Systolic performance of the single ventricle, exercise capacity, and endothelial function in pediatric Fontan patients

Abstract

Background

By age 40, roughly half of the individuals with Fontan circulation will have died or undergone heart transplantation. Poor exercise capacity and endothelial dysfunction accelerate disease progression.

Objective

This study aims to assess the systolic function of the single ventricle (SV) in pediatric Fontan patients entering an exercise intervention (RE-ENERGIZE FONTAN) and how it is associated with exercise capacity and endothelial function.

Methods

This cohort comes from an ongoing randomized trial in Fontan patients, using live video conferencing for supervised exercise. Participants (ages 8-19) cleared for exercise underwent 2D/3D echocardiograms, cardiopulmonary testing, and endothelial function (RHI). 2D longitudinal strain (LS, right ventricle), 2D global longitudinal strain (GLS, left ventricle), and circumferential strain were measured with TomTec, and 3D ejection fraction (3D-EF) and 3D-GLS were calculated.

Results

We have enrolled 114 Fontan patients. Median age was 12.7 years (IQR 10.2, 15.6). The median time from Fontan operation was 8.8 years (IQR 6.2, 12.0). Fifty-seven patients (50%) had a single right ventricle. SV systolic performance measures were: 2D-LS/GLS −15.6% ± 4.19%, circumferential strain was −18.7% ± 6.83%, 3D-EF 49.9% ± 7.26%, and 3D-GLS −16.8% ± 4.37%. Peak VO₂ was 1,290 ± 502 mL/min, and percent predicted peak VO₂ was 67.8% ± 15.6%. RHI was 1.44 ± 0.576. 2D-LS/GLS and 3D EF correlated with percent predicted peak VO₂ (R = −0.28, P = .007 and R = 0.24, P = .019). 3D-EF correlated positively with RHI (R = 0.29, P = .0071).

Conclusions

In this cohort of pediatric Fontan patients, SV systolic function was diminished at baseline, and there was a direct correlation between 2D strain and 3D-EF with percent predicted peak VO₂, and additionally, 3D-EF with endothelial function.

Clinical trial number

NCT04195451.

Background

Congenital heart disease (CHD) has a significant impact on the lives of children worldwide, and one of the most complex anatomies is single ventricle (SV) physiology, exemplified by patients with total cavo-pulmonary anastomosis or Fontan circulation. Patients with Fontan circulation have undergone a staged surgical palliation that redirects systemic venous blood directly to the pulmonary arteries, bypassing the heart. Pioneered in 1968, the Fontan procedure has improved survival rates in infants born today with SV physiology, with an estimated 30-year survival of ~80% to 85%.^1–4 However, long-term complications are frequent, given the hemodynamic changes, including elevated central venous pressures and nonpulsatile pulmonary circulation. Approximately 50% of Fontan patients will experience significant comorbidity in their lifetime, including liver and renal disease, protein-losing enteropathy, and plastic bronchitis.⁵ The factors contributing to the progression and mortality of these comorbidities in Fontan patients are not fully understood. However, it has been established in the literature that patients with SV physiology have decreased exercise capacity, which is a significant contributor to poor outcomes.^6–8 Specifically, longitudinal cardiopulmonary exercise testing (CPET) is essential for monitoring Fontan patients, as declining exercise capacity often precedes clinical deterioration. Fernandes et al. found that the hazard risk for mortality increased nearly 7-fold in those patients with a peak VO₂ (maximal oxygen uptake level).⁹ Additionally, a decline in percent predicted peak VO₂ of greater than 3% annually has been shown to be a predictor of the 5-year risk of cardiovascular adverse events.¹⁰ The impact of excess weight in this population cannot be overlooked, although none in this cohort met that criterion; prior studies have shown a correlation between low peak VO₂ performance and high rates of obesity.¹¹

Furthermore, Fontan patients also have endothelial dysfunction, which is known to contribute to disease progression.^12,13 Decreased endothelial function has been associated with reduced aerobic capacity in adolescents with Fontan circulation.¹⁴ The exact mechanisms underlying these factors may be related to impaired systolic performance of the SV, though it is not fully understood. As demonstrated in a recent study, echo indices of diastolic and systolic measures with medical management may explain improved exercise performance at the ventilatory anaerobic threshold observed in Fontan patients receiving udenafil.¹⁵ The absence of a subpulmonary ventricular pump, combined with passive pulmonary circulation, leads to altered systolic function.

