppler-obtained peak A-wave velocity and E/A ratio did not differ between the groups. PW-TDI-acquired peak A velocity was significantly lower in controls than in HLHS fetuses (P = 0.04; Table 1). There were no significant differences between controls and HLHS fetuses for peak S and E velocities, but the E/E ratio was significantly lower in controls than in HLHS fetuses (P = 0.04). The PW-TDI right-ventricular MPI and TAPSE values showed no significant differences between controls and HLHS fetuses. ICT (0.047 s vs 0.056 s), IRT (0.057 s vs 0.059 s) and ET (0.168 s vs 0.175 s) did not differ significantly between controls and HLHS fetuses. All echocardiographic measurements showed good interobserver and intraobserver reliability (Table 2). The
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
This study demonstrates that right ventricular diastolic function may be altered during gestation in fetuses with HLHS compared with controls. First, altered right ventricular diastolic function in HLHS fetuses might be reflected by the finding of higher spectral Doppler-derived tricuspid valve peak E-wave compared with that of normal controls. Spectral Doppler-derived tricuspid valve peak A-wave showed a tendency for higher values in the right ventricle of HLHS fetuses compared with normal controls, but this did not reach statistical significance. It may suggest a strong reliance of right ventricular filling on atrial contraction in HLHS fetuses. Second, neither tricuspid valve peak velocities nor the E/A ratio increased in HLHS fetuses with ongoing gestation, as observed in our study in normal controls and reported in the literature33,34 . The result of a fixed E/A ratio over gestation in HLHS fetuses in our study might be suggestive of impaired maturation of ventricular relaxation, which can be observed in normal fetuses. Data on changes in the E/A ratio in pathological fetal conditions are not consistent. A reduction of mitral and tricuspid E/A ratios has been shown in recipient twins in twin–twin transfusion syndrome (TTTS)35 . However, other studies have shown an increase in the E/A ratio in cardiovascular-compromised fetuses (e.g. intrauterine growth restriction (IUGR) and intrathoracic malformations with hydrops fetalis36,37 ). Third, this study demonstrates different tissue Doppler velocities in the right-ventricular free wall of normal controls and fetuses with HLHS, suggesting altered right-ventricular mechanics in fetuses with HLHS. A higher peak A velocity has been reported to be sensitive in the detection of atrial mechanical dysfunction38 . The E/E ratio has been evaluated in measuring atrial pressure and diastolic ventricular filling pressures in adulthood, and a higher E/E ratio was suggested to be a sensitive measure of diastolic dysfunction in fetuses with hydrops fetalis27,39 . In our study, the E/E ratio was elevated in HLHS fetuses, suggesting higher atrial filling pressures compared with controls. Over gestation, peak E velocities of the tricuspid valve annulus increased in controls but not in HLHS fetuses, suggesting altered maturation of diastolic function in fetuses with HLHS. The myocardial right-ventricular peak S velocity increased over gestation in both controls and HLHS fetuses, and the mean values for S velocities were not significantly different between the groups, presuming preserved systolic function of the right ventricle in fetuses with HLHS in our study.
