Design and implementation of multicenter pediatric and congenital studies with cardiovascular magnetic resonance: Big data in smaller bodies.

Cardiovascular magnetic resonance (CMR) has become the reference standard for quantitative and qualitative assessment of ventricular function, blood flow, and myocardial tissue characterization. There is a preponderance of large CMR studies and registries in adults; However, similarly powered studies are lacking for the pediatric and congenital heart disease (PCHD) population. To date, most CMR studies in children are limited to small single or multicenter studies, thereby limiting the conclusions that can be drawn. Within the PCHD CMR community, a collaborative effort has been successfully employed to recognize knowledge gaps with the aim to embolden the development and initiation of high-quality, large-scale multicenter research. In this publication, we highlight the underlying challenges and provide a practical guide toward the development of larger, multicenter initiatives focusing on PCHD populations, which can serve as a model for future multicenter efforts.

Leg-focused high-weight resistance training improves ventricular stroke volume, exercise capacity and strength in young patients with a Fontan circulation.

AIMS: Effective therapy to improve exercise capacity in Fontan patients is lacking. Leg-focused high-weight resistance training might augment the peripheral muscle pump and thereby improve exercise capacity. METHODS AND RESULTS: This randomized semi-cross-over controlled trial investigated the effects of a 12-week leg-focused high-weight resistance training plus high-protein diet, on (sub)maximal exercise capacity, cardiac function (assessed with cardiovascular magnetic resonance), muscle strength, and quality of life in paediatric Fontan patients. Twenty-eight paediatric Fontan patients were included, 27 patients, (median age 12.9 [10.5-15.7]), and successfully completed the programme. Peak oxygen uptake (PeakVO2) at baseline was reduced [33.3 mL/kg/min (27.1-37.4), 73% (62-79) of predicted]. After training PeakVO2/kg and Peak workload improved significantly with +6.2 mL/kg/min (95%CI: 3.4-9.0) (+18%) P < 0.001 and +22 Watts (95%CI: 12-32) (+18%) P < 0.001, respectively, compared to the control period. Indexed single ventricle stroke volume increased significantly [43 mL/beat/m2 (40-49) vs. 46 (41-53), P = 0.014], as did inferior vena cava flow [21 mL/beat/m2 (18-24) vs. 23 (20-28), P = 0.015], while superior vena cava flow remained unchanged. The strength of all measured leg-muscles increased significantly compared to the control period. Self-reported quality of life improved on the physical functioning and change in health domains of the child health questionnaire, parent-reported quality of life improved the bodily pain, general health perception, and change in health domains compared to the control period. CONCLUSION: In a relatively large group of 27 older Fontan children, 12-weeks of leg-focused high-weight resistance training improved exercise capacity, stroke volume, (sub)maximal exercise capacity, muscle strength, and domains of quality of life. REGISTRATION: International Clinical Trials: Trial NL8181.

Is leg-focused high-weight resistance training an effective therapy to improve reduced exercise capacity in patients with a Fontan circulation? Key Finding: Twelve weeks of leg-focused high-weight resistance training in children with a Fontan circulation improved exercise capacity, single ventricular stroke volume, (sub)maximal exercise capacity, muscle strength, and physical domains of quality of life. Take-home Message: Leg-focused high-weight resistance training results in improved exercise capacity, cardiac function, and quality of life patients with a Fontan circulation. Patients with a Fontan circulation should be motivated to perform lower limb strengthening exercises.

Long-term surgical outcomes of congenital supravalvular aortic stenosis: a systematic review, meta-analysis and microsimulation study.

OBJECTIVES: Congenital supravalvular aortic stenosis (SVAS) is a rare form of congenital outflow tract obstruction and long-term outcomes are scarcely reported. This study aims to provide an overview of outcomes after surgical repair for congenital SVAS. METHODS: A systematic review of published literature was conducted, including observational studies reporting long-term clinical outcome (>2 years) after SVAS repair in children or adults considering >20 patients. Early risks, late event rates and time-to-event data were pooled and entered into a microsimulation model to estimate 30-year outcomes. Life expectancy was compared to the age-, sex- and origin-matched general population. RESULTS: Twenty-three publications were included, encompassing a total of 1472 patients (13 125 patient-years; pooled mean follow-up: 9.0 (6.2) years; median follow-up: 6.3 years). Pooled mean age at surgical repair was 4.7 (5.8) years and the most commonly used surgical technique was the single-patch repair (43.6%). Pooled early mortality was 4.2% (95% confidence interval: 3.2-5.5%) and late mortality was 0.61% (95% CI: 0.45-0.83) per patient-year. Based on microsimulation, over a 30-year time horizon, it was estimated that an average patient with SVAS repair (mean age: 4.7 years) had an observed life expectancy that was 90.7% (95% credible interval: 90.0-91.6%) of expected life expectancy in the matched general population. The microsimulation-based 30-year risk of myocardial infarction was 8.1% (95% credible interval: 7.3-9.9%) and reintervention 31.3% (95% credible interval: 29.6-33.4%), of which 27.2% (95% credible interval: 25.8-29.1) due to repair dysfunction. CONCLUSIONS: After surgical repair for SVAS, 30-year survival is lower than the matched-general-population survival and the lifetime risk of reintervention is considerable. Therefore, lifelong monitoring of the cardiovascular system and in particular residual stenosis and coronary obstruction is recommended.