Echocardiography remains an invaluable tool for assessing the systolic performance of the SV in Fontan patients. Novel measures like SV 3-dimensional ejection fraction (3D-EF) and strain analysis provide further information on ventricular volume, regional wall motion abnormalities, and overall systolic performance. Evaluation of SV anatomy and specifically 3D-EF has been shown to be well correlated with recognized standardized functional measurements, including magnetic resonance imaging.^16,17 Several studies have demonstrated decreased SV ejection fraction (EF) and abnormal ventricular mechanics at baseline in pediatric patients with Fontan circulation compared to healthy controls.^18–21 Additionally, strain analysis of the SV in patients with Fontan circulation has demonstrated reduced longitudinal and circumferential strain.²²

Exercise training improves cardiovascular health and exercise capacity in various patient populations, including children, adolescents, and young adults with congenital cardiac conditions.^23–25 Understanding the relationship between systolic function, strain, exercise capacity, and endothelial function in pediatric Fontan patients is crucial to developing appropriate cardiac rehabilitation programs to improve outcomes in this population. Here, we present baseline data in pediatric Fontan patients prior to entering an ongoing exercise intervention (RE-ENERGIZE FONTAN), specifically the systolic performance of the SV and its association with exercise capacity and endothelial function.

Methods

An overview of the methodology for patient selection and baseline study testing is outlined below. Detailed descriptions of each outcome measure and detailed study design can be found in the original RE-ENERGIZE FONTAN Trial Design manuscript.²⁶

Patient selection and recruitment

Patients must meet all the following inclusion criteria for study participation: (1) 8 to 19 years of age at the time of the baseline study visit; (2) Fontan operation; (3) Ability to fast overnight; (4) cardiac clearance to exercise by a primary cardiologist; (5) Presence of an adult at home during exercise sessions for patients <14 years old; (6) English-speaking proficiency. Patients are excluded if they meet any of the following criteria: (1) NYHA Class IV (severe heart failure); (2) Acute illness within the past 3 months; (3) Active protein-losing enteropathy (albumin <2.5 mg/dL); (4) Implanted pacemaker; (5) Cognitive delay deemed severe enough to inhibit the ability to follow the exercise program.

To ensure accessibility to patients from different socioeconomic backgrounds, all enrolled patients will receive a tablet, which they can keep, along with Internet service during the intervention if Internet access is insufficient for video conferencing at home.

Study recruitment is conducted following the protocol approved by the Stanford Institutional Review Board. Through the Lucile Packard Children’s Hospital (LPCH) Stanford Heart Center, incoming patients are screened and approached if all eligibility criteria are met. Consented patients are randomly assigned to the intervention or control groups (receiving usual care). The randomization process utilizes the SAS Proc Plan (SAS9.4, SAS Institute, Inc., Cary, NC) and considers 2 stratification variables: Tanner Stage (5 stages) and sex (M/F). This method aims to address potential confounding biological factors. The study coordinator inputs the Tanner stage score and sex into the randomizing module on REDCap and informs the participants of their assignment at the end of the baseline visit.

Testing protocol

Following enrollment, patients are scheduled for a baseline study visit. At the visit, the medical team collects data on each participant’s temperature, height, weight, blood pressure, and medical history. Subsequently, participants undergo various testing protocols as described below (Figure 1):

Figure 1.

We analyzed baseline data in Fontan patients entering a randomized controlled trial utilizing live-video conferencing to deliver a supervised exercise intervention. In this cohort, single ventricle (SV) systolic function was diminished and there was a direct correlation between SV systolic function and endothelial function.