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Table 1 Findings of tricuspid valve pulsed-wave (PW) Doppler and PW tissue Doppler imaging (TDI) examinations in fetuses with hypoplastic left heart syndrome (HLHS) and in healthy controls Parameter Gestational age (weeks) PW Doppler E (cm/s) A (cm/s) E/A ratio PW-TDI S (cm/s) E (cm/s) A (cm/s) ICT (s) ET (s) IRT (s) E/E ratio MPI M-mode TAPSE (mm)
HLHS
Control
P
31.6 ± 4.6 (28)
29.8 ± 4.6 (31)
0.15
40.14 ± 1.25 (24) 61.16 ± 2.75 (26) 0.69 ± 0.04 (24)
35.47 ± 1.36 (28) 54.64 ± 2.32 (28) 0.65 ± 0.02 (28)
0.02* 0.08 0.26
6.20 ± 0.2 (25) 5.98 ± 0.23 (26) 10.39 ± 0.31 (27) 0.056 ± 0.003 (28) 0.175 ± 0.005 (28) 0.059 ± 0.004 (27) 7.37 ± 0.71 (23) 0.69 ± 0.04 (26)
6.53 ± 0.19 (28) 6.09 ± 0.22 (29) 9.50 ± 0.29 (29) 0.047 ± 0.003 (27) 0.168 ± 0.005 (27) 0.057 ± 0.004 (27) 5.77 ± 0.25 (27) 0.63 ± 0.04 (27)
0.23 0.73 0.04* 0.053 0.32 0.73 0.04* 0.30
7.65 ± 0.58 (28)
7.88 ± 0.47 (30)
0.76
Data are given as mean ± SD (n) for gestational age and mean ± standard error (n) for all cardiac function parameters. Comparison of gestational age was performed using the Student’s t-test and cardiac function parameters using ANCOVA or MIXED random intercept model. *P < 0.05 was considered statistically significant. A, peak active (late) wave; A , peak annular velocity during atrial contraction; E, peak early (passive) wave; ET , ejection time; E , early diastolic annular relaxation velocity; ICT , isovolumetric contraction time; IRT , isovolumetric relaxation time; MPI , myocardial performance index; S , peak annular velocity during ventricular systole; TAPSE, tricuspid annular plane systolic excursion. Table 2 Interobserver and intraobserver variability of tricuspid valve echocardiographic measurements using pulsed-wave (PW) Doppler or PW tissue Doppler imaging (TDI) Agreement Echocardiographic parameter PW Doppler E A PW-TDI E A S ICT ET IRT
Interobserver*
Intraobserver†
0.979 0.979
0.995 0.962
0.994 0.981 0.999 0.822 0.740 0.775
0.998 0.994 0.997 0.778 0.830 0.824
*Intraclass correlation coefficient (ICC) (two-way-random, absolute agreement, single rater). †Cronbach’s alpha. ICC and Cronbach’s alpha values between 0.7 and 0.8 indicate good agreement between measurements and values > 0.8 indicate strong agreement. A, peak active (late) wave; A , peak annular velocity during atrial contraction; E, peak early (passive) wave; ET , ejection time; E , early diastolic annular relaxation velocity; ICT , isovolumetric contraction time; IRT , isovolumetric relaxation time; S , peak annular velocity during ventricular systole.
This is in line with the results of Brooks et al. but in contrast to the results of Natarjan et al., who found lower systolic myocardial velocities in the right ventricle of HLHS fetuses17,18 . Elevated MPI values have been reported in HLHS fetuses compared with controls and in other pathologic fetal conditions (e.g. TTTS, IUGR, inflammation, diabetes mellitus and hydrops fetalis40 – 42 ). The main parameter of the MPI that is altered in such conditions is the IRT. In our study, the MPI in HLHS fetuses showed a tendency for higher values in
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
the right ventricle compared with controls; however, this did not reach statistical significance. Similarly to other studies, we observed stable, slightly varying, MPI values over gestation, in both HLHS fetuses and controls40,43 . Natarajan et al. and Brooks et al. reported higher PW-Doppler-derived MPI values in HLHS fetuses compared with normal fetuses17,18 . Measuring MPI using this approach might be cumbersome for the right ventricle, requiring measurements in two different locations44 . We used the PW-TDI method for MPI measurement in the right ventricle, which can be performed within the same cardiac cycle, and there is a debate whether PW-TDI and PW-Doppler evaluation of MPI give the same results45 . No significant changes over gestation were found in ICT , IRT and ET among HLHS and control fetuses. It has been shown postnatally that the duration of systole is prolonged in HLHS patients46 . However, the physiological increase in postnatal