Serial RV wall stress measurements: association with right ventricular function in repaired Tetralogy of Fallot patients.

Background: Optimal timing of pulmonary valve replacement (PVR) in Tetralogy of Fallot (TOF) patients remains challenging. Ventricular wall stress is considered to be an early marker of right ventricular (RV) dysfunction. Objectives: To investigate the association of RV wall stresses and their change over time with functional parameters in TOF patients. Methods: Ten TOF patients after surgical repair with moderate/severe pulmonary regurgitation were included. At two timepoints (median follow-up time 7.2 years), patient-specific computational biventricular models for wall stress assessment were created using CMR short-axis cine images and echocardiography-based RV pressures. RV ejection fraction (RVEF), NT-proBNP and cardiopulmonary exercise tests were used as outcome measures reflecting RV function. Associations between regional RV diastolic wall stress and RV function were investigated using linear mixed models. Results: Increased wall stress correlated with lower RV mass (rrm = -0.70, p = 0.017) and lower RV mass-to-volume (rrm = -0.80, p = 0.003) using repeated measures. Wall stress decreased significantly over time, especially in patients with a stable RVEF (p < 0.001). Higher wall stress was independently associated with lower RVEF, adjusted for left ventricular ejection fraction, RV end-diastolic volume and time since initial surgery (decrease of 1.27% RVEF per kPa increase in wall stress, p = 0.029) using repeated measurements. No association was found between wall stress, NT-proBNP, and exercise capacity. Conclusions: Using a computational method to calculate wall stress locally in geometrically complex ventricles, we demonstrated that lower wall stress might be important to maintain ventricular function. RV wall stress assessment can be used in serial follow-up, and is potentially an early marker of impending RV dysfunction.

Body composition in patients with Fontan physiology: a systematic review.

Fontan circulation is a highly abnormal circulatory state that may affect various organ systems. The effect on body composition is an important factor to assess the condition of the patient. This systematic review assesses body composition and possibly related adverse outcomes in patients with a Fontan circulation, to provide an overview of current insights. Studies evaluating body composition by compartment (either fat mass or lean/muscle mass) in Fontan patients published up to April 2023 were included in this systematic review. Of 1392 potential studies, 18 studies met the inclusion criteria. In total, body composition measurements of 774 Fontan patients were included. Body composition was measured using dual-energy X-ray absorptiometry (DXA) (n = 12), bioelectrical impedance analysis (BIA) (n = 5), computer tomography (CT) (n = 1), or magnetic resonance imaging (MRI) (n = 1). All studies reported a normal body mass index (BMI) in Fontan patients, compared to controls. Five out of nine studies reported significantly higher body fat values, and twelve out of fifteen studies reported significantly lower muscle or lean mass values in the Fontan population compared to the healthy population. Unfavorable body composition in Fontan patients was associated with decreased exercise capacity, worse cardiac function, and adverse outcomes including hospital admissions and death.   Conclusions: Despite having a normal BMI, Fontan patients have an increased fat mass and decreased muscle mass or lean mass compared to the healthy population. This unfavorable body composition was associated with various adverse outcomes, including a decreased exercise capacity and worse cardiac function. What is Known: • Patients with a Fontan circulation have a decreased exercise capacity compared to healthy peers, an unfavorable body composition might be a contributor to their impaired exercise capacity. What is New: • Fontan patients are predisposed to an unfavorable body composition, characterized by increased fat mass and decreased muscle mass accompanied by a normal BMI compared to the healthy population. • Among others, unfavorable body composition was associated with decreased exercise capacity, cardiac function, and increased morbidity in patients with a Fontan circulation.

Aortic valve repair in neonates, infants and children: a systematic review, meta-analysis and microsimulation study.