Echocardiogram parameters

According to our imaging protocol, we obtain echocardiograms utilizing Philips Epiq ultrasound systems (Philips Epiq CVx, Philips Ultrasound USA, Andover, MA). Offline analysis includes 3-dimensional (3D) echocardiography data to produce 3D diastolic and systolic volumes, EF, and 3D global longitudinal strain (GLS) using Tom-Tec software, Cardiac Performance Analysis 1 version 51.02 (Cardiac Analysis 1, version 51.02, TomTec Corp., Chicago, IL). We measure EF by the 5/6 Area-Length method (morphologic left ventricle (LV)), fractional area change (FAC, morphologic right ventricle (RV)), 2D global longitudinal strain (GLS LV/longitudinal strain (LS) RV), and circumferential strain values. Normative values used for reference in this study include: 3D-EF for systemic RV and LV >55%,²⁷ 2D mean LV GLS of −20.2% with a 95% CI −20.8% to −19.6%,²⁸ 2D mean RV LS of −29.0% with a 95% CI −31.5% to −26.5%,²⁹ 3D mean LV GLS of −19.8% with a 95% CI −18.9% to −20.8%,³⁰ and circumferential strain of −17% with a 95% CI of −20% to −13%.³¹

Cross-sectional images of the SV are acquired to measure the LS from a mid-ventricular view. Apical 4-chamber images of the single LV or RV are obtained with modifications to the standard plane to allow optimal visualization of the ventricular apex and free wall. Temporal resolution is optimized to achieve frame rates within 10 percent of the heart rate to produce cine-loops at or near 60 frames per cardiac cycle. Automated analysis is employed using the TomTec software, with adjustments made as necessary by the analyzing investigator to refine the position of the atrioventricular annular plane and the endocardial border detection. Next, using 3D volume acquisitions, the software generates a 3D rendering of the SV throughout the cardiac cycle and includes necessary adjustments by the analyzing investigator to refine the endocardial detection (Figure 2). Analysis of the 3D dataset includes calculations of diastolic and systolic volumes and EF. Where possible, GLS using 3D imaging is acquired using a 3-beat capture and a 6-beat stitch protocol. The frame rate is modulated to be within 10 percent of the heart rate to produce data at or near 60 frames per cardiac cycle. The 3D datasets are used for the single LV and RV using the 4D LV-Analysis 3. A total of 21 patients in the cohort (10 with RV morphology and 11 with LV) could not have circumferential strain obtained due to poor windows. 3D strain was feasible in 95 of 114 participants (83%). Image quality, arrhythmia, or stitching artifact prevented analysis in the remainder.

Figure 2.

Three-dimensional echocardiography rendering: Offline analysis Using Tom-Tec software produced 3D diastolic and systolic volumes, ejection fraction, and global longitudinal strain.

Endothelial function testing

Assessment of endothelial function is conducted using a noninvasive diagnostic test, EndoPAT (Endothelial Peripheral Arterial Tone, Itamar Medical Ltd.). EndoPAT is designed to measure endothelial function using the concept of reactive hyperemia. A detailed EndoPAT testing protocol is performed following a previously published laboratory protocol.³² Participants lie flat with their arms resting comfortably by their side. A pneumatic finger probe is placed on each index finger to measure the pulse-wave amplitude throughout the entirety of the 20-minute test (Figure 3): 5-minute baseline recording, 5-minute occlusion of the brachial artery in the nondominant arm using a blood pressure cuff, and 10-minute postocclusion recording. The data obtained is analyzed through computer-automated software (ENDOPAT 2000 Version 3.62) to determine the reactive hyperemia index (RHI). The endothelium’s ability to dilate and regulate blood flow is an essential indicator of vascular health, with a lower RHI suggesting impaired endothelial function. Feasibility and normal values for RHI and lnRHI have been published by the study team, with a threshold of 1.9 established as normal in healthy pediatric populations.³²

Figure 3.