preload, which increases the duration of systole, and in afterload, which prolongs IRT, might, in part, account for the difference seen among prenatal and postnatal findings47 . Values for TAPSE in HLHS did not increase over gestation compared with the increase seen in controls, further suggesting an altered long-axis function of the right ventricle in HLHS fetuses. In addition, altered tricuspid valve inflow velocities and right-ventricular myocardial tissue velocities, and the lack of increase in tricuspid inflow and myocardial velocities over gestation, point toward altered myocardial function in HLHS fetuses in the present study. Our relatively small sample size precluded subgroup analysis of ventricular function. Natarajan et al. showed
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Table 3 Correlation of right ventricular tissue Doppler imaging indices with neonatal and surgical outcomes of fetuses with hypoplastic left heart syndrome Outcome Umbilical cord blood pH value 1-min Apgar score 5-min Apgar score 10-min Apgar score Surgical outcome
ICT
ET
−0.209 (11) −0.466 (11) −0.151 (11) −0.208 (11) −0.182 (11) −0.438 (9)
0.053 (11) 0.110 (11) 0.241 (11) 0.369 (9)
IRT
E
0.429 (11)
0.456 (11)
0.076 (11) 0.003 (11) −0.161 (11) −0.464 (9)
0.280 (11) 0.301 (11) 0.235 (11) −0.072 (9)
A
S
MPI
E/E ratio
0.152 (10)
0.338 (11) −0.363 (10)
−0.041 (11) 0.143 (10) −0.096 (11) 0.258 (10) −0.275 (11) 0.403 (10) −0.378 (9) −0.307 (9)
−0.056 (11) −0.041 (10) −0.151 (11) −0.082 (10) −0.289 (11) −0.116 (10) −0.653 (9) 0.247 (9)
0.176 (11)
Data are given as point-biserial (Pearson’s) correlation coefficient (r) and number of cases (n). For surgical outcome, r = 1 indicates postoperative death and r = 0 indicates 30-day postoperative survival. A , peak annular velocity during atrial contraction; E, peak early (passive) wave; E , early diastolic annular relaxation velocity; ET , ejection time; ICT , isovolumetric contraction time; IRT , isovolumetric relaxation time; MPI , myocardial performance index; S , peak annular velocity during ventricular systole.
that HLHS with endocardial fibroelastosis, of the left ventricle in particular, negatively affects right ventricular myocardial function17 . Fetal cardiac function in HLHS has further been evaluated by two-dimensional speckle-tracking techniques, such as velocity vector imaging (VVI)18 . However, VVI techniques allow for endocardial or epicardial wall motion tracking only and not the whole myocardium, which might result in limited information on the whole myocardial mass18,45,46 . Another technical limitation of VVI is that, in the absence of fetal electrocardiography gating, data transfer is often only possible in standard archived digital imaging and communications in medicine (DICOM) format with 25–30 frames/s, which limits image frequencies that can be transferred from the ultrasound system to the storage system47,48 . There were limitations to our study. PW-TDI is a Doppler-based technique, displaying frequency shifts of low velocity and high intensity. Therefore, one main limitation is that PW-TDI does not allow multiple myocardial regions to be studied simultaneously. The relatively small sample size increased the risk for a Type 1 statistical error. Furthermore, there was substantial overlap of the examined parameter values among HLHS and normal fetuses, calling into question the clinical usefulness of the techniques applied. In conclusion, this study demonstrates that fetuses with HLHS present echocardiographic evidence of altered right ventricular diastolic properties compared with normal gestational-age-matched fetuses. Further investigation of fetal cardiac function using more sophisticated techniques (e.g. two-dimensional or three-dimensional speckle tracking49 ) might allow more precise assessment of functional outcome in single-ventricle hearts.
ACKNOWLEDGMENT This research study was funded in part by a grant from the German Society of Ultrasound in Medicine ¨ Ultraschall in der Medizin, (Deutsche Gesellschaft fur DEGUM) and technical support was provided by Toshiba Medical Systems Corporation, Otawara, Tochigi, Japan.