OBJECTIVES: To support clinical decision-making in children with aortic valve disease, by compiling the available evidence on outcome after paediatric aortic valve repair (AVr). METHODS: A systematic review of literature reporting clinical outcome after paediatric AVr (mean age at surgery <18 years) published between 1 January 1990 and 23 December 2021 was conducted. Early event risks, late event rates and time-to-event data were pooled. A microsimulation model was employed to simulate the lives of individual children, infants and neonates following AVr. RESULTS: Forty-one publications were included, encompassing 2 623 patients with 17 217 patient-years of follow-up (median follow-up: 7.3 years; range: 1.0-14.4 years). Pooled mean age during repair for aortic stenosis in children (<18 years), infants (<1 year) or neonates (<30 days) was 5.2 ± 3.9 years, 35 ± 137 days and 11 ± 6 days, respectively. Pooled early mortality after stenosis repair in children, infants and neonates, respectively, was 3.5% (95% confidence interval: 1.9-6.5%), 7.4% (4.2-13.0%) and 10.7% (6.8-16.9%). Pooled late reintervention rate after stenosis repair in children, infants and neonates, respectively, was 3.31%/year (1.66-6.63%/year), 6.84%/year (3.95-11.83%/year) and 6.32%/year (3.04-13.15%/year); endocarditis 0.07%/year (0.03-0.21%/year), 0.23%/year (0.07-0.71%/year) and 0.49%/year (0.18-1.29%/year); and valve thrombosis 0.05%/year (0.01-0.26%/year), 0.15%/year (0.04-0.53%/year) and 0.19%/year (0.05-0.77%/year). Microsimulation-based mean life expectancy in the first 20 years for children, infants and neonates with aortic stenosis, respectively, was 18.4 years (95% credible interval: 18.1-18.7 years; relative survival compared to the matched general population: 92.2%), 16.8 years (16.5-17.0 years; relative survival: 84.2%) and 15.9 years (14.8-17.0 years; relative survival: 80.1%). Microsimulation-based 20-year risk of reintervention in children, infants and neonates, respectively, was 75.2% (72.9-77.2%), 53.8% (51.9-55.7%) and 50.8% (47.0-57.6%). CONCLUSIONS: Long-term outcomes after paediatric AVr for stenosis are satisfactory and dependent on age at surgery. Despite a high hazard of reintervention for valve dysfunction and slightly impaired survival relative to the general population, AVr is associated with low valve-related event occurrences and should be considered in children with aortic valve disease.

Left ventricular deformation and myocardial fibrosis in pediatric patients with Duchenne muscular dystrophy.

BACKGROUND: Left ventricular (LV) strain and rotation are emerging functional markers for early detection of LV dysfunction and have been associated with the burden of myocardial fibrosis in several disease states. This study examined the association between LV deformation (i.e., LV strain and rotation) and extent and location of LV myocardial fibrosis in pediatric patients with Duchenne muscular dystrophy (DMD). METHODS AND RESULTS: 34 pediatric patients with DMD underwent cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) to assess LV myocardial fibrosis. Offline CMR feature-tracking analysis was used to assess global and segmental longitudinal and circumferential LV strain, and LV rotation. Patients with fibrosis (n = 18, 52.9%) were older than those without fibrosis (14 ± 3 years (yrs) vs 11 ± 2 yrs., p = 0.01). There was no significant difference in LV ejection fraction (LVEF) between subjects with and without fibrosis (54 ± 6% vs 56 ± 4%, p = 0.18). However, lower endocardial global circumferential strain (GCS), but not LV rotation, was associated with presence of fibrosis (adjusted Odds Ratio 1.25 [95% CI 1.01-1.56], p = 0.04). Both GCS and global longitudinal strain correlated with the extent of fibrosis (r = .52, p = 0.03 and r = .75, p < 0.01, respectively). Importantly, segmental strain did not seem to correspond to location of fibrosis. CONCLUSION: A lower global, but not segmental, strain is associated with presence and extent of LV myocardial fibrosis in pediatric DMD patients. Therefore, strain parameters might detect structural myocardial alterations, however currently more research is needed to evaluate its value (e.g., prognostic) in clinical practice.

Stress imaging in patients with a Fontan circulation: A systematic review.

INTRODUCTION: The aims of this study were to provide an overview of the cardiac stress response in Fontan patients and of the use, safety and clinical value of stress imaging in Fontan patients. METHODS: Studies evaluating cardiac function using stress imaging in Fontan patients published up until 12 December 2021 were included in this review. RESULTS: From 1603 potential studies, 32 studies met the inclusion criteria. In total, stress imaging tests of 728 Fontan patients were included. Cardiac function was most often measured using physical stress (61%), all other studies used dobutamine-induced stress. Stroke volume (SV) increased in most studies (71%), mean SV at rest ranged from 27 mL/m2 to 60 mL/m2 versus 27 mL/m2 to 101 mL/m2 during stress, and increased with an average of 4%. Ejection fraction increased in almost all studies, whereas both end-systolic volume and end-diastolic volume decreased during stress. Higher heart rates were obtained with physical stress (82-180) compared to dobutamine induced stress (73-128). Compared to controls, increases in heartrate and SV were lower and end-diastolic volume decreased abnormally in 75% of reporting studies. No major adverse events were reported. Poorer cardiac stress response was related to decreased exercise capacity and higher risk for long-term (adverse) outcomes in Fontan patients. DISCUSSION: Cardiac stress response in Fontan patients differs from healthy subjects, reflected by lower increases in heart rate, diminished preload and decreased cardiac output, especially during higher levels of exercise. Stress imaging is safe, however the added clinical value needs to be investigated in more detail.

