Longitudinal Follow-Up of Children With HLHS and Association Between Norwood Shunt Type and Long-Term Outcomes: The SVR III Study.

OBJECTIVE: In the SVR trial (Single Ventricle Reconstruction), newborns with hypoplastic left heart syndrome were randomly assigned to receive a modified Blalock-Taussig-Thomas shunt (mBTTS) or a right ventricle-to-pulmonary artery shunt (RVPAS) at Norwood operation. Transplant-free survival was superior in the RVPAS group at 1 year, but no longer differed by treatment group at 6 years; both treatment groups had accumulated important morbidities. In the third follow-up of this cohort (SVRIII [Long-Term Outcomes of Children With Hypoplastic Left Heart Syndrome and the Impact of Norwood Shunt Type]), we measured longitudinal outcomes and their risk factors through 12 years of age. METHODS: Annual medical history was collected through record review and telephone interviews. Cardiac magnetic resonance imaging (CMR), echocardiogram, and cycle ergometry cardiopulmonary exercise tests were performed at 10 through 14 years of age among participants with Fontan physiology. Differences in transplant-free survival and complication rates (eg, arrhythmias or protein-losing enteropathy) were identified through 12 years of age. The primary study outcome was right ventricular ejection fraction (RVEF) by CMR, and primary analyses were according to shunt type received. Multivariable linear and Cox regression models were created for RVEF by CMR and post-Fontan transplant-free survival. RESULTS: Among 549 participants enrolled in SVR, 237 of 313 (76%; 60.7% male) transplant-free survivors (mBTTS, 105 of 147; RVPAS, 129 of 161; both, 3 of 5) participated in SVRIII. RVEF by CMR was similar in the shunt groups (RVPAS, 51±9.6 [n=90], and mBTTS, 52±7.4 [n=75]; P=0.43). The RVPAS and mBTTS groups did not differ in transplant-free survival by 12 years of age (163 of 277 [59%] versus 144 of 267 [54%], respectively; P=0.11), percentage predicted peak Vo2 for age and sex (74±18% [n=91] versus 72±18% [n=84]; P=0.71), or percentage predicted work rate for size and sex (65±20% versus 64±19%; P=0.65). The RVPAS versus mBTTS group had a higher cumulative incidence of protein-losing enteropathy (5% versus 2%; P=0.04) and of catheter interventions (14 versus 10 per 100 patient-years; P=0.01), but had similar rates of other complications. CONCLUSIONS: By 12 years after the Norwood operation, shunt type has minimal association with RVEF, peak Vo2, complication rates, and transplant-free survival. RVEF is preserved among the subgroup of survivors who underwent CMR assessment. Low transplant-free survival, poor exercise performance, and accruing morbidities highlight the need for innovative strategies to improve long-term outcomes in patients with hypoplastic left heart syndrome. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT0245531.

Cardiopulmonary exercise testing on adaptive equipment in children and adults with Friedreich ataxia.

INTRODUCTION/AIMS: Traditional exercise is often difficult for individuals with Friedreich ataxia (FRDA), and evidence is limited regarding how to measure exercise performance in this population. We evaluated the feasibility, reliability, and natural history of adaptive cardiopulmonary exercise test (CPET) performance in children and adults with FRDA. METHODS: Participants underwent CPET on either an arm cycle ergometer (ACE) or recumbent leg cycle ergometer (RLCE) at up to four visits (baseline, 2 weeks, 4 weeks, and 1 year). Maximum work, oxygen consumption (peak VO2), oxygen (O2) pulse, and anaerobic threshold (AT) were measured in those who reached maximal volition. Test-retest reliability was assessed with intraclass coefficients, and longitudinal change was assessed using regression analysis. RESULTS: In our cohort (N = 23), median age was 18 years (interquartile range [IQR], 14-23), median age of FRDA onset was 8 years (IQR 6-13), median Friedreich Ataxia Rating Scale score was 58 (IQR 54-62), and GAA repeat length on the shorter FXN allele (GAA1) was 766 (IQR, 650-900). Twenty-one (91%) completed a maximal CPET (n = 8, ACE and n = 13, RLCE). Age, sex, and GAA1 repeat length were each associated with peak VO2. Preliminary estimates demonstrated reasonable agreement between visits 2 and 3 for peak work by both ACE and RLCE, and for peak VO2, O2 pulse, and AT by RLCE. We did not detect significant performance changes over 1 year. DISCUSSION: Adaptive CPET is feasible in FRDA, a relevant clinical trial outcome for interventions that impact exercise performance and will increase access to participation as well as generalizability of findings.