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REFERENCES 1. Allan LD, Sharland GK, Milburn A, Lockhart SM, Groves AM, Anderson RH, Cokk AC, Nuala LK. Prospective diagnosis of 1,006 consecutive cases of congenital heart disease in the fetus. J Am Coll Cardiol 1994; 23: 1452–1458. 2. Hoffman JIE. Incidence of congenital heart disease: II. Prenatal incidence. Pediatr Cardiol 1995; 16: 155–165. 3. Hoffman JIE, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol 2002; 39: 1890–1900. 4. Ferencz C, Rubin JD, McCarter RJ, Brenner JI, Neill CA, Perry LW, Hepner SI, Downing JW. Congenital heart disease: prevalence at livebirth. The Baltimore-Washington infant study. Am J Epidemiol 1985; 121: 31–36. 5. Fyler DC, Buckley LP, Hellenbrand WE, Cohn HE. Report of the New England Regional Infant Cardiac Care Program. Pediatrics 1980; 65: 375–461. 6. Freedom RM. Atresia or hypoplasia of the left atrioventricular and/or ventriculoarterial junction. In Paediatric Cardiology, vol. 2, Anderson RH, McCartney FJ, Shinebourne EA, Tynan M (eds). Churchill Livingstone: Edinburgh, London, Melbourne, New York, 1987; 737–765. 7. Allan LD, Anderson RH, Cook AC. Atresia or absence of the left-sided atrioventricular connection in the fetus: echocardiographic diagnosis and outcome. Ultrasound Obstet Gynecol 1996; 8: 295–302. 8. Axt-Fliedner R, Enzensberger C, Fass N, Vogel M, Kawecki A, Weichert J, Kohl T, Gembruch U, Germer U, Krapp M, Degenhardt J. Fetal diagnosis of hypoplastic left heart, associations and outcomes in the current era. Ultraschall Med 2012; 33: E51–6. 9. Axt-Fliedner R, Kreiselmaier P, Schwarze A, Krapp M, Gembruch U. Development of hypoplastic left heart syndrome after diagnosis of aortic stenosis in the first trimester by early echocardiography. Ultrasound Obstet Gynecol 2006; 28: 106–109. 10. Enzensberger C, Vogel M, Degenhardt J, Fass N, Kawecki A, Kohl T, Widriani E, Axt-Fliedner R. Fetal pulmonary venous flow and restrictive foramen ovale in hypoplastic left heart. Ultraschall Med 2012; 33: E38–45. 11. Hartge DR, Weichert J, Krapp M, Germer U, Gembruch U, Axt-Fliedner R. Results of early foetal echocardiography and cumulative detection rate of congenital heart disease. Cardiol Young 2011; 21: 505–517. 12. Furck AK, Uebing A, Hansen JH, Scheewe J, Jung O, Fischer G, Rickers C, Holland-Letz T, Kramer HH. Outcome of the norwood operation in patients with hypoplastic left heart syndrome: a 12 year single-center survey. J Thorac Cardiovasc Surg 2010; 139: 359–365. 13. 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: 1214–1219. 14. Kaltman JR, Di H, Tian Z, Rychik J. Impact of congenital heart disease on cerebrovascular blood flow dynamics in the fetus. Ultrasound Obstet Gynecol 2005; 25: 32–36. 15. Donofrio MT, Bremer YA, Schieken RM, Gennings C, Morton LD, Eidem BW, Cetta F, Falkensammer CB, Huhta JC, Kleinman CS. Autoregulation of cerebral blood flow in the fetus with congential heart disease: the brain sparing effect. Pediatr Cardiol 2003; 24: 436–443. 16. Miller SP, McQuillen PS, Hamrick S, Xu D, Glidden DV, Charlton N, Karl T, Azakie A, Ferriero DM, Barkovich AJ, Vigneron DB. Abnormal brain development in newborns with congenital heart disease. N Engl J Med 2007; 357: 1928–1938. 17. Natarjan S, Szwast A, Tian Z, McCann M, Soffer D, Rychik J. Right ventricular mechanics in the fetus with hypoplastic left heart syndrome. J Am Soc Echocardiogr 2013; 26: 515–520. 18. Brooks PA, Khoo NS, Mackie AS, Hornberger LK. Right ventricular function in fetal hypoplastic left heart syndrome. J Am Soc Echocardiogr 2012; 25: 1068–1074. 19. 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: 169–178. 20. Comas M, Crispi F. Assessment of fetal cardiac function using tissue Doppler techniques. Fetal Diagn Ther 2012; 32: 30–38. 21. Godfrey ME, Messing B, Cohen SM, Valsky DV, Yagel S. Functional assessment of the fetal heart: a review. Ultrasound Obstet Gynecol 2012; 39: 131–144. 22. ISUOG Practice Guidelines (updated): sonographic screening examination of the fetal heart. International Society of Ultrasound in Obstetrics and Gynecology, Carvalho JS, Allan LD, Chaoui R, Copel JA, DeVore GR, Hecher K, Lee W, Munoz H, Paladini D, Tutschek B, Yagel S. Ultrasound Obstet Gynecol 2013; 41: 348–359.
