Background
Infants with single ventricular physiology have volume and pressure overload that adversely affect ventricular mechanics. The impact of superior cavopulmonary anastomosis (SCPA) on single left ventricles versus single right ventricles is not known.
Methods
As part of the Pediatric Heart Network placebo-controlled trial of enalapril in infants with single ventricular physiology, echocardiograms were obtained before SCPA and at 14 months and analyzed in a core laboratory. Retrospective analysis of the following measurements included single ventricular end-diastolic volume (EDV), end-systolic volume (ESV), mass, mass-to-volume ratio (mass/volume), and ejection fraction. Qualitative assessment of atrioventricular valve regurgitation and assessment of diastolic function were also performed.
Results
A total of 156 participants underwent echocardiography at both time points. Before SCPA, mean ESV and mass Z scores were elevated (3.4 ± 3.7 and 4.2 ± 2.9, respectively) as were mean EDV and mass/volume Z scores (2.1 ± 2.5 and 2.0 ± 2.9, respectively). EDV, ESV, and mass decreased after SCPA, but mass/volume and the degree of atrioventricular valve regurgitation did not change. Subjects with morphologic left ventricles demonstrated greater reductions in ventricular volumes and mass than those with right ventricles (mean change in Z score: left ventricular [LV] EDV, −1.9 ± 2.1; right ventricular EDV, −0.7 ± 2.5; LV ESV, −2.3 ± 2.9; right ventricular ESV, −0.9 ± 4.6; LV mass, −2.5 ± 2.8; right ventricular mass, −1.3 ± 2.6; P ≤ .03 for all). Approximately one third of patients whose diastolic function could be assessed had abnormalities at each time point.
Conclusions
Decreases in ventricular size and mass occur in patients with single ventricle after SCPA, and the effect is greater in those with LV morphology. The remodeling process resulted in commensurate changes in ventricular mass and volume such that the mass/volume did not change significantly in response to the volume-unloading surgery.
Highlights
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Single ventricular size and mass decrease after superior cavopulmonary anastomosis.
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Mass-to-volume ratio does not change significantly after superior cavopulmonary anastomosis.
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Morphologic left ventricles demonstrated a greater reduction in ventricular volumes and mass than morphologic right ventricles.
In neonates and infants with single ventricle (SV) heart disease, the functioning ventricle must support both the systemic and pulmonary circulations, resulting in volume and pressure overload. One major aim in the surgical management of these patients is to mitigate the impact of the chronic volume overload that can lead to ventricular dilation and hypertrophy and ultimately to decreased systolic function. One of the effects of the superior cavopulmonary anastomosis (SCPA) procedure is to decrease the ventricular volume overload by directing systemic venous blood from the upper part of the body to the lungs, bypassing the SV. The SCPA procedure has been shown to reduce the incidence of systolic ventricular dysfunction in SV patients by providing an incremental decrease in volume overload early in infancy.
Several investigators have attempted to define the changes in ventricular volumes, systolic function, and mass-to-volume ratio (mass/volume) in SV patients in small case series. Others have made an effort to characterize changes in diastolic function. Each of these studies has used different methods of assessment, precluding comparisons of the groups studied. Most reports focus on patients with left ventricular (LV) morphology, and if patients with LV and right ventricular (RV) morphologies are included, the results are typically combined for analysis.
The National Heart, Lung, and Blood Institute–sponsored Pediatric Heart Network completed a multicenter randomized placebo-controlled trial of the angiotensin-converting enzyme inhibitor enalapril in infants with single ventricular physiology, the Infant Single Ventricle (ISV) study. Clinical and echocardiographic data were prospectively gathered on all subjects. No difference was found in the primary outcome of weight-for-age Z score or in ventricular volumes, mass, or ejection fraction (EF) between the placebo and enalapril-treated groups. Using this large, well-characterized cohort, we sought to describe the changes in LV and RV geometry and systolic function that occur in response to SCPA surgery, to explore factors that are associated with those changes, and to characterize diastolic function in infants with single ventricular physiology.
