Abstract
Patients with single-ventricle physiology who received enalapril in the Pediatric Heart Network Infant Single-ventricle Trial displayed no differences in heart failure outcomes compared to those who received a placebo. The objective of this study was to use noninvasive pressure-volume loop analysis to assess for differences in cardiac mechanics between the enalapril and placebo groups. Core-lab echocardiogram measures prior to superior cavopulmonary connection (SCPC) and post-SCPC at 14 months of age were obtained. End-systolic elastance (Ees), a measure of contractility, and arterial elastance (Ea), a measure of afterload, were calculated. Ventriculo-arterial coupling was expressed as Ea/Ees. Data from 150 patients were analyzed. There was no difference in Ees, Ea, or Ea/Ees between study groups at either time point. The failure of enalapril to improve heart failure outcomes in this cohort may have some association with its failure to improve cardiac mechanics in single-ventricle physiology.
Keywords: Enalapril, heart failure, pressure-volume loop analysis, single ventricle
INTRODUCTION
The Infant Single Ventricle (ISV) Trial[1] was a placebo-controlled multicenter clinical trial that showed enalapril use in infants with single-ventricle physiology did not improve growth or heart failure outcomes in comparison to placebo; however, it did not fully investigate the physiologic basis behind these findings. Specifically, enalapril’s effect on cardiac mechanics was not assessed. The purpose of this study was to examine whether the failure of enalapril to improve heart failure outcomes was due to the lack of improvement of cardiac mechanics or other factors not accounted for in the ISV Trial. We hypothesized that there would be no difference in noninvasive measures of afterload or ventriculo-arterial coupling between the enalapril and placebo groups in these single-ventricle patients.
METHODS
This was a secondary analysis of the NIH/NHLBI pediatric heart network (PHN) ISV Trial.[1] Echocardiographic assessments were performed in this clinical trial at both the pre-superior cavopulmonary connection (SCPC) and 14-month time points for infants in both the enalapril and placebo groups. The demographic, clinical, and core-lab echocardiography data used for analysis were obtained from the PHNs ISV Trial deidentified public use database (https://www.pediatricheartnetwork.org/public-use-data-sets/). Only subjects with complete echocardiogram data at both pre-SCPC and 14-month time points were included in the analysis. Subjects were considered part of the enalapril group only if they were taking enalapril at both time points.
Echocardiographic measurements of ventricular volumes and ejection fraction in these single-ventricle patients via a modified Simpson’s method have been reported previously.[1] This method showed adequate agreement and reproducibility compared to cardiac magnetic resonance imaging.[2] Blood pressure by sphygmomanometer was measured at the time of both echocardiograms.
Cardiac mechanical measures of interest were derived from noninvasive estimates of pressure-volume loop analysis indices. End-systolic elastance (Ees), a measure of contractility, was calculated as (0.9 × systolic blood pressure/end-systolic volume).[3] Arterial elastance (Ea), a measure of arterial stiffness, was calculated as (0.9 × systolic blood pressure/stroke volume). The ratio Ea/Ees is a measure of ventriculo-arterial coupling, as it describes the interaction between myocardial performance and vascular function.[4] These measures have been validated in adults and children against the invasive reference standard in biventricular and single-ventricle physiology.[5,6]
Data are reported as mean ± standard deviation or median (interquartile range) for parametric and nonparametric variables, respectively. Differences between continuous variables between the enalapril and placebo groups at each time point were assessed using an independent t-test or Mann-Whitney U-test as appropriate. A P < 0.05 was considered statistically significant. SPSS v. 27 (IBM, Armonk, New York, USA) was used for analysis.
RESULTS
Of the 185 patients who completed the ISV study, only 150 had complete echocardiographic data at both the pre-SCPC and 14-month time points. Seventy-four subjects were on enalapril. Of these, 65 were right ventricular dominant, 9 were co-dominant ventricles, and 0 were left ventricular dominant. Seventy-six placebo subjects were analyzed. Of these, 68 were right ventricular dominant, 8 were co-dominant ventricles, and 0 were left ventricular dominant. There were no statistically significant differences between the cohorts in terms of clinical characteristics, including age, weight, height, systolic blood pressure, diastolic blood pressure, right ventricular end-diastolic volume, or ejection fraction at either the pre-SCPC or 14-month timepoint [Table 1]. There were no significant differences at both pre-SCPC and 14-month time points in Ees, Ea, and Ea/Ees between groups [Figure 1].
Table 1.