The Fontan Udenafil Exercise Longitudinal Trial: Subgroup Analysis.

The Pediatric Heart Network's Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT02741115) demonstrated improvements in some measures of exercise capacity and in the myocardial performance index following 6 months of treatment with udenafil (87.5 mg twice daily). In this post hoc analysis, we evaluate whether subgroups within the population experienced a differential effect on exercise performance in response to treatment. The effect of udenafil on exercise was evaluated within subgroups defined by baseline characteristics, including peak oxygen consumption (VO2), serum brain-type natriuretic peptide level, weight, race, gender, and ventricular morphology. Differences among subgroups were evaluated using ANCOVA modeling with fixed factors for treatment arm and subgroup and the interaction between treatment arm and subgroup. Within-subgroup analyses demonstrated trends toward quantitative improvements in peak VO2, work rate at the ventilatory anaerobic threshold (VAT), VO2 at VAT, and ventilatory efficiency (VE/VCO2) for those randomized to udenafil compared to placebo in nearly all subgroups. There was no identified differential response to udenafil based on baseline peak VO2, baseline BNP level, weight, race and ethnicity, gender, or ventricular morphology, although participants in the lowest tertile of baseline peak VO2 trended toward larger improvements. The absence of a differential response across subgroups in response to treatment with udenafil suggests that the treatment benefit may not be restricted to specific sub-populations. Further work is warranted to confirm the potential benefit of udenafil and to evaluate the long-term tolerability and safety of treatment and to determine the impact of udenafil on the development of other morbidities related to the Fontan circulation.Trial Registration NCT0274115.

The pediatric heart network's study on long-term outcomes of children with HLHS and the impact of Norwood Shunt type in the single ventricle reconstruction trial cohort (SVRIII): Design and adaptations.

BACKGROUND: The Single Ventricle Reconstruction (SVR) Trial was the first randomized clinical trial of a surgical approach for treatment of congenital heart disease. Infants with hypoplastic left heart syndrome (HLHS) and other single right ventricle (RV) anomalies were randomized to a modified Blalock Taussig Thomas shunt (mBTTS) or a right-ventricular-to-pulmonary-artery shunt (RVPAS) at the time of the Norwood procedure. The aim of the Long-term Outcomes of Children with HLHS and the Impact of Norwood Shunt Type (SVR III) study is to compare early adolescent outcomes including measures of cardiac function, transplant-free survival, and neurodevelopment, between those who received a mBTTS and those who received an RVPAS. METHODS: Transplant-free survivors of the SVR cohort were enrolled at 10 to 15 years of age for multifaceted in-person evaluation of cardiac function (cardiac magnetic resonance [CMR], echocardiogram and exercise test) and neurodevelopmental evaluation. Right ventricular ejection fraction measured by CMR served as the primary outcome. Development of arrhythmias, protein losing enteropathy, and other comorbidities were assessed through annual medical history interview. Through the course of SVR III, protocol modifications to engage SVR trial participants were designed to enhance recruitment and retention. CONCLUSIONS: Evaluation of long-term outcomes will provide important data to inform decisions about the shunt type placed at the Norwood operation and will improve the understanding of cardiovascular and neurodevelopmental outcomes for early adolescents with HLHS.

Safety and Feasibility of Exercise Rehabilitation in Children with Ventricular Assist Devices.