Endothelial pulse amplitude testing (EndoPAT) pneumatic finger probe: a measure of peripheral arterial blood flow, a probe was placed on the index finger of each participant over a 20-minute duration to measure the pulse-wave amplitude of the brachial artery. This data is then analyzed to determine the reactive hyperemia index (RHI).

Cardiopulmonary exercise stress test

The subjects undergo progressive CPET with continuous monitoring by 12-lead electrocardiogram (EKG) and gas exchange by measuring breath-to-breath ventilation. The cardiopulmonary exercise test is performed using a clinical laboratory protocol (ramping protocol) on the treadmill, with peak VO₂ as the primary measure of cardiopulmonary fitness and aerobic capacity. The test is performed in a temperature-controlled laboratory using a MedGraphics Ultima Cardio2/PFX metabolic cart and a Trackmaster TMX428CP treadmill. The pneumotach is calibrated daily, and the gas analyzer is calibrated before each test. Once baseline blood pressure (every 2-3 minutes), EKG (continuous), and oxygen saturation (O₂) (continuous) are obtained, the participants undergo a symptom-limited treadmill test using a continuous ramping protocol. The test begins with a gradual increase in speed. Once the patient reaches 3 mph, both the speed and incline of the treadmill are increased until peak exercise, measured as Respiratory Exchange Ratio (RER > 1.0), is reached. The participants breathe through a low-resistance mouthpiece and a pneumotach while exercising to volitional exhaustion. Gas exchange is analyzed continuously using a breath-by-breath technique and rapid-response O₂ and carbon dioxide (CO₂) analyzers. The percent predicted peak VO₂ is calculated for all participants using the following formula: 28.5 × weight + 288.2 for girls <18 years of age; 52.8 × weight - 303.4 for boys <18 years of age.³³ Indexed peak VO₂ was calculated by dividing absolute peak VO₂ (mL/min) by weight (kg). CPET was generally performed after the echocardiogram was completed. However, in cases where there was variability in this timing sequence, at least 20 minutes was allowed after the CPET was completed and the echocardiogram was initiated.

Statistical methods

Summarized statistics were used to describe patients at the baseline with mean (standard deviation, SD) or median (Interquartile range, IQR) for continuous variables and proportions for categorical variables. Pearson correlations were calculated to explore the relationship between echocardiography parameters and secondary outcomes. A P-value <.05 was considered statistically significant, and 2-sided tests of hypotheses were used throughout. Inter-observer variability of RV and LV EF, RV LS, LV GLS, and RV and LV 3D GLS was calculated by blinded repeat analysis of 10 randomly chosen patients. All analyses were performed using R (version 4.2.1, R Foundation for Statistical Computing) with appropriate adjustments and exclusions for missing data.

Baseline results on the enrolled patients

Patients

Baseline anthropometric results are summarized in Table 1. The participating cohort’s median height and weight were 151 cm and 45.5 kg, respectively. Median baseline systolic and diastolic blood pressures were 108/63, with a mean blood pressure of 73 mmHg.

Table 1.

Baseline anthropometric characteristics of the cohort

Baseline anthropometrics	Median [IQR]
Height (cm)	151 [137, 165]
Height z-score	−0.525 [−1.06, 0.229]
Weight (kg)	45.5 [31.9, 60.6]
Weight z-score	−0.0389 [−0.924, 1.02]
Body surface area (m2)	1.40 [1.10, 1.68]
BMI (kg/m2)	19.5 [16.3, 24.5]
BMI z-score	0.391 [−0.816, 1.40]
Systolic blood pressure (mmHg)	108 [101, 115]
Diastolic blood pressure (mmHg)	63 [58, 68]
Mean blood pressure (mmHg)	73 [69, 80]

Data are presented as median (IQR).