Methods
Details of the study design and main results of the ISV trial have been published. In brief, infants with single ventricular physiology were enrolled between 7 and 45 days of age, across 10 North American centers, between August 2003 and May 2007. Subjects were included if they had stable hemodynamics and if they were anticipated to undergo SCPA surgery. The trial followed subjects through the SCPA surgery to the final study visit at 14 months of age. Written informed consent was obtained from a parent or guardian. The study was approved by the institutional review or ethics board at each participating institution.
Patient data collected included detailed anatomic diagnosis, age at enrollment and at SCPA surgery, gestational age, gender, race, medication history, and medical and surgical data from the SCPA procedure. Ventricular morphology was characterized as LV dominant (e.g., tricuspid atresia) or RV dominant (e.g., hypoplastic left heart syndrome). Patients with indeterminate or mixed ventricular morphology (e.g., unbalanced atrioventricular canal defects with two ventricles present) were not included in the RV-LV comparison analyses for this report.
Echocardiographic Data
A detailed quantitative echocardiographic evaluation was performed, including ventricular volumes and systolic and diastolic function, at two time points during the study: before SCPA and at 14 months (final study visit). Sedation was used according to local practice. Echocardiography was performed according to a prospective, standardized imaging protocol, and studies were sent to the echocardiographic core laboratory for interpretation by a single reader.
The systemic ventricle was imaged from the apical (ventricular long-axis) and parasternal short-axis planes. The endocardial border was traced at end-diastole and end-systole; the epicardial border was traced at end-diastole in both planes. End-diastolic volume (EDV), end-systolic volume (ESV), and mass were then calculated using a modified Simpson biplane method. The percentage ventricular EF was calculated as [(EDV − ESV)/EDV] × 100. Ventricular mass was calculated as myocardial EDV (epicardial volume − endocardial volume) × myocardial density (1.05 g/mL). Inter- and intraobserver variabilities for this method of assessing morphologic SVs have been reported previously. The degree of atrioventricular valve (AVV) regurgitation (AVVR) was qualitatively assessed and grouped as none/mild or moderate/severe.
Doppler assessment of AVV inflow was performed for E, A, early deceleration time, and a-wave duration. If the AVV inflow demonstrated partially fused E and A waves, which is common at infant heart rates, only the E velocity was recorded. If the waveforms were completely fused, no Doppler measurements were used. Doppler tissue imaging of annular myocardial velocities recorded E′ and A′ diastolic velocities at the two walls, which were averaged. Similar to AVV inflow assessment, if the tissue Doppler tracing demonstrated partial E′ and A′ fusion, only E′ velocity was recorded, and no measurements were used if E′ and A′ were completely fused. Figure 1 depicts examples of AVV inflow waveform fusion, and Figure 2 shows examples of Doppler tissue imaging waveform fusion. Figure 3 demonstrates the effect of the R-R interval on fusion of the waveforms. Duration of pulmonary vein flow reversal and ventricular flow propagation (V fp ) were also recorded. E/E′ values > 10 and V fp values > 45 were considered abnormal.
Echocardiographic data were reviewed and measurements made using custom software (Marcus Laboratories, Boston, MA).
Statistical Analysis
The data used in the analyses were obtained in a prospective manner; the analyses reported here were retrospectively proposed and implemented. To adjust echocardiographic measurements to account for the effect of body size (volume, mass) and age (EF, Doppler variables), Z score values were used. Z score calculations were derived from the systemic left ventricle in a group of normal control subjects; the ventricular size and function Z scores used are therefore based on systemic LV measurements.