Children with advanced heart failure may require ventricular assist devices (VAD) while awaiting heart transplantation. Currently, no data exist regarding the safety of exercise rehabilitation (ER) in children on VAD support. The purpose of this study was to determine the safety and feasibility of ER in children on VAD support awaiting heart transplantation. Eligible patients underwent VAD placement between 1998 and 2019; both inpatient and outpatient participants were included. After VAD implantation and when ambulatory, patients were enrolled in ER. Exercise sessions were scheduled three times a week and consisted of aerobic and musculoskeletal conditioning. A total of 29 patients (59% male, mean age 14 ± 3.2 years) were included with a median VAD duration of 120 ± 109 days. Cardiac diagnoses included cardiomyopathy (81%) and congenital heart disease (19%). VAD type included pulsatile (59%) and continuous-flow devices (41%). Eight hundred and sixty-four (85%) ER sessions were successfully completed and began at a mean of 49 days (range 19-108) after VAD implant. No adverse events, including episodes of hypotension, significant complex arrhythmia, or VAD malfunction occurred during exercise testing or ER, and no sessions were discontinued prematurely. Pediatric patients on VAD support can safely participate in ER with relatively high compliance, and sessions can be implemented early after VAD implantation. Given the safety profile, ER in pediatric VAD recipients, which is a modifiable pre-transplant risk factor that may improve functional capacity, warrants further study as a potential modality to improve post-transplant outcomes.

Practices and Procedures in Clinical Pediatric Exercise Laboratories in North America.

Interinstitutional differences in clinical pediatric exercise laboratory (CPEL) practices may affect patient care and efficacy of multicenter research. PURPOSE: To describe current practices/procedures in CPELs and explore differences in CPELs employing exercise physiologists to those that do not. METHODS: A 40-item survey was distributed to CPELs in North America focusing on (1) staffing; (2) exercise stress testing (EST) volumes, reporting, and interpretation; and (3) EST procedures/protocols. RESULTS: Of the 55 responses, 89% were in the United States, 85% were children's hospitals with university affiliation, and 58% were cardiology specific. Exercise physiologists were employed in 56% of CPELs, and 78% had master's degrees or higher. Certifications were required in most CPELs (92% emergency life-support, 27% professional, and 21% clinical). Median volume was 201 to 400 ESTs per year, 80% used treadmill, and 10% used cycle ergometer as primary modalities. Ninety-three percent of CPELs offered metabolic ESTs, 87% offered pulmonary function testing, 20% used institution-specific EST protocols, and 72% offered additional services such as cardiac/pulmonary rehabilitation. CPELS staffing exercise physiologists performed higher volumes of ESTs (P = .004), were more likely to perform metabolic ESTs (P = .028), participated in more research (P < .001), and provided services in addition to ESTs (P = .001). CONCLUSIONS: Heterogeneity in CPELs staffing and operation indicates need for standardization.

Assessing the utility of screening electrocardiograms in paediatric patients following COVID-19.

OBJECTIVE: To determine the utility of screening electrocardiograms after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among children in detecting myocarditis related to coronavirus disease 2019 (COVID-19). STUDY DESIGN: A retrospective chart review was performed at a large paediatric academic institution to identify patients with prior SARS-CoV-2 infection who received a screening electrocardiogram by their primary care providers and were subsequently referred for outpatient cardiology consultation due to an abnormal electrocardiogram. The outcomes were the results from their cardiology evaluations, including testing and final diagnoses. RESULTS: Among 46 patients, during their preceding COVID-19 illness, the majority had mild symptoms, 4 were asymptomatic, and 1 had moderate symptoms. The median length of time from positive SARS-CoV-2 test to screening electrocardiogram was 22 days, and many electrocardiogram findings that prompted cardiology consultation were normal variants in asymptomatic adolescent athletes. Patients underwent frequent additional testing at their cardiology appointments: repeat electrocardiogram (72%), echocardiogram (59%), Holter monitor (11%), exercise stress test (7%), and cardiac MRI (2%). Five patients were incidentally diagnosed with CHD or structural cardiac abnormalities, and three patients had conduction abnormalities (pre-mature atrial contractions, pre-mature ventricular contractions, borderline prolonged QTc), although potentially incidental to COVID-19. No patients were diagnosed with myocarditis or ventricular dysfunction. CONCLUSION: In a small cohort of children with prior COVID-19, who were primarily either asymptomatic or mildly symptomatic, subsequent screening electrocardiograms identified various potential abnormalities prompting cardiology consultation, but no patient was diagnosed with myocarditis. Larger multi-centre studies are necessary to confirm these results and to evaluate those with more severe disease.