Baseline demographic results are summarized in Table 2. About 114 patients completed the outlined baseline study components, 68 males (60%). The participants had a median age of 12.7 years at their initial baseline visit and were 8.8 years post-Fontan procedure. The overall SV morphology breakdown was 57 participants (50%) with a single LV and 57 (50%) with a single RV. Fifty-eight patients (51%) were on an angiotensin-converting enzyme (ACE) inhibitor, twenty-three (20%) were on a diuretic medication, and 6 (5%) were on beta-blockers. Eighty-one participants (71%) had a New York Heart Association (NYHA) functional classification of I, thirty-two (28%) were classified II, 1 participant was classified III, and no participants were classified IV.

Table 2.

Baseline demographic and clinical characteristics

Demographics and clinical characteristics	n (% of total or within category) or median [IQR] N= 114
Sex (male/female)	68 (60%)/ 46 (40%)
Age at baseline visit (years)	12.7 [10.2, 15.6]
Time since Fontan procedure (years)	8.8 [6.2, 12.0]
Race/Ethnicity
White, non hispanic	35 (31%)
Black, non hispanic	2 (2%%)
Hispanic	58 (51%)
Tanner stage
1	35 (31%)
2	23 (20%)
3	17 (15%)
4	27 (24%)
5	12 (11%)
Single ventricle morphology
RV	57 (50%)
LV	57 (50%)
NYHA functional classification
I	81 (71%)
II	32 (28%)
III	1 (1%)
IV	0 (0%)
Medication use
ACE	58 (51%)
Diuretic	23 (20%)
Beta-Blocker	6 (5%)

ACE, angiotensin-converting enzyme inhibitors; NYHA, New York Heart Association.

Data are presented as percentages or medians [IQR] as appropriate.

Echocardiogram

As summarized in Table 3 and shown in Figure 1, the mean 3D-EF was diminished at 49.9%. Participants had an overall mean 2D-LS/GLS of −15.6% ± 4.19%. The mean 3D GLS was −16.8% ± 4.37%. Circumferential strain was −18.7% ± 6.83%.

Table 3.

Baseline testing results

Baseline results	Mean (SD)
Echocardiographic parameters
2D longitudinal strain (RV)/Global longitudinal strain (LV) (%)	−15.6 (± 4.19)
3D ejection fraction (%)	49.9 (± 7.26)
3D global longitudinal strain (%)	−16.8 (± 4.37)
Circumferential strain (%)	−18.7 (± 6.83)
Cardiopulmonary exercise testing
Peak VO2 (mL/min)	1,290 (± 502)
Indexed peak VO2 (mL/kg/min)	27.9 (± 6.48)
Percent predicted peak VO2 (%)	67.8 (± 15.6)
Endothelial pulse amplitude testing
EndoPAT index (RHI)	1.44 (± 0.576)
Natural log EndoPAT index (lnRHI)	0.308 ( ± 0.349)

3D, 3-dimensional; EndoPAT, endothelial pulse amplitude testing; LV, left ventricle; RHI= reactive hyperemia index; RV, right ventricle; VO₂, oxygen uptake level. Data are presented as mean ± standard deviation.

Cardiopulmonary fitness

Baseline cardiopulmonary fitness results are summarized in Table 3. In this cohort, the mean peak VO₂ was 1,290 ± 502 mL/min, with a mean indexed peak VO₂ of 27.9 ± 6.48 mL/kg/min. The percent predicted peak VO₂ was 67.8% ± 15.6%.

Endothelial function

The EndoPAT index or RHI was 1.44 ± 0.576, with lower values indicating impaired endothelial function. The natural log (lnRHI) was 0.308 ± 0.349 (Table 3).

Correlations between echocardiographic parameters and exercise capacity and endothelial function

2D-LS/GLS and 3D EF correlated with percent predicted peak VO₂ (R = −0.28, P = .007 and R = 0.24, P = .019, respectively). 3D-EF had a modest correlation with vascular testing metrics, including the RHI (R = 0.29, P = .0071) and the lnRHI (R = 0.24, P = .03). No significant association was found between 2D-LS/GLS and vascular testing or 3D strain and the measured outcomes (Figure 4). Circumferential strain was not found to be associated with measures of either CPET or endothelial function.