Ultrasound Obstet Gynecol 2015; 45: 670–677.
Right ventricular function in fetal HLHS 23. Tutschek B, Zimmermann T, Buck T, Bender HG. Fetal tissue Doppler echocardiography: detection rates of cardiac structures and quantitative assessment of the fetal heart. Ultrasound Obstet Gynecol 2003; 21: 26–32. 24. Naujorks AA, Zielinsky P, Beltrame PA, Castagna RC, Petracco R, Busato A, Nicoloso AL, Piccoli A, Manica JL. Myocardial tissue Doppler assessment of diastolic function in the growth-restricted fetus. Ultrasound Obstet Gynecol 2009; 34: 68–73. 25. Comas M, Crispi F, Gomez O, Puerto B, Figueras F, Gratacos E. Gestational age- and estimated fetal weight-adjusted reference ranges for myocardial tissue Doppler indices at 24–41 weeks’ gestation. Ultrasound Obstet Gynecol 2011; 37: 57–64. 26. Park YS, Park JH, Ahn KT, Jang WI, Park HS, Kim JH, Lee JH, Choi SW, Jeong JO, Seong IW. Usefulness of mitral annular systolic velocity in the detection of left ventricular systolic dysfunction: comparison with three dimensional echocardiographic data. J Cardiovasc Ultrasound 2010; 18: 1–5. 27. Watanabe S, Hashimoto I, Saito K, Watanabe K, Hirono K, Uese K, Ichida F, Saito S, Miyawaki T, Niemann P, Sahn DJ. Characterization of ventricular myocardial performance in the fetus by tissue Doppler imaging. Circ J 2009; 73: 943–947. 28. Nagueh SF, Middleton KJ, Kopelen HA, Zoghbi WA, Quinones MA. Doppler tissue imaging: a non invasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol 1997; 30: 1527–1533. 29. Sohn DW, Chai IH, Lee DJ, Kim HC, Kim HS, Oh BH, Lee MM, Park YB, Choi YS, Seo JD, Lee YW. Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997; 30: 474–480. 30. Ommen SR, Nishimura RA, Appleton CP, Miller FA, Oh JK, Redfield MM, Tajik AJ. Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: a comparative simultaneous Doppler-cathererization study. Circulation 2000; 102: 1788–1794. 31. Comas M, Crispi F, Cruz-Martinez R, Martinez JM, Figueras F, Gratacos E. Usefulness of myocardial tissue Doppler vs conventional echocardiography in the evaluation of cardiac dysfunction in early-onset intrauterine growth restriction. Am J Obstet Gynecol 2010; 203: 45e41–47. 32. Carvalho JS, O´Sullivan C, Shinebourne EA, Henein MY. Right and left ventricular long-axis function in the fetus using angular M-Mode. Ultrasound Obstet Gynecol 2001; 18: 619–622. 33. Tulzer G, Khowsathit P, Gudmundsson S, Wood DC, Tian ZY, Schmitt K, Huhta JC. Diastolic function of the fetal heart during second and third trimester: a prospective longitudinal Doppler-echocardiographic study. Eur J Pediatr 1994; 153: 151–154. 34. Rizzo G, Arduini D, Romanini C. Doppler echocardiographic assessment of fetal cardiac function. Ultrasound Obstet Gynecol 1992; 2: 434–445. 35. Stirnemann JJ, Mougeot M, Proulx F, Nasr B, Essaoui M, Fouron JC, Ville Y. Profiling fetal cardiac function in twin-twin transfusion syndrome. Ultrasound Obstet Gynecol 2010; 35: 19–27.