Observation of Aerosol Generation by Human Subjects During Cardiopulmonary Exercise Testing Using a High-Powered Laser Technique: A Pilot Project.

Purpose: Human respiratory aerosols may have important implications for transmission of pathogens. The study of aerosol production during vigorous breathing activities such as exercise is limited. In particular, data on aerosol production during cardiopulmonary exercise testing (CPET) are lacking. Methods: In this pilot project, we used a high-powered, pulsed Nd:YAG laser to illuminate a region of interest in front of two healthy adult subjects during CPET. Subjects exercised to the point of respiratory compensation. Images were captured with a high-speed, high-resolution camera to determine net exhaled particle (NEP) counts at different phases of CPET, including resting breathing, submaximal exercise, peak exercise, and active recovery. Experiments were performed with the room ventilation activated. Results: Net exhaled particle counts remained relatively constant until late/peak exercise when they decreased prior to rebounding into recovery. NEP counts at resting breathing were higher than those reported using other methods of measurement. Exhaled particles were in the submicron size range. Conclusion: Our method of aerosol particle quantification enables measurement of significant quantities of ultrafine particles and dynamic assessment of aerosol production during CPET. The unique pattern of aerosol production observed during submaximal and peak exercise suggests that extension of results from resting breathing to CPET may not be appropriate.

Results of the FUEL Trial.

BACKGROUND: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. METHODS: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. RESULTS: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (-0.2%) in the placebo group (P=0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus -9±193 [-0.9%] mL/min, P=0.012), ventilatory equivalents of carbon dioxide (-0.8 versus -0.06, P=0.014), and work rate (+3.8 versus +0.34 W, P=0.021). There was no difference in change of myocardial performance index, the natural log of the reactive hyperemia index, or serum brain-type natriuretic peptide level. CONCLUSIONS: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02741115.

Normative Values for Cardiopulmonary Exercise Stress Testing Using Ramp Cycle Ergometry in Children and Adolescents.

OBJECTIVES: To provide sex, age, and race specific reference values for ramp cycle ergometer cardiopulmonary exercise test (CPET) in children in the US. STUDY DESIGN: Retrospective review was conducted of all cardiopulmonary CPET data from our Exercise Physiology Laboratory on healthy children and adolescents (6-18 years) with body mass index between the 5th and 95th percentiles and structurally normal hearts who performed a ramp cycle ergometry stress test between 1999 and 2015. Twenty-eight exercise variables were included: peak oxygen consumption, oxygen consumption at ventilatory anaerobic threshold, peak work rate, resting and peak heart rate and blood pressure, resting pulmonary function testing, and ventilatory responses to progressive exercise using breath-by-breath gas exchange. Owing to the nonlinear association between CPET results and age, fractional polynomials were used in the mixed-effects regression models to describe the sex- and age-specific normative values with 95% CIs, after adjusting for race and body mass index. RESULTS: We analyzed data on 1829 children (average age, 13.6 ± 2.6 years; 52% male). After 12 years of age, males generally had higher peak values for aerobic capacity and work rate. There were progressive increases with age for both sexes in resting pulmonary function and ventilatory response to exercise, peak aerobic and work rate, and oxygen pulse. Notably, there was an age-related decrease in ventilatory equivalents of oxygen and carbon dioxide at the ventilatory anaerobic threshold. CONCLUSIONS: Future research using prospective, inclusive, and statistically planned cohorts with standardized laboratory approaches and confirmed interoperability should be considered as a focus for validating normative pediatric CPET values in the future.

Exercise Capacity and Predictors of Performance After Fontan: Results from the Pediatric Heart Network Fontan 3 Study.