Figure 4.

Correlations between single-ventricle echocardiographic parameters and baseline exercise parameters. The 3 echocardiogram-derived measurements include 2D Longitudinal strain (RV = Right ventricle)/Global longitudinal strain (LV = Left ventricle), 3D Ejection fraction, and 3D Global longitudinal strain. Each parameter was analyzed with 4 baseline exercise measures plotted above in the following order: peak VO₂, percent predicted peak VO₂, RHI, and log RHI. There was a direct correlation between 3D-EF and endothelial function as well as 2D strain and 3D-EF with percent predicted peak VO2.

Subgroup analysis

Supplementary correlation analysis was performed between 3D-EF and FAC for single RV patients (R = 0.34, P < .001) and 5/6 area/length for single LV patients (R = 0.62, P < .001); Supplementary Figures 1, 2. In patients with single RV morphology, 3D-EF was 47.4% ± 6.6% as compared to a single LV at 52.4% ± 7.0%, P = .00054; Supplementary Figure 3. Additionally, 2D strain analysis was performed specifically for SV anatomy categorization, with LS calculated for single RV and GLS completed for single LV. Single RV had lower LS −14.7% ± 4.42% vs −16.5% ± 3.78% (P = .027) compared to the patients with single LV morphology; Supplementary Figure 4. 2D RV circumferential strain was −16.7% ± 6.02% and an LV circumferential strain of −20.8% ± 7.06% (P = .0096); Supplementary Figure 5. 3D RV GLS of −16.0% ± 4.54% and a 3D LV GLS of −17.5% ± 4.13% (P = .128); Supplementary Figure 6.

Discussion

Although exercise training has been shown to enhance exercise capacity, cardiac function, and quality of life in Fontan patients, the optimal training modality, intensity, duration, and long-term outcomes have not yet been clearly defined. Our baseline echocardiographic, vascular, and exercise stress tests confirm that this cohort of post-Fontan children and adolescents has reduced systolic function by 3D echocardiography and strain values, abnormal endothelial health by EndoPAT testing, and reduced percent predicted peak VO2 by exercise testing. Baseline data from this study are presented in relation to previously established normative values in control groups as described in the methods subsection above. These results highlight the limitations of the Fontan circulation, even in relatively healthy Fontan patients. While exercise training in Fontan patients has been explored previously, this study offers one of the largest and most comprehensive baseline characterizations of systolic function, endothelial function, and exercise capacity in this population to date.

Despite improvements in surgical techniques, postoperative care, and longitudinal surveillance, long-term morbidity-free survival for pediatric Fontan patients remains low, with many experiencing arrhythmia, thromboembolic events, surgical re-intervention, and cardiac transplantation as they move into adolescence and adulthood. Lower exercise capacity is associated with worse outcomes; however, exercise programs for those with a Fontan circulation have largely been localized to a few centers and have not been incorporated more generally into clinical care practices. Furthermore, this study focuses on a novel set of outcomes with echocardiographic, exercise, and vascular parameters in a large cohort of pediatric Fontan patients. Here, we report the systolic function of the SV in a cohort of pediatric Fontan patients entering an exercise intervention (RE-ENERGIZE FONTAN) and how it is associated with exercise capacity and endothelial function.

Echocardiogram parameters and exercise testing

Prior studies have demonstrated the utility of echocardiography in assessing these patients’ systolic performance using measures, such as function and strain (longitudinal, global, and circumferential), as helpful predictive tools in monitoring Fontan patients.³⁴ The increased implementation of 3D analysis in pediatric echocardiographic laboratories can be a valuable tool for longitudinal follow-up and risk-stratifying these patients. 3D echocardiographic analysis of Fontan patients has been proven feasible and correlated in our study with the percent predicted peak VO₂, the gold standard for cardiopulmonary fitness.³⁵

Strain has become an important prognostic tool for long-term health management in Fontan patients. A recent study in hypoplastic left heart syndrome patients with subsequent Fontan palliation found that higher GLS and global circumferential strain of the SV served as independent predictive variables for mortality or need for transplant.³⁴ This study again highlights the correlation that exists between 2D-LS/GLS and CPET, providing a key area of follow-up in future studies.