Paediatric aortic valve replacement: a meta-analysis and microsimulation study.

AIMS: To support decision-making in children undergoing aortic valve replacement (AVR), by providing a comprehensive overview of published outcomes after paediatric AVR, and microsimulation-based age-specific estimates of outcome with different valve substitutes. METHODS AND RESULTS: A systematic review of published literature reporting clinical outcome after paediatric AVR (mean age <18 years) published between 1/1/1990 and 11/08/2021 was conducted. Publications reporting outcome after paediatric Ross procedure, mechanical AVR (mAVR), homograft AVR (hAVR), and/or bioprosthetic AVR were considered for inclusion. Early risks (<30d), late event rates (>30d) and time-to-event data were pooled and entered into a microsimulation model. Sixty-eight studies, of which one prospective and 67 retrospective cohort studies, were included, encompassing a total of 5259 patients (37 435 patient-years; median follow-up: 5.9 years; range 1-21 years). Pooled mean age for the Ross procedure, mAVR, and hAVR was 9.2 ± 5.6, 13.0 ± 3.4, and 8.4 ± 5.4 years, respectively. Pooled early mortality for the Ross procedure, mAVR, and hAVR was 3.7% (95% CI, 3.0%-4.7%), 7.0% (5.1%-9.6%), and 10.6% (6.6%-17.0%), respectively, and late mortality rate was 0.5%/year (0.4%-0.7%/year), 1.0%/year (0.6%-1.5%/year), and 1.4%/year (0.8%-2.5%/year), respectively. Microsimulation-based mean life-expectancy in the first 20 years was 18.9 years (18.6-19.1 years) after Ross (relative life-expectancy: 94.8%) and 17.0 years (16.5-17.6 years) after mAVR (relative life-expectancy: 86.3%). Microsimulation-based 20-year risk of aortic valve reintervention was 42.0% (95% CI: 39.6%-44.6%) after Ross and 17.8% (95% CI: 17.0%-19.4%) after mAVR. CONCLUSION: Results of paediatric AVR are currently suboptimal with substantial mortality especially in the very young with considerable reintervention hazards for all valve substitutes, but the Ross procedure provides a survival benefit over mAVR. Pros and cons of substitutes should be carefully weighed during paediatric valve selection.

The right ventricle in tetralogy of Fallot: adaptation to sequential loading.

Right ventricular dysfunction is a major determinant of outcome in patients with complex congenital heart disease, as in tetralogy of Fallot. In these patients, right ventricular dysfunction emerges after initial pressure overload and hypoxemia, which is followed by chronic volume overload due to pulmonary regurgitation after corrective surgery. Myocardial adaptation and the transition to right ventricular failure remain poorly understood. Combining insights from clinical and experimental physiology and myocardial (tissue) data has identified a disease phenotype with important distinctions from other types of heart failure. This phenotype of the right ventricle in tetralogy of Fallot can be described as a syndrome of dysfunctional characteristics affecting both contraction and filling. These characteristics are the end result of several adaptation pathways of the cardiomyocytes, myocardial vasculature and extracellular matrix. As long as the long-term outcome of surgical correction of tetralogy of Fallot remains suboptimal, other treatment strategies need to be explored. Novel insights in failure of adaptation and the role of cardiomyocyte proliferation might provide targets for treatment of the (dysfunctional) right ventricle under stress.

Ventricular function and biomarkers in relation to repair and pulmonary valve replacement for tetralogy of Fallot.

