Many Fontan patients with and without systolic ventricular dysfunction are being treated with angiotensin-converting enzyme (ACE) inhibitors, despite its effectiveness remaining unclear. In the present study, we evaluated the short-term effect of enalapril on exercise capacity, vascular and ventricular function in pediatric Fontan patients with moderate-good systolic ventricular function. Fontan patients between 8 and 18 years with moderate-good systolic ventricular function and without previous ACE inhibitor treatment were included and were treated with enalapril for 3 months. During the first 2 weeks, the dosage was titrated according to systolic blood pressure (SBP). Exercise tests, ventricular function assessed by echocardiography, arterial stiffness measurements, and plasma levels of N-terminal pro-B–type natriuretic peptide assessed before and after a 3-month enalapril treatment period was compared. A total of 28 Fontan patients (median age 13.9 years, 6 to 15 years after Fontan operation) completed the study with a mean dosage of 0.3 ± 0.1 mg/kg/d. A total of 6 patients (21%) experienced a significant drop in SBP and 6 others (21%) experienced other adverse events. Enalapril treatment lowered the SBP (from 110 to 104 mmHg, p = 0.003) and levels of N-terminal pro-B–type natriuretic peptide (from 80 to 72 ng/L, p = 0.036). However, enalapril treatment did not improve exercise capacity, ventricular function, or arterial stiffness. In conclusion, short-term ACE inhibition has no beneficial effect in Fontan patients with moderate-good systolic ventricular function.
Although survival of Fontan patients has improved, life expectancy is still less than normal, and many patients suffer from morbidities. Exercise performance, diastolic and systolic ventricular function are already reduced at a young age. , Because severe diastolic and systolic dysfunction may not be present yet, both functions deteriorate over time in these patients, which may eventually result in heart failure. , In patients with biventricular heart circulation, angiotensin-converting enzyme (ACE) inhibitors have become the cornerstone of systolic heart failure treatment as they have been shown to improve exercise performance, diastolic and systolic ventricular function, and decrease systemic vascular resistance in adult and pediatric patients with mild to severe systolic heart failure. Because its effectiveness in biventricular heart patients, many Fontan patients are currently treated with ACE inhibitors, including those without overt systolic ventricular dysfunction, despite the lack of evidence of its efficacy in this patient population. , Therefore, in this study we evaluated the effect of ACE inhibition in pediatric Fontan patients with moderate-good systolic ventricular function and hypothesized that it may improve exercise performance and ventricular and vascular function. Additionally, adverse events and tolerability were evaluated.
Methods
Fontan patients from 8 to 18 years old who were operated at the Leiden University Medical Center were recruited from July 2017 to October 2019. Patients with pre-existent ACE inhibitor use and those unable to exercise were excluded. Written informed consent was obtained from all participants or their parents or guardians. The study was approved by the Medical Ethical Committee Leiden-Den Haag-Delft.
For this study patients were treated with enalapril, an ACE inhibitor, for 3 months. This period was chosen as previous studies have shown beneficial effects of ACE inhibitors within 12 weeks of treatment, especially on exercise capacity, the primary end point of this study. , , , Initial enalapril dosage was 5 mg/day and was titrated, as tolerated, to the target dose of 0.5 mg/kg/day or a maximum of 20 mg/day. Enalapril dosage was titrated by blood pressure measured weekly for at least 2 weeks after initiation of treatment. If systolic blood pressure (SBP) fell >20%, or if patients experienced side effects, the dosage was lowered. Renal function (urea and creatinine blood levels) was assessed at baseline, after 2 weeks of treatment with the maximal tolerated dosage, and at the end of the study. At baseline patients were asked if they were familiar with syncope, dizziness, low blood pressure, or if they experienced other complaints, such as palpitations. During the titration period and after 3 months of treatment, patients were asked about it again. At baseline, and after 3 months of treatment, a cardiopulmonary exercise test, echocardiography, arterial stiffness measurement, and blood sample were performed, as described later.
Exercise testing was performed on an upright bicycle ergometer (Jaeger ER 900; Viasys Healthcare, Höchberg, Germany) with breath-by-breath analysis using a flowmeter (Triple V volume transducer) and computerized gas analyzer (Jaeger Oxycon Champion, Viasys Healthcare or Carefusion Vyntus, Vyaire Medical). Starting wattage and workload increment per minute were determined by the age of the patient. Patients were encouraged to exercise until exhaustion. Tests were considered maximally performed when the peak respiratory exchange ratio was ≥1.0. Maximal exercise parameters were only assessed in patients with a maximal test. Peak work rate, heart rate at peak, peak oxygen uptake (VO 2 peak ), VO 2 peak per heartbeat, the respiratory minute to CO 2 production slope (VE/VCO 2 ), and the oxygen uptake efficiency slope were derived from the exercise test following previously published methods.
Transthoracic echocardiography was performed on a Vivid S6/S60 ultrasound machine (General Electric Healthcare, Norway). Images were stored and analyzed offline using EchoPac (version 203, GE Healthcare, Little Chalfont, United Kingdom). Measurements of 3 consecutive cardiac cycles were averaged for analysis. Pulse wave Doppler recordings were performed across the atrioventricular valve to assess early and late diastolic velocities and calculate the ratio of those velocities (E/A). Through Tissue Doppler imaging, myocardial velocity curves from the basal part of the single ventricles’ lateral wall and ventricular septum were obtained to assess peak systolic and peak early and late diastolic velocities. Furthermore, the ratio between the pulse wave and tissue Doppler peak early diastolic velocities (E/E′) of the lateral wall was calculated. Longitudinal global peak strain, evaluating systolic performance, was obtained from the dominant ventricle using speckle-tracking strain analysis from the 4-chamber apical view as previously described. To assess global longitudinal strain, at least 5 of 6 segments had to show acceptable curves. Furthermore, if the ventricular septum defect was larger than 1 segment, the strain was conducted from both lateral walls.