Echocardiogram parameters and endothelial function

The baseline results of this study illuminate 2 significant issues related to the Fontan circulation. First is the intricate relationship between SV systolic performance and endothelial function. Second is the observed correlations between systolic performance indices, such as EF and strain, and endothelial function measures, which underscore the pivotal role of ventricular function in influencing the patients’ long-term cardiovascular health. These findings emphasize the need to evaluate both cardiac mechanics and vascular health in the long-term follow-up of Fontan patients. Furthermore, assessing endothelial function contributes a novel dimension to understanding Fontan physiology, with prior research demonstrating abnormal endothelial function in a cohort of asymptomatic Fontan patients.¹³ The observed impairments in endothelial function, reflected by reduced vascular reactivity, point toward potential underlying mechanisms that may contribute to exercise limitations and cardiovascular complications in these patients.^36,37 In individuals with ischemic heart failure, EndoPAT testing has emerged as an independent predictor of mortality within 1 year.³⁸ However, studies have not robustly studied this potential relationship in Fontan patients.

The American Heart Association recommends regular exercise in high-risk pediatric patients (which includes those with Fontan physiology).³⁹ Prior studies of other patients with congenital heart disease have shown that aerobic capacity and quality of life increase after participating in an exercise and cardiac rehabilitation program.^40,41 Additionally, Ferrer-Sargues et al. reported on a 3-month cardiac rehabilitation regimen for 15 patients with CHD after undergoing corrective surgery or heart transplant.⁴² Their analysis showed substantial compliance with the program and noteworthy improvements in muscle strength and the 6-minute walk test. Notably, these benefits persisted even during a reevaluation 6 months postprogram . When completed, our RE-ENERGIZE FONTAN study will be the largest cohort and most comprehensive assessment of an exercise intervention in the pediatric SV population.

Limitations

Our study design does not include a control arm with healthy patients. When available, gender-specific data and healthy normative control values were presented; however, there are limited agreed-upon existing normative values in the literature, a limitation of this study. Additionally, these results may not be generalizable to all Fontan patient populations, given the inherent participation bias of those taking part in this exercise program. There may be an inherent increased interest in exercise participation that may not be applicable to all populations. Additional limitations include the cross-sectional design and inability to control for potential confounders such as age, pubertal status, ACE inhibitor use, or arrhythmia. These factors may influence both vascular and functional outcomes.

Conclusions

In this cohort of pediatric Fontan patients, SV systolic function was diminished at baseline, and there was a direct correlation between 3D-EF and endothelial function and percent predicted peak VO_2, as well as 2D-LS/GLS and percent predicted peak VO₂. Within the existing literature landscape, a discernible gap exists about the comprehensive exploration of the programmatic intricacies involved in implementing such interventions within this unique patient demographic. Following randomization and clinical trial completion, analysis of the current study’s results will reveal the impact and feasibility of the proposed lifestyle intervention. By scrutinizing echocardiographic, vascular, and exercise changes, this investigation aims to shed light on the intricate nuances of the intervention’s effects, contributing significantly to understanding the patient’s overall well-being. The overarching objective is to facilitate the seamless integration of a comparable “exercise prescription” within diverse clinical settings, targeting the long-term care needs of pediatric Fontan patients. This strategic integration, with a spotlight on echocardiographic parameters, seeks to redefine the landscape of post-Fontan care by emphasizing nonpharmaceutical approaches to reduce long-term morbidity and mortality.

Supplementary Material

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ahj.2025.05.015.