OBJECTIVE: Cardiac surgery may cause temporarily impaired ventricular performance and myocardial injury. We aim to characterise the response to perioperative injury for patients undergoing repair or pulmonary valve replacement (PVR) for tetralogy of Fallot (ToF). METHODS: We enrolled children undergoing ToF repair or PVR from four tertiary centres in a prospective observational study. Assessment-including blood sampling and speckle tracking echocardiography-occurred before surgery (T1), at the first follow-up (T2) and 1 year after the procedures (T3). Ninety-two serum biomarkers were expressed as principal components to reduce multiple statistical testing. RNA Sequencing was performed on right ventricular (RV) outflow tract samples. RESULTS: We included 45 patients with ToF repair aged 4.3 (3.4 - 6.5) months and 16 patients with PVR aged 10.4 (7.8 - 12.7) years. Ventricular function following ToF repair showed a fall-and-rise pattern for left ventricular global longitudinal strain (GLS) (-18±4 to -13±4 to -20±2, p < 0.001 for each comparison) and RV GLS (-19±5 to -14±4 to 20±4, p < 0.002 for each comparison). This pattern was not seen for patients undergoing PVR. Serum biomarkers were expressed as three principal components. These phenotypes are related to: (1) surgery type, (2) uncorrected ToF and (3) early postoperative status. Principal component 3 scores were increased at T2. This increase was higher for ToF repair than PVR. The transcriptomes of RV outflow tract tissue are related to patients' sex, rather than ToF-related phenotypes in a subset of the study population. CONCLUSIONS: The response to perioperative injury following ToF repair and PVR is characterised by specific functional and immunological responses. However, we did not identify factors relating to (dis)advantageous recovery from perioperative injury. TRIAL REGISTRATION NUMBER: Netherlands Trial Register: NL5129.

Exercise in patients with repaired tetralogy of Fallot: a systematic review and meta-analysis.

OBJECTIVE: Children and adults with repaired tetralogy of Fallot (rTOF) have an impaired exercise capacity, a less active lifestyle and an increased long-term risk of adverse outcomes compared with healthy peers. This study aimed to summarise the current evidence for the effectiveness and safety of exercise training interventions in patients with rTOF. METHODS: PubMed/MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, Scopus and reference lists of relevant articles were searched for prospective studies published by November 2021. Random-effects meta-analysis and descriptive synthesis were performed to assess the effectiveness and safety of exercise training in patients with rTOF. RESULTS: Of the 9677 citations identified, 12 articles were included that reported on 10 unique studies and covered 208 patients with rTOF (range of mean/median age: 7.4-43.3 years). All studies implemented 2 to 7 aerobic or respiratory training sessions per week with durations ranging from 6 to 26 weeks. Meta-analysis of the included randomised controlled trials showed that exercise training was associated with a significant improvement in peak VO2 (pooled mean difference: +3.1 mL/min/kg; 95% CI: 0.76 to 5.36 mL/min/kg, p=0.019). Cardiac imaging studies revealed no subclinical adverse remodelling after the exercise interventions. No serious adverse events including arrhythmias were reported in these studies. CONCLUSION: Current evidence suggests that exercise training can improve exercise capacity in patients with rTOF with a low risk for adverse events. Exercise prescription may be a safe and effective tool to help improving outcomes in patients with rTOF. PROSPERO REGISTRATION NUMBER: CRD42021292809.

Multivendor Evaluation of Automated MRI Postprocessing of Biventricular Size and Function for Children With and Without Congenital Heart Defects.

BACKGROUND: Manually segmenting cardiac structures is time-consuming and produces variability in MRI assessments. Automated segmentation could solve this. However, current software is developed for adults without congenital heart defects (CHD). PURPOSE: To evaluate automated segmentation of left ventricle (LV) and right ventricle (RV) for pediatric MRI studies. STUDY TYPE: Retrospective comparative study. POPULATION: Twenty children per group of: healthy children, LV-CHD, tetralogy of Fallot (ToF), and univentricular CHD, aged 11.7 [8.9-16.0], 14.2 [10.6-15.7], 14.6 [11.6-16.4], and 12.2 [10.2-14.9] years, respectively. SEQUENCE/FIELD STRENGTH: Balanced steady-state free precession at 1.5 T. ASSESSMENT: Biventricular volumes and masses were calculated from a short-axis stack of images, which were segmented manually and using two fully automated software suites (Medis Suite 3.2, Medis, Leiden, the Netherlands and SuiteHeart 5.0, Neosoft LLC, Pewaukee, USA). Fully automated segmentations were manually adjusted to provide two further sets of segmentations. Fully automated and adjusted automated segmentation were compared to manual segmentation. Segmentation times and reproducibility for each method were assessed. STATISTICAL TESTS: Bland Altman analysis and intraclass correlation coefficients (ICC) were used to compare volumes and masses between methods. Postprocessing times were compared by paired t-tests. RESULTS: Fully automated methods provided good segmentation (ICC > 0.90 compared to manual segmentation) for the LV in the healthy and left-sided CHD groups (eg LV-EDV difference for healthy children 1.4 ± 11.5 mL, ICC: 0.97, for Medis and 3.0 ± 12.2 mL, ICC: 0.96 for SuiteHeart). Both automated methods gave larger errors (ICC: 0.62-0.94) for the RV in these populations, and for all structures in the ToF and univentricular CHD groups. Adjusted automated segmentation agreed well with manual segmentation (ICC: 0.71-1.00), improved reproducibility and reduced segmentation time in all patient groups, compared to manual segmentation. DATA CONCLUSION: Fully automated segmentation eliminates observer variability but may produce large errors compared to manual segmentation. Manual adjustments reduce these errors, improve reproducibility, and reduce postprocessing times compared to manual segmentation. Adjusted automated segmentation is reasonable in children with and without CHD. EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 2.