Data are described as frequencies, medians with 25th and 75th percentile values, and means with SDs as appropriate. For some of the evaluations below, echocardiograms with partial data were included; each section lists the number of subjects included for subanalysis. Echocardiographic measurements of the LV and RV groups were compared using Student’s t test for nonskewed variables and the Wilcoxon rank sum test for other measures. In the subset of patients who had complete data available at both the pre-SCPA and 14-month time points, the distributions of changes in ventricular size and function were compared with the normal population mean of zero using the one-sample t test. The changes in AVVR between the two time points were assessed using the McNemar test. The Fisher exact and Mantel-Haenszel χ 2 tests for linear trend were used to evaluate the effect of enalapril on the ventricle and to compare the changes in subjects with single right ventricles with those in subjects with single left ventricles. Subgroup analyses of treatment effect on changes in mass-volume Z scores were performed between single left ventricle and single right ventricle (subgroups prespecified in the ISV trial) subjects. LV-RV group-by-treatment interaction tests were used to assess the treatment effect across subgroups. Generalized additive models were used to account for nonlinearity in regression models.
Data analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC). P values < .05 were considered to indicate statistical significance.
Results
Patient Population
Of the 230 subjects randomized for the main trial, 28 were withdrawn before the pre-SCPA visit, and 14 subjects did not undergo SCPA. The remaining subjects underwent SCPA as follows: 134 had bidirectional cavopulmonary anastomoses, 28 had bilateral bidirectional cavopulmonary anastomoses, and 26 had hemi-Fontan procedures. A total of 156 subjects had complete studies at both time points. Briefly with regard to the surgical procedures, bidirectional SCPA involves dividing the superior vena cava (SVC) from the heart, oversewing the cardiac end, and attaching the SVC to the right pulmonary artery in an end-to-side fashion. A bilateral bidirectional SCPA is required when there is a persistent left-sided SVC in addition to the usual right-sided SVC. In this procedure, both cavae are removed from the heart and sewn end to side to the branch pulmonary arteries. A hemi-Fontan is a modification of the SCPA procedure performed by some surgeons in which both cranial and cardiac ends of the SVC are anastomosed to the superior and inferior surfaces of the right pulmonary artery, and a patch is placed to occlude the SVC–right atrial orifice. The intent of this modification is to streamline the subsequent Fontan procedure. The hemodynamic impact of all of these procedures (bidirectional SCPA, bilateral bidirectional SCPA, and hemi-Fontan) is the same. By directing venous return from the SVC(s) directly to the pulmonary arteries, a portion of the volume load on the SV is removed, while allowing reasonable pulmonary blood flow.
For the entire group, the median age at the time of SCPA and the time from SCPA to the 14-month visit were 5.3 months (range, 2.3–14.9 months) and 8.9 months (range, 1.7–11.9 months), respectively. Male subjects constituted 46% of the cohort; 81% were classified as white, 13% as black, and 6% as “other”; 13% reported their ethnicity as Hispanic. RV-dominant morphology was present in 71%.
Changes in Ventricular Geometry, Systolic Function, and AVVR between the Pre-SCPA and 14-Month Time Points
Calculated values for ventricular volumes, mass, mass/volume, and EF for the entire cohort at each time point are shown in Table 1 ; the Z scores for the group and the changes in Z scores between the two time points are also shown. Mean Z scores for ventricular EDV, ESV, mass, and mass/volume were all >2 at the pre-SCPA visit. EDV, ESV, and mass all demonstrated decreases in Z scores between the pre-SCPA and 14-month visits. Mass/volume did not significantly change between the two time points. EF demonstrated a statistically significant but small improvement.