Impaired exercise following Fontan is a surrogate of morbidity. Single-center longitudinal data exist, but there is a lack of contemporary multi-center data. Ramp cycle ergometry was re-performed in consented participants who had originally participated in the Pediatric Heart Network's Fontan cross-sectional study. Annualized change was evaluated at maximal and submaximal exercise. Associations between these outcomes and patient characteristics were analyzed. There were 336 participants in Fontan 3, mean age 23.2 years. Paired measurements of peak oxygen consumption (peak VO2) were available for 95; peak exercise data at Fontan 3 were available for 275. Percent-predicted peak VO2 declined by 0.8 ± 1.7% per year (p < 0.001). At Fontan 3, the lowest performing peak VO2 tertile had the highest rate of overweight and obesity (p < 0.001). Female gender was more prevalent in the highest performing tertile (p = 0.004). Paired data at the ventilatory anaerobic threshold (VO2 at VAT) were available for 196; VAT data at Fontan 3 were available for 311. Percent-predicted VO2 at VAT decreased by 0.8 ± 2.6% per year (p < 0.001). At Fontan 3, VO2 at VAT was better preserved than peak VO2 across all tertiles, with higher rates of overweight and obesity in the lower performing group (p = 0.001). Female gender (p < 0.001) and left ventricular morphology (p = 0.03) were associated with better performance. Submaximal exercise is better preserved than maximal in the Fontan population, but declined at the same rate over the study period. The overall longitudinal rate of decline in exercise performance is slower than what has been described previously.

Marked skeletal muscle deficits are associated with 6-minute walk distance in paediatric pulmonary hypertension.

BACKGROUND: Poor growth is common in children with pulmonary hypertension; however, skeletal muscle deficits have not been described and the association between muscle deficits and functional status is unknown. METHODS: Patients aged 8-18 years with pulmonary hypertension (diagnostic Groups 1, 2, or 3) and World Health Organization functional class I or II underwent dual-energy absorptiometry to measure leg lean mass Z-score (a surrogate for skeletal muscle). Muscle strength was assessed using dynamometry. Physical activity questionnaires were administered. Clinical data, including 6-minute walk distance, were reviewed. Relationships between skeletal muscle, physical activity score, and 6-minute walk distance were assessed by correlations and linear regression. RESULTS: Sixteen patients (12.1 ± 3.2 years, 50% female, 56% Group 1, 56% functional class II) were enrolled. Leg lean mass Z-score was significantly less than reference data (-1.40 ± 1.12 versus 0.0 ± 0.9, p < 0.001) and worse in those with functional class II versus I (-2.10 ± 0.83 versus -0.50 ± 0.73, p < 0.01). Leg lean mass Z-score was positively associated with right ventricular systolic function by tricuspid annular plane systolic Z-score (r = 0.54, p = 0.03) and negatively associated with indexed pulmonary vascular resistance (r = -0.78, p < 0.001). Leg lean mass Z-score and forearm strength were positively associated with physical activity score. When physical activity score was held constant, leg lean mass Z-score independently predicted 6-minute walk distance (R2 = 0.39, p = 0.03). CONCLUSIONS: Youth with pulmonary hypertension demonstrate marked skeletal muscle deficits in association with exercise intolerance. Future studies should investigate whether low leg lean mass is a marker of disease severity or an independent target that can be improved.

Determinants of Exercise Performance in Children and Adolescents with Repaired Tetralogy of Fallot Using Stress Echocardiography.