Exercise capacity in a cohort of children with congenital heart disease.

In patients with congenital heart disease (CHD), reduced exercise capacity can be a predictor for late complications and may be used to guide interventions. Yet, the interpretation of exercise capacity is challenged by changes in body composition during growth. Our aim was to create an overview of disease-specific exercise capacity in children with CHD. We performed a multicentre retrospective study of exercise capacity of CHD patients, aged 6-18 years, tested between January 2001 and October 2018. Sex-specific distribution graphs were made using the LMS method and height to relate to body size. We included all CHD with N > 50, including severe defects (e.g., univentricular heart, tetralogy of Fallot) and "simple" lesions as ventricular septum defect and atrial septum defect. We included 1383 tests of 1208 individual patients for analysis. The peak oxygen uptake (VO2peak, 37.3 ml/min/kg (25th-75th percentile 31.3-43.8)) varied between specific defects; patients with univentricular hearts had lower VO2peak compared with other CHD. All groups had lower VO2peak compared to healthy Dutch children. Males had higher VO2peak, Wpeak and O2pulsepeak than females. Sex- and disease-specific distribution graphs for VO2peak, Wpeak and O2pulsepeak showed increase in variation with increase in height.   Conclusion: Disease-specific distribution graphs for exercise capacity in children with CHD from a large multicentre cohort demonstrated varying degrees of reduced VO2peak and Wpeak. The distribution graphs can be used in the structured follow-up of patients with CHD to predict outcome and identify patients at risk. What is Known: • Children with congenital heart disease (COnHD) are at risk to develop heart failure, arrhytmia's and other complications. Exercise capacity may be an important predictor for outcome in children with ConHD. In children, the interpretation of exercise capacity poses an additional challenge related to physical changes during growth. What is New: • In this report of a multi-center cohort >1300 childrewn with ConHD, we related the changes in exercise capacity to length. We demonstrated that exercise capacity was reduced as compared with healthy children and we observed variation between disease groups. Patients with a univentricular circulation (Fontan) had worse exercise capacity. We constructed disease specific charts of development of exercise capacity throughout childhood, accessible via a web-site. These graphs may help practitioner to guide children with ConHD.

Comprehensive Evaluation of Pediatric Patients with Ebstein Anomaly Requires Both Echocardiography and Cardiac Magnetic Resonance Imaging.

With the trend towards childhood surgery in patients with Ebstein anomaly (EA), thorough imaging is crucial for patient selection. This study aimed to assess biventricular function by echocardiography and cardiac magnetic resonance (CMR) and compare EA severity classifications. Twenty-three patients (8-17 years) underwent echocardiography and CMR. Echocardiographic parameters included tricuspid annular plane systolic excursions (TAPSE), fractional area change of the functional right ventricle (fRV-FAC), fRV free wall peak systolic myocardial velocity (fRVs'), and tricuspid regurgitation (TR). End-diastolic and end-systolic volume (EDV resp. ESV), fRV- and LV ejection fraction (EF) and TR were obtained by CMR. EA severity classifications included displacement index, Celermajer index and the total-right/left-volume index. Median fRV-FAC was 38% (IQR 33-42). TAPSE and fRVs' were reduced in 39% and 75% of the patients, respectively. Echocardiographic TR was visually graded as mild, moderate, or severe in nine, six and eight patients, respectively. By CMR, median fRVEF was 49% (IQR 36-58) and TR was graded as mild, moderate, or severe in nine, twelve and two patients, respectively. In 70% of cases, fRV-EDV was higher than LV-EDV. LVEF was decreased in 17 cases (74%). There was excellent correlation between echocardiography-derived fRV-FAC and CMR-derived fRVEF (rho = 0.812, p < 0.001). While echocardiography is a versatile tool in the complex geometry of the Ebstein heart, it has limitations. CMR offers a total overview and has the advantage of reliable volume assessment of both ventricles. Comprehensive evaluation of pediatric patients with EA may therefore require a synergistic implementation of echocardiography and CMR.

Standardizing submaximal exercise intensities for use of supine push-pull exercise during cardiovascular magnetic resonance.