The oscillometric arteriograph device (Tensiomed, Budapest, Hungary) was used to measure pulse wave velocity of the aorta, augmentation index of the aorta, and central SBP. Measurements were performed in a supine position with the cuff on the left arm. The arteriograph software calculates average values and determines the accuracy of the measurement with an SD. Since automatic calculation was not always possible because of small pulse waves or movement, we analyzed each cardiac cycle individually using the software. Measurements were considered valid after a visual check and when a reliable value could be calculated with an SD of the pulse wave velocity of the aorta <1.0 m/s.
From a venous puncture plasma creatinine, urea, and N-terminal pro-B–type natriuretic peptide (NT-pro BNP) levels were assessed.
Data analysis was performed using SPSS Statistics software(Version 25.0 IBM SPSS, New York, United States).
Variables were tested for normality with histograms and QQ-plots. Continuous data are reported as mean ± SD or as median with first to third quartile (Q1-Q3) in case of non-normality. Categorical data are presented as a number with percentages. A paired sample t test or a Wilcoxon signed-rank test for non-normal distributed values were used for comparison between pre-enalapril and follow-up measurements. A p <0.05 was considered significant. The primary end point for this study was exercise performance and specifically the VO 2peak . Using Cohen’s D of 0.49 as effect size, calculated with mean and SD from previously published data, an alpha of 0.05% and 80% power, we calculated that 35 subjects would be sufficient to detect a 10% increase in VO 2 peak.
Results
A total of 74 Fontan patients were eligible for inclusion, of which 36 agreed to participate (49%). Patients who participated did not differ from those who did not in terms of age (median of 14.0 years [12.7 to 16.6] for participants vs 13.0 years [11.7 to 16.0] for nonparticipants, p = 0.364) and morphology of the main single ventricle (p = 0.374). As only 6 patients participated in the baseline measurements, a total of 30 patients were enrolled in this study and started with enalapril treatment. During the study 1 patient withdrew at the request of parents and 1 patient was excluded for further analysis because of medication noncompliance. The remaining 28 patients completed the study of whom baseline characteristics are summarized in Table 1 . Initial diagnosis and ventricular morphology differed in the group.
| Characteristics | n = 28 |
|---|---|
| Age (years) | 13.9 [13.0-16.7] |
| Males | 18 (64%) |
| Height (cm) | 164.1 (12.5) |
| Weight (kg) | 53.3 (12.6) |
| BSA (m 2 ) | 1.57 (0.2) |
| Oxygen saturation (%) | 95.6 (2.1) |
| Diagnosis | |
| Tricuspid atresia | 6 (21%) |
| Pulmonary atresia | 1 (4%) |
| Double inlet left ventricle | 4 (14%) |
| Double outlet right ventricle | 1 (4%) |
| Hypoplastic left heart syndrome | 8 (29%) |
| Unbalanced atrioventricular septal defect | 4 (14%) |
| Other | 4 (14%) |
| Main ventricle | |
| Left | 13 (46%) |
| Right | 12 (43%) |
| Undifferentiated | 3 (11%) |
| Age at Glenn operation (years) | 0.5 [0.37-0.75] |
| Age at Fontan operation (years) | 3.1 (0.6) |
| Type Fontan tunnel | |
| TCPC-EC | 28 (100%) |
| Initial Fenestration | 26 (92%) |
| Open | 1 (4%) |
| Closed (naturally or by device) | 25 (96%) |
An overview of blood pressure measurements and plasma urea and creatinine levels is shown in Table 2 . SBP was significantly lower during the study as compared with baseline. Plasma levels of urea and creatinine did not change significantly. Eleven patients could not reach the targeted dosage because of a decrease in SBP (n = 6, 21%) or other adverse events, consisting of syncope (n = 2), dizziness (n = 2), and palpitations (n = 1). Furthermore, 1 patient reported a hacking cough after completion of the study which disappeared after discontinuation of enalapril. This means that 21% of the patients experienced adverse events other than the predetermined drop in SBP, which was higher when compared with baseline where 2 patients (7.1%) reported that they were familiar with syncope (n = 2) and palpitations (n = 1). All patients completed the study with a mean dosage of 0.29 ± 0.1 mg/kg/day, dosages ranging from 5 to 20 mg/day.
| Week 1 | Week 2 | Week 3 | Week 5-6 | 3 Months | |
|---|---|---|---|---|---|
| Baseline | Control BP 1 | Control BP 2 | Control plasma urea and creatinine | Follow-up | |
| Systolic BP (mmHg) | 120.4 (9.2) | 109.9 * (12.5) | 111.0 † [99-119] | 117.7 † (10.2) | |
| ΔSBP from start (%) | -8.6 (10.2) | -7.3 (9.2) | |||
| Creatinine (umol/L) | 62.5 [56-68] | 64.5 [501-73] | 63.0 [58-72] | ||
| Urea (mmol/L) | 5.3 (±1.1) | 5.7 (±1.5) | 5.2 [4.5-6.38] |
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