Exercise performance is variable and often impaired in patients with repaired tetralogy of Fallot (rTOF). We sought to identify factors associated with exercise performance by comparing high to low performers on cardiopulmonary exercise testing (CPET) in patients with rTOF. We conducted a cross-sectional study of subjects presenting for CPET who underwent echocardiograms at rest and peak exercise. Patients with pacemakers and arrhythmias were excluded. Right ventricular (RV) global longitudinal strain was used as a measure of systolic function. Pulmonary insufficiency (PI) was assessed with the diastolic systolic ratio and the diastolic systolic time-velocity integral ratio by Doppler interrogation of the pulmonary artery. CPET measures included percent-predicted maximum [Formula: see text][Formula: see text], percent-predicted maximum work and oxygen pulse. High versus low performers were identified as those achieving [Formula: see text] of at least 80% or falling below, respectively. Differences in echocardiographic parameters from rest to peak exercise were examined using mixed-effects regression models. Compared to the low performers (n = 17), high performers (n = 12) were younger (12.8 ± 3.3 years vs. 18.3 ± 4.8 years), had normal chronotropic response (peak heart rate > 185 bpm) with greater heart rate reserve and superior physical working capacity. High performers also had a greater reduction in PI at peak exercise, despite greater PI severity at rest. Oxygen pulse was comparable between groups. For both groups, there was no association of PI severity and RV systolic function at rest with exercise parameters. There was no group difference in the magnitude of change in RV strain and diastolic parameters from rest to peak exercise. Chronotropic response to exercise appears to be an important parameter with which to assess exercise performance in rTOF. Chronotropic health should be taken into consideration in this population, particularly given that RV function and PI severity at rest were not associated with exercise performance.

Design and rationale of the Fontan Udenafil Exercise Longitudinal (FUEL) trial.

The Fontan operation creates a circulation characterized by elevated central venous pressure and low cardiac output. Over time, these characteristics result in a predictable and persistent decline in exercise performance that is associated with an increase in morbidity and mortality. A medical therapy that targets the abnormalities of the Fontan circulation might, therefore, be associated with improved outcomes. Udenafil, a phosphodiesterase type 5 inhibitor, has undergone phase I/II testing in adolescents who have had the Fontan operation and has been shown to be safe and well tolerated in the short term. However, there are no data regarding the long-term efficacy of udenafil in this population. The Fontan Udenafil Exercise Longitudinal (FUEL) Trial is a randomized, double-blind, placebo-controlled phase III clinical trial being conducted by the Pediatric Heart Network in collaboration with Mezzion Pharma Co, Ltd. This trial is designed to test the hypothesis that treatment with udenafil will lead to an improvement in exercise capacity in adolescents who have undergone the Fontan operation. A safety extension trial, the FUEL Open-Label Extension Trial (FUEL OLE), offers the opportunity for all FUEL subjects to obtain open-label udenafil for an additional 12 months following completion of FUEL, and evaluates the long-term safety and tolerability of this medication. This manuscript describes the rationale and study design for FUEL and FUEL OLE. Together, these trials provide an opportunity to better understand the role of medical management in the care of those who have undergone the Fontan operation.

Perioperative Factors Influence the Long-Term Outcomes of Children and Adolescents with Repaired Tetralogy of Fallot.

Tetralogy of Fallot (TOF) often carries long-term seqüelae following surgical intervention. We hypothesized that early perioperative factors are associated with long-term adverse right ventricular (RV) remodeling, diminished exercise capacity, and increased morbidity. We conducted a retrospective cohort study of patients operated for TOF that underwent cardiac magnetic resonance imaging study (CMR), exercise stress test (EST), and detailed review of past medical history. Outcome variables included measures of RV size, and function, maximal work rate, and oxygen consumption, and interim hospitalizations, surgeries, and catheterizations. Thirty-nine subjects were included. Age at surgical repair was 0.3 ± 0.3 years and age at testing was 9.7 ± 1.4 years. On CMR, there was borderline RV dilation with moderate pulmonary insufficiency (PI) [RF 32% (8; 43)] and normal RV ejection fraction [60% (55; 67)]. On EST, there was low percent-predicted maximal oxygen consumption (77 ± 20%), and percent-predicted maximal work rate (84 ± 23%). On multivariable analysis, mechanical ventilation and Blalock-Taussig (BT) shunt prior to complete surgical repair were associated with the number of future hospitalizations. Duration of cardiopulmonary bypass and prior BT shunt were associated with future catheterizations. Prior BT shunt was a predictor of worse RVEF, while duration of mechanical ventilation and use of transannular patch were predictors of worse PI. Longer duration of mechanical ventilation (or LOS) was associated with worse maximal work rate. Surgical and perioperative factors may portend long-term RV remodeling and outcome in TOF. Further studies are warranted to explore these associations and potential underlying mechanisms.

Atenolol versus losartan in children and young adults with Marfan's syndrome.