| Variable | Calculated values | Z score ∗ | ||||
|---|---|---|---|---|---|---|
| Pre-SCPA | 14 months | Pre-SCPA | 14 months | Change in Z score ‡ | ||
| Mean ± SD ( n ) | Mean ± SD ( n ) | Mean ± SD ( n ) | Mean ± SD ( n ) | Mean ± SD ( n ) | P † | |
| EDV (mL) | 23.5 ± 9.6 (160) | 29.8 ± 10.7 (163) | 2.1 ± 2.5 (157) | 1.2 ± 2.2 (163) | −1.0 ± 2.5 (153) | <.001 |
| ESV (mL) | 10.2 ± 5.4 (160) | 12.7 ± 7.2 (163) | 3.4 ± 3.7 (157) | 2.2 ± 3.7 (163) | −1.2 ± 4.1 (153) | <.001 |
| Mass (g) | 26.2 ± 9.2 (158) | 32.2 ± 10.3 (161) | 4.2 ± 2.9 (155) | 2.6 ± 2.3 (161) | −1.6 ± 2.6 (151) | <.001 |
| EF (%) | 57.4 ± 9.3 (160) | 58.8 ± 9.9 (163) | −1.1 ± 1.8 (160) | −0.8 ± 1.9 (163) | 0.3 ± 2.3 (156) | .02 |
| Mass/volume (g/mL) | 1.2 ± 0.5 (158) | 1.2 ± 0.4 (161) | 2.0 ± 2.9 (158) | 1.6 ± 2.6 (161) | −0.2 ± 3.0 (154) | .33 |
∗ Three subjects were missing weight measurements at the time of echocardiography, precluding Z score assignment for EDV, ESV, and mass.
† To compare the distributions of change scores in our SV sample with the normal population mean of zero, we used the Wilcoxon signed rank test for EF and the one-sample t test for all other changes in Z scores.
‡ Z score at the 14-month visit minus Z score at the pre-SCPA visit.
To evaluate the change in AVVR between the pre-SCPA and 14-month time points, subjects were grouped into two categories: none/mild AVVR and moderate/severe AVVR. Excluding six subjects who underwent atrioventricular valvuloplasty at the time of SCPA, 161 subjects had AVVR assessments at both time points, including 132 subjects with no change in the degree of AVVR between the two time points. Before SCPA surgery, 35 subjects (22%; 29 RV, four LV, and two mixed) had moderate/severe AVVR. Of these, 16 (15 RV and one LV) had continued moderate/severe AVVR at the 14-month visit, while 19 (14 RV, three LV, and two mixed) improved to none/mild. Of 126 subjects with none/mild AVVR before SCPA, 10 progressed to moderate/severe AVVR (six RV and four LV) at the 14-month visit; these findings were statistically not significant ( P = .095, McNemar test).
Comparison of the Effect of Angiotensin-Converting Enzyme Inhibition versus Placebo on Changes in Ventricular Size and Function
Of the subjects who underwent SCPA and who had paired echocardiographic data for ventricular size and function, 79 were on enalapril therapy and 77 were assigned to placebo. No significant difference was seen between the treatment groups in terms of change in EDV, ESV, ventricular mass, EF, or mass/volume. We also found no difference in the changes in AVVR between the two study visits by treatment arm, reported previously.
Changes in Ventricular Geometry and Function in Subjects with Single Right Ventricles Compared with Single Left Ventricles
Table 2 includes the Z scores for the ventricular characteristics for LV versus RV morphology and the changes in Z scores between the two time points. The raw data are presented in Supplemental Table 1 (available at www.onlinejase.com ). As assessed by change in EDV, ESV, and ventricular mass, single right ventricles and single left ventricles differed in their response to volume unloading at SCPA. Greater absolute and relative declines in Z scores (indicating more movement toward the mean) for these parameters were noted for left ventricles than right ventricles, secondary to all three variables’ having higher values for left ventricles versus right ventricles before SCPA and all three variables’ having lower values for left ventricles versus right ventricles at 14 months. Of note, there was no difference in age at SCPA, follow-up time or incidence of coarctation in the RV group relative to the LV group in our cohort to explain these findings.