BACKGROUND: Cardiovascular magnetic resonance (CMR) imaging during supine exercise at (sub)maximal oxygen consumption (VO2 ) offers unique diagnostic insights. However, maximal VO2 is not achievable in the supine position and standardizing submaximal exercise intensities remains challenging. Using heart rate or workload could be a viable option to translate VO2 -based submaximal exercise intensities. AIM: To translate submaximal exercise intensities upright cycling exercise (UCE) to supine push-pull exercise (SPPE), by comparing heart rate or workload determined during UCE, with heart rate and workload during SPPE at similar exercise intensities. METHODS AND RESULTS: Sixteen healthy young adults (20.4 ± 2.2 years; 8 female) underwent cardiopulmonary UCE and SPPE testing [mean ± standard deviation maximal VO2 : 3.2 ± 0.6 vs. 5 ± 0.3 L min-1 , p < 0.001 and median (interquartile range) of the maximum workload: 310 (244, 361) vs. 98 (98, 100), p < 0.001, respectively]. Heart rate at 40% and 60% of maximal VO2 , as determined by UCE, showed low bias (-3 and 0 bpm, respectively) and wide limits of agreement (±26 and ±28 bpm, respectively), in Bland-Altman analysis. VO2 /Workload relation was exponential and less efficient during SPPE compared to UCE. Generalized estimated equation analysis predicted model-based mean workload during SPPE, with acceptable 95% confidence interval. CONCLUSION: Heart rate during UCE at submaximal exercise intensities can reasonably well be used to for SPPE in healthy subjects. Using workload, an ergometer specific, model-based mean can be used to determine exercise intensities during SPPE. Individual variations in response to posture and movement change are high. During clinical interpretation of exercise CMR, individual exercise intensity has to be considered.

Functional Echocardiographic and Serum Biomarker Changes Following Surgical and Percutaneous Atrial Septal Defect Closure in Children.

Background Ventricular performance is temporarily reduced following surgical atrial septal defect closure. Cardiopulmonary bypass and changes in loading conditions are considered important factors, but this phenomenon is incompletely understood. We aim to characterize biventricular performance following surgical and percutaneous atrial septal defect closure and to relate biomarkers to ventricular performance following intervention. Methods and Results In this multicenter prospective study, children scheduled for surgical or percutaneous atrial septal defect closure were included. Subjects were assessed preoperatively, in the second week postintervention (at 2-weeks follow-up), and 1-year postintervention (1-year follow-up). At each time point, an echocardiographic study and a panel of biomarkers were obtained. Sixty-three patients (median age, 4.1 [interquartile range, 3.1-6.1] years) were included. Forty-three patients underwent surgery. At 2-weeks follow-up, right ventricular global longitudinal strain was decreased for the surgical, but not the percutaneous, group (-17.6±4.1 versus -27.1±3.4; P<0.001). A smaller decrease was noted for left ventricular global longitudinal strain at 2-weeks follow-up for the surgical group (surgical versus percutaneous, -18.6±3.2 versus -20.2±2.4; P=0.040). At 1-year follow-up, left ventricular performance returned to baseline, whereas right ventricular performance improved, but did not reach preintervention levels. Eight biomarkers relating to cardiovascular and immunological processes differed across study time points. Of these biomarkers, only NT-proBNP (N-terminal pro-B-type natriuretic peptide) correlated with less favorable left ventricular global longitudinal strain at 2-weeks follow-up. Conclusions Right, and to a lesser degree left, ventricular performance was reduced early after surgical atrial septal defect closure. Right ventricular performance at 1-year follow-up remained below baseline levels. Several biomarkers showed a pattern over time similar to ventricular performance. These biomarkers may provide insight into the processes that affect ventricular function. Registration URL: https://www.trialregister.nl/; Unique identifier: NL5129.

Fontan Circulation Associated Organ Abnormalities Beyond the Heart, Lungs, Liver, and Gut: A Systematic Review.

Introduction: Patients with a Fontan circulation are at risk for sequelae of Fontan physiology during follow-up. Fontan physiology affects all organ systems and an overview of end-organ damage is needed. Methods: We performed a systematic review of abnormalities in multiple organ systems for patients with a longstanding Fontan circulation. We searched online databases for articles describing abnormalities in multiple organ systems. Cardio-pulmonary abnormalities, protein losing enteropathy, and Fontan associated liver disease have already extensively been described and were excluded from this systematic review. Results: Our search returned 5,704 unique articles. After screening, we found 111 articles relating to multiple organ systems. We found abnormalities in, among others, the nervous system, pituitary, kidneys, and musculoskeletal system. Pituitary edema-relating to the unique pituitary vasculature- may affect the thyroid axis. Renal dysfunction is common. Creatinine based renal function estimates may be inappropriate due to myopenia. Both lean muscle mass and bone mineral density are decreased. These abnormalities in multiple organ systems may be related to Fontan physiology, cyanosis, iatrogenic factors, or lifestyle. Conclusions: Health care providers should be vigilant for hypothyroidism, visual or hearing deficits, and sleep disordered breathing in Fontan patients. We recommend including cystatin C for assessment of renal function. This review may aid health care providers and guide future research.Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021232461, PROSPERO, identifier: CRD42021232461.