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
677 36. Mahle WT, Rychik J, Tian ZY, Cohen MS, Howell LJ, Crombleholem TM, Flake AW, Adzick NS. Echocardiographic evaluation of the fetus with congenital cystic adenomatoid malformation. Ultasound Obstet Gynecol 2000; 16: 620–624. 37. Crispi F, Hernandez-Andrade E, Pelsers MM, Plasencia W, Benavives-Serralde JA, Eixarch E, LeNoble F, Ahmed A, Glatz JF, Nicolaides KH, Gratacos E. Cardiac dysfunction and cell damage across clinical stages of severity in growth-restricted fetuses. Am J Obstet Gynecol 2008; 199: 254.e1–8. 38. Yu CM, Fung JW, Zhang Q, Kum LC, Lin H, Yip GW, Wang M, Sanderson JE. Tissue Doppler echocardiographic evidence of atrial mechanical dysfunction in coronary artery disease. Int J Cardiol 2005; 105: 178–185. 39. Aoki M, Harada K, Ogawa M, Tanaka T. Quantitative assessment of right ventricular function using Doppler tissue imaging in fetuses with and without heart failure. J Am Soc Echocardiogr 2004; 17: 28–35. 40. Eidem BW, Edwards JM, Cetta F. Quantitative assessement of fetal ventricular function: establishing normal values of the myocardial perfromance index in the fetus. Echocardiography 2001; 18: 9–13. 41. Letti Muller AL, Barrios Pde M, Kliemann LM, Valerio EG, Gasnier R, Magalhaes JA. Tei Index to assess fetal cardiac performance in fetuses at risk for fetal inflammatory response syndrome. Ultrasound Obstet Gynecol 2010; 36: 26–31. 42. Szwast A, Tian Z, McCann M, Donaghue D, Bebbington M, Johnson M, Wislon RD, Rychik J. Impact of altered loading conditions on ventricular performance in fetuses with congential cystic adenomatoid malformation and twin-twin transfusion syndrome. Ultrasound Obstet Gynecol 2007; 30: 40–46. 43. Friedman D, Buyon J, Kim M, Glickstein JS. Fetal cardiac function assessed by Doppler myocardial performance index (Tei index). Ultrasound Obstet Gynecol 2003; 21: 33–36. 44. Hernandez-Andrade E, Benavides-Serralde JA, Cruz-Martinez R, Welsh A, Mancilla-Ramirez J. Evaluation of conventional Doppler fetal cardiac funtion parameters: E/A ratios, out flow tracts and myocardial performance index. Fetal Diagn Ther 2012; 32: 22–29. 45. Rojo EC, Rodrigo JL, Perez de Isla L, Almeria C, Gonzalo N, Aubele A, Cinza R, Zamorano J, Macaya C. Disagreement between tissue Doppler imaging and conventional pulsed wave Doppler in the measurement of myocardial performance index. Eur J Echocardiogr 2006; 7: 356–364. 46. 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: 749–755. 47. Goodlin RC, Girard J, Hollmann A. Systolic time intervals in the fetus and neonate. Obstet Gynecol 1972; 39: 295–303. 48. Germanakis I, Gardiner H. Assessment of fetal myocardial deformation using speckle tracking techniques. Fetal Diagn Ther 2012; 32: 39–46. 49. Enzensberger C, Degenhardt J, Tenzer A, Doelle A, Axt-Fliedner R. First experience with three-dimensional speckle tracking (3D Wall Motion Tracking) in fetal echocardiography. Ultraschall Med 2014; 35: 566–572.
Ultrasound Obstet Gynecol 2015; 45: 670–677.