| LV Z score | RV Z score | Change in Z scores (value at 14 months minus value at pre-SCPA) | ||||||
|---|---|---|---|---|---|---|---|---|
| Pre-SCPA Mean ± SD ( n ) | 14 mo Mean ± SD ( n ) | Pre-SCPA Mean ± SD ( n ) | 14 mo Mean ± SD ( n ) | Left ventricle Mean ± SD ( n ) | Right ventricle Mean ± SD ( n ) | Mean difference ∗ | P † | |
| EDV | 2.8 ± 2.4 (32) | 0.9 ± 1.5 (33) | 2.0 ± 2.6 (111) | 1.3 ± 2.4 (114) | −1.9 ± 2.1 (32) | −0.7 ± 2.5 (108) | −1.2 | .01 |
| ESV | 4.2 ± 3.2 (32) | 1.9 ± 2.0 (33) | 3.4 ± 4.0 (111) | 2.6 ± 4.2 (114) | −2.3 ± 2.9 (32) | −0.9 ± 4.6 (108) | −1.4 | .03 |
| Mass | 4.5 ± 3.1 (32) | 2.2 ± 1.9 (33) | 4.0 ± 2.9 (109) | 2.7 ± 2.4 (114) | −2.5 ± 2.8 (32) | −1.3 ± 2.6 (107) | −1.2 | .03 |
| EF | −1.2 ± 1.2 (33) | −0.9 ± 1.5 (33) | −1.2 ± 2.0 (113) | −0.9 ± 2.1 (114) | 0.3 ± 1.7 (33) | 0.3 ± 2.6 (110) | 0.0 | .98 |
| Mass/volume | 1.3 ± 2.2 (33) | 1.2 ± 1.5 (33) | 1.9 ± 2.8 (111) | 1.6 ± 2.8 (114) | −0.1 ± 2.6 (33) | −0.3 ± 3.1 (109) | 0.2 | .76 |
We then sought to determine whether the differences in response to SCPA that were seen between the ventricular subtypes were related to treatment group (enalapril vs placebo) by performing a subgroup analysis by treatment. These results are presented in Table 3 . The interaction P values ranged from .11 to .95, indicating that there was no significant effect of enalapril on the changes in Z scores between right and left ventricles. In fact, the largest overall changes occurred in the placebo group, not the enalapril group.
| Change in mass/volume Z score ∗ by treatment arm | LV Δ Z score Mean ± SD ( n ) | RV Δ Z score Mean ± SD ( n ) | Mean difference between left and right ventricles † | P ‡ | ANOVA interaction P value § |
|---|---|---|---|---|---|
| EDV | .40 | ||||
| Enalapril | −1.86 ± 2.12 (18) | −1.05 ± 2.64 (53) | −0.81 | .22 | |
| Placebo | −2.01 ± 2.05 (14) | −0.37 ± 2.38 (55) | −1.64 | .009 | |
| ESV | .37 | ||||
| Enalapril | −1.92 ± 2.23 (18) | −1.24 ± 4.86 (53) | −0.68 | .27 | |
| Placebo | −2.87 ± 3.65 (14) | −0.57 ± 4.01 (55) | −2.3 | .009 | |
| Mass | .11 | ||||
| Enalapril | −1.58 ± 2.57 (18) | −1.14 ± 2.63 (53) | −0.44 | .48 | |
| Placebo | −3.62 ± 2.65 (14) | −1.48 ± 2.57 (54) | −2.14 | .01 | |
| EF | .48 | ||||
| Enalapril | 0.09 ± 1.41 (18) | 0.42 ± 2.67 (54) | −0.33 | .43 | |
| Placebo | 0.51 ± 2.02 (15) | 0.18 ± 2.34 (56) | 0.33 | .74 | |
| Mass/volume | .95 | ||||
| Enalapril | 0.24 ± 2.56 (18) | 0.14 ± 3.23 (54) | 0.1 | .75 | |
| Placebo | −0.52 ± 2.55 (15) | −0.70 ± 2.85 (55) | 0.18 | .57 |
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