Associations between blood biomarkers, cardiac function and adverse outcome in a young tetralogy of Fallot cohort.

BACKGROUND: To determine the potential prognostic value and clinical correlations of blood biomarkers in a cohort of patients with Tetralogy of Fallot (TOF). METHODS: In the setting of multicenter prospective research studies TOF patients underwent blood sampling, cardiopulmonary exercise testing and low-dose dobutamine stress cardiac magnetic resonance (CMR) imaging. In the blood sample NT-proBNP, GDF-15, Galectin-3, ST-2, DLK-1, FABP4, IGFBP-1, IGFBP-7, MMP-2, and vWF were assessed. During subsequent follow-up, patients were evaluated for reaching the study endpoint (cardiac death, arrhythmia-related hospitalization or cardioversion/ablation, VO2 max ≤65% of predicted). Regression analysis was used to explore the correlation between blood biomarkers (corrected for age and gender) and other clinical parameters. The potential predictive value of blood biomarkers and events were assessed with Kaplan-Meier analysis and Cox proportional hazard analysis. RESULTS: We included 137 Fallot patients, median age 19.2 (interquartile range: 14.6-25.7) years, median age at TOF-repair 0.9 (0.5-1.9) years. After a median follow-up of 8.7 (6.3-10.7) years, 20 (14.6%) patients reached the composite endpoint. In a multivariable cox-regression analysis corrected for age at study baseline, elevated IGFBP-7 and MMP-2 levels were associated with the composite endpoint. We also noted a correlation between DLK-1 and relative change in right ventricular end systolic volume during dobutamine stress CMR (ß = -0.27, p = 0.010), a correlation between FABP4 and Max VO2 (ß = -0.41, p ≤0.001 and between MMP-2 and tricuspid valve E/A ratio (ß = -0.15, p = 0.037). CONCLUSIONS: IGFBP-7, MMP-2 and DLK-1 levels are related to cardiac function and long-term outcome in TOF patients.

CeRebrUm and CardIac Protection with ALlopurinol in Neonates with Critical Congenital Heart Disease Requiring Cardiac Surgery with Cardiopulmonary Bypass (CRUCIAL): study protocol of a phase III, randomized, quadruple-blinded, placebo-controlled, Dutch multicenter trial.

BACKGROUND: Neonates with critical congenital heart disease (CCHD) undergoing cardiac surgery with cardiopulmonary bypass (CPB) are at risk of brain injury that may result in adverse neurodevelopment. To date, no therapy is available to improve long-term neurodevelopmental outcomes of CCHD neonates. Allopurinol, a xanthine oxidase inhibitor, prevents the formation of reactive oxygen and nitrogen species, thereby limiting cell damage during reperfusion and reoxygenation to the brain and heart. Animal and neonatal studies suggest that allopurinol reduces hypoxic-ischemic brain injury and is cardioprotective and safe. This trial aims to test the hypothesis that allopurinol administration in CCHD neonates will result in a 20% reduction in moderate to severe ischemic and hemorrhagic brain injury. METHODS: This is a phase III, randomized, quadruple-blinded, placebo-controlled, multicenter trial. Neonates with a prenatal or postnatal CCHD diagnosis requiring cardiac surgery with CPB in the first 4 weeks after birth are eligible to participate. Allopurinol or mannitol-placebo will be administered intravenously in 2 doses early postnatally in neonates diagnosed antenatally and 3 doses perioperatively of 20 mg/kg each in all neonates. The primary outcome is a composite endpoint of moderate/severe ischemic or hemorrhagic brain injury on early postoperative MRI, being too unstable for postoperative MRI, or mortality within 1 month following CPB. A total of 236 patients (n = 188 with prenatal diagnosis) is required to demonstrate a reduction of the primary outcome incidence by 20% in the prenatal group and by 9% in the postnatal group (power 80%; overall type 1 error controlled at 5%, two-sided), including 1 interim analysis at n = 118 (n = 94 with prenatal diagnosis) with the option to stop early for efficacy. Secondary outcomes include preoperative and postoperative brain injury severity, white matter injury volume (MRI), and cardiac function (echocardiography); postnatal and postoperative seizure activity (aEEG) and regional cerebral oxygen saturation (NIRS); neurodevelopment at 3 months (general movements); motor, cognitive, and language development and quality of life at 24 months; and safety and cost-effectiveness of allopurinol. DISCUSSION: This trial will investigate whether allopurinol administered directly after birth and around cardiac surgery reduces moderate/severe ischemic and hemorrhagic brain injury and improves cardiac function and neurodevelopmental outcome in CCHD neonates. TRIAL REGISTRATION: EudraCT 2017-004596-31. Registered on November 14, 2017. ClinicalTrials.gov NCT04217421. Registered on January 3, 2020.