BACKGROUND: Aortic-root dissection is the leading cause of death in Marfan's syndrome. Studies suggest that with regard to slowing aortic-root enlargement, losartan may be more effective than beta-blockers, the current standard therapy in most centers. METHODS: We conducted a randomized trial comparing losartan with atenolol in children and young adults with Marfan's syndrome. The primary outcome was the rate of aortic-root enlargement, expressed as the change in the maximum aortic-root-diameter z score indexed to body-surface area (hereafter, aortic-root z score) over a 3-year period. Secondary outcomes included the rate of change in the absolute diameter of the aortic root; the rate of change in aortic regurgitation; the time to aortic dissection, aortic-root surgery, or death; somatic growth; and the incidence of adverse events. RESULTS: From January 2007 through February 2011, a total of 21 clinical centers enrolled 608 participants, 6 months to 25 years of age (mean [±SD] age, 11.5±6.5 years in the atenolol group and 11.0±6.2 years in the losartan group), who had an aortic-root z score greater than 3.0. The baseline-adjusted rate of change in the mean (±SE) aortic-root z score did not differ significantly between the atenolol group and the losartan group (-0.139±0.013 and -0.107±0.013 standard-deviation units per year, respectively; P=0.08). Both slopes were significantly less than zero, indicating a decrease in the aortic-root diameter relative to body-surface area with either treatment. The 3-year rates of aortic-root surgery, aortic dissection, death, and a composite of these events did not differ significantly between the two treatment groups. CONCLUSIONS: Among children and young adults with Marfan's syndrome who were randomly assigned to losartan or atenolol, we found no significant difference in the rate of aortic-root dilatation between the two treatment groups over a 3-year period. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00429364.).

Results of a phase I/II multi-center investigation of udenafil in adolescents after fontan palliation.

BACKGROUND: The Fontan operation results in a circulation that is dependent on low pulmonary vascular resistance to maintain an adequate cardiac output. Medical therapies that lower pulmonary vascular resistance may augment cardiac output and improve long-term outcomes. OBJECTIVES: This phase I/II clinical trial conducted by the Pediatric Heart Network was designed to evaluate short-term safety, pharmacokinetics (PK), and preliminary efficacy of udenafil in adolescents following Fontan. METHODS: A 5-day dose-escalation trial was conducted in five study cohorts of six subjects each (37.5, 87.5, and 125 mg daily, 37.5 and 87.5 mg by mouth twice daily). A control cohort with 6 subjects underwent exercise testing only. Adverse events (AEs) were recorded, PK samples were collected on study days six through eight, and clinical testing was performed at baseline and day five. RESULTS: The trial enrolled 36 subjects; mean age 15.8 years (58% male). There were no significant differences in subject characteristics between cohorts. No drug-related serious AEs were reported during the study period; 24 subjects had AEs possibly or probably related to study drug. Headache was the most common AE, occurring in 20 of 30 subjects. The 87.5 mg bid cohort was well tolerated, achieved the highest maximal concentration (506 ng/mL) and the highest average concentration over the dosing interval (279 ng/mL), and was associated with a suggestion of improvement in myocardial performance. Exercise performance did not improve in any of the dosing cohorts. CONCLUSIONS: Udenafil was well-tolerated at all dosing levels. The 87.5 mg bid cohort achieved the highest plasma drug level and was associated with a suggestion of improvement in myocardial performance. These data suggest that the 87.5 mg bid regimen may be the most appropriate for a Phase III clinical trial.

Exercise Performance and 22q11.2 Deletion Status Affect Quality of Life in Tetralogy of Fallot.