Demographic, blood pressure, and echocardiographic measures between the enalapril and placebo groups at the presuperior cavopulmonary connection and 14-month timepoints
| Pre-SCPC | Enalapril (n=74) | Placebo (n=76) | P |
|---|---|---|---|
| Age (days) | 143 (115–168) | 141 (117–172) | 0.763 |
| Height (cm) | 61.8±4.9 | 62.0±4.0 | 0.811 |
| Weight (kg) | 5.9±1.0 | 5.8±0.9 | 0.771 |
| SBP (mmHg) | 85 (77–98) | 88 (80–96) | 0.490 |
| DBP (mmHg) | 42 (36–50) | 42 (37–50) | 0.765 |
| RV EDV (mL) | 21.4 (16.3–28.4) | 21.5 (16.4–28.8) | 0.799 |
| RV EF (%) | 57.9±10.3 | 57.5±10.2 | 0.847 |
| 14 months | |||
| Age (days) | 425 (410–439) | 426 (414–444) | 0.297 |
| Height (cm) | 74.8±3.0 | 75.2±3.0 | 0.530 |
| Weight (kg) | 9.3±1.1 | 9.4±1.3 | 0.830 |
| SBP (mmHg) | 86 (79–100) | 87 (81–99) | 0.747 |
| DBP (mmHg) | 45 (38–57) | 46 (40–58) | 0.458 |
| RV EDV (mL) | 26.9 (22.1–34.9) | 29.6 (22.6–37.3) | 0.272 |
| RV EF (%) | 60.1 (53.9–65.4) | 58.3 (53.5–65.4) | 0.592 |
Results reported as mean±SD or median (IQR). DBP: Diastolic blood pressure, Ea: Arterial elastance, Ees: End-systolic elastance, EF: Ejection fraction, SBP: Systolic blood pressure, IQR: Interquartile range, EDV: End-diastolic volume, SD: Standard deviation, DBP: Diastolic blood pressure, RV: Right ventricular, SCPC: Superior cavopulmonary connection
Figure 1.
Differences in noninvasive measures of cardiac mechanics between the enalapril and placebo groups at (a) the presuperior cavolpulmonary connection timepoint and (b) the 14-month assessment timepoint. Ea: Arterial elastance, Ees: End-systolic elastance, SCPC: Superior cavopulmonary anastomosis
DISCUSSION
Our results show that infants treated with enalapril at both the pre-SCPC and 14-month time points exhibited no differences in contractility, afterload, or ventriculo-arterial coupling compared to the placebo group. The negative results of the ISV Trial may have been influenced by the fact that enalapril did not improve the cardiac mechanics of patients in this cohort.
Similar to the ISV Trial, numerous studies have demonstrated the inefficacy of enalapril in improving single-ventricle outcomes, despite its known effects on the renin-angiotensin-aldosterone system.[7] This study cannot determine the pathophysiology behind the lack of efficacy of enalapril in improving in single-ventricle patient cardiac mechanics, however, future studies should investigate the possibilities that arch reconstruction decreases the efficacy of angiotensin-converting enzyme (ACE) inhibition, RAAS abnormalities are not the primary drivers of heart failure in single-ventricle patients, or that venous endothelial abnormalities drive abnormal afterload in this population, which are not improved with ACE inhibition. Limitations to this study include the absence of baseline data prior to starting enalapril versus placebo and the small sample size.
In conclusion, there were no differences in contractility, afterload, or ventriculo-arterial coupling in single-ventricle patients receiving enalapril versus placebo prior to SCPC or at 14 months. The failure of enalapril to improve heart failure outcomes in this cohort may be related to its failure to improve cardiac mechanics in single-ventricle physiology. Further research needs to be performed investigating why enalapril fails to improve cardiac mechanics in infants with single-ventricle physiology.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Dr. Chowdhury is supported by NIH/NHLBI HL133447. The PHN ISV Study was supported by the U01 HL68269, HL68270, HL68292, HL68290, HL68288, HL68285, HL68281, and HL68279.
REFERENCES
- 1.Hsu DT, Zak V, Mahony L, Sleeper LA, Atz AM, Levine JC, et al. Enalapril in infants with single ventricle: Results of a multicenter randomized trial. Circulation. 2010;122:333–40. doi: 10.1161/CIRCULATIONAHA.109.927988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Margossian R, Schwartz ML, Prakash A, Wruck L, Colan SD, Atz AM, et al. Comparison of echocardiographic and cardiac magnetic resonance imaging measurements of functional single ventricular volumes, mass, and ejection fraction (from the Pediatric Heart Network Fontan Cross-Sectional Study) Am J Cardiol. 2009;104:419–28. doi: 10.1016/j.amjcard.2009.03.058. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Burkhoff D, Mirsky I, Suga H. Assessment of systolic and diastolic ventricular properties via pressure-volume analysis: A guide for clinical, translational, and basic researchers. Am J Physiol Heart Circ Physiol. 2005;289:H501–12. doi: 10.1152/ajpheart.00138.2005. [DOI] [PubMed] [Google Scholar]
- 4.Fox JM, Maurer MS. Ventriculovascular coupling in systolic and diastolic heart failure. Curr Heart Fail Rep. 2005;2:204–11. doi: 10.1007/BF02696651. [DOI] [PubMed] [Google Scholar]
- 5.Chowdhury SM, Butts RJ, Taylor CL, Bandisode VM, Chessa KS, Hlavacek AM, et al. Validation of noninvasive measures of left ventricular mechanics in children: A simultaneous echocardiographic and conductance catheterization study. J Am Soc Echocardiogr. 2016;29:640–7. doi: 10.1016/j.echo.2016.02.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Yotti R, Bermejo J, Benito Y, Sanz-Ruiz R, Ripoll C, Martínez-Legazpi P, et al. Validation of noninvasive indices of global systolic function in patients with normal and abnormal loading conditions: A simultaneous echocardiography pressure-volume catheterization study. Circ Cardiovasc Imaging. 2014;7:164–72. doi: 10.1161/CIRCIMAGING.113.000722. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Garcia AM, Beatty JT, Nakano SJ. Heart failure in single right ventricle congenital heart disease: Physiological and molecular considerations. Am J Physiol Heart Circ Physiol. 2020;318:H947–65. doi: 10.1152/ajpheart.00518.2019. [DOI] [PMC free article] [PubMed] [Google Scholar]