OBJECTIVE: To identify mediators of health status and quality of life (QOL) in children and adolescents aged 8-18 years old following surgical repair for tetralogy of Fallot (TOF), including resource use, exercise performance, and 22q11.2 deletion status. STUDY DESIGN: We performed a corollary study to a cross-sectional analysis of subjects following repair for TOF that completed cardiac magnetic resonance imaging, cardiopulmonary exercise tests, and instruments assessing health status and QOL. General linear models were used to test for mediation. RESULTS: A total of 29 of 151 (19%) patients carried a 22q11.2 deletion. Parents of children with a deletion compared with those without a deletion reported worse physical and psychosocial functioning on the Child Health Questionnaire. The patients with a 22q11.2 deletion and their parents reported lower total and Disease Impact scores compared with the group without a deletion on the Pediatric Cardiac Quality of Life Inventory. Medical care use negatively correlated with measures of health status/QOL. Greater maximum work correlated with better patient health status and QOL, regardless of deletion status. Exercise performance mediated the association between deletion status and parent-reported outcomes (unstandardized effects ranging from 2.4 to 4.2) and patient-reported Disease Impact (0.99; 95% CI 0.02-2.70). CONCLUSION: Children and adolescents following repair for TOF seem to suffer significant challenges to their health status and QOL, which is amplified markedly in the context of the 22q11.2 deletion syndrome, and related to exercise performance.

Relationship Between Habitual Exercise and Performance on Cardiopulmonary Exercise Testing Differs Between Children With Single and Biventricular Circulations.

Increasing habitual exercise has been associated with improved cardiopulmonary exercise testing (CPET) performance, specifically maximal oxygen consumption in children with operatively corrected congenital heart disease. This has not been studied in children following Fontan palliation, a population in whom CPET performance is dramatically diminished. A single-center cross-sectional study with prospective and retrospective data collection was performed that assessed habitual exercise preceding a clinically indicated CPET in children and adolescents with Fontan palliation, transposition of the great arteries following arterial switch operation (TGA), and normal cardiac anatomy without prior operation. Data from contemporaneous clinical reports and imaging studies were collected. The association between percent predicted VO2max and habitual exercise duration adjusted for known covariates was tested. A total of 175 subjects (75 post-Fontan, 20 with TGA, and 80 with normal cardiac anatomy) were enrolled. VO2max was lower in the Fontan group than patients with normal cardiac anatomy (p < 0.0001) or TGA (p < 0.0001). In Fontan subjects, both univariate and multivariate analysis failed to demonstrate a significant association between habitual exercise and VO2max (p = 0.6), in sharp contrast to cardiac normal subjects. In multivariate analysis, increasing age was the only independent risk factor associated with decreasing VO2max in the Fontan group (p = 0.003). Habitual exercise was not associated with VO2max in subjects with a Fontan as compared to biventricular circulation. Further research is necessary to understand why their habitual exercise is ineffective and/or what aspects of the Fontan circulation disrupt this association.

Quality of life and exercise performance in unoperated children with anomalous aortic origin of a coronary artery from the opposite sinus of valsalva.

BACKGROUND: Anomalous aortic origin of a coronary artery is a congenital cardiac condition that can be associated with increased risk of sudden death. To date, quality of life and exercise performance have not been evaluated in patients with this condition who do not undergo surgical repair. METHODS: We carried out a cross-sectional analysis of patients with unoperated anomalous aortic origin of a coronary artery at our institution from 1 January, 2000 to 31 January, 2016. We prospectively assessed quality of life using standardised questionnaires. Medical records were reviewed for clinical and exercise stress test data. Statistical analyses were performed using Student's t-tests and Spearman's correlation coefficients. RESULTS: In total, 56 families completed the questionnaires. The average age at enrolment was 14.7±6 years. The majority were male (n=44, 78.6%) and had interarterial anomalous right coronary artery (n=38, 67.9%). Patients had normal quality of life on the PedsQL 4.0 Report, Child Health Questionnaire Child Form 87, and SF-36v2. Their parents had normal quality of life on the PedsQL 4.0 Parent Report, but parents of exercise-restricted patients had decreased Physical Functioning, General Health Perception, Emotional Impact on Parent, and Physical Summary scores (p<0.001-0.048) on the Child Health Questionnaire Parent Form 50. CONCLUSIONS: Patients with unoperated anomalous aortic origin of a coronary artery appear to have normal quality of life, but parents of exercise-restricted patients have decreased general health and emotional and physical quality of life scores. Improved counselling of families may be beneficial in this group. Future studies with more patients should evaluate quality of life and exercise performance over time.