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.

Pulmonary arterial hypertension associated with pulmonary arteriovenous malformations and pulmonary veno-occlusive disease: A devastating combination.

We describe a case of an adolescent male with the rare combination of pulmonary arterial hypertension (PAH) and pulmonary arteriovenous malformations (PAVM's) without confirmed hereditary hemorrhagic telangiectasia (HHT). The patient showed clinical deterioration on standard vasodilator therapy, leading us to question our initial diagnosis. Post-mortem evaluation confirmed the presence of pulmonary veno-occlusive disease of which no conclusive signs were recognized at diagnostic work-up. This case demonstrates the heterogeneity in the diseases causing PAH and shows that an unexpected treatment response should alert the physician to question the original diagnosis.

Ventricular response to dobutamine stress cardiac magnetic resonance imaging is associated with adverse outcome during 8-year follow-up in patients with repaired Tetralogy of Fallot.

AIMS: The aim of this study was to evaluate the possible value of dobutamine stress cardiac magnetic resonance imaging (CMR) to predict adverse outcome in Tetralogy of Fallot (TOF) patients. METHODS AND RESULTS: In previous prospective multicentre studies, TOF patients underwent low-dose dobutamine stress CMR (7.5 µg/kg/min). Subsequently, during regular-care patient follow-up, patients were assessed for reaching the composite endpoint (cardiac death, arrhythmia-related hospitalization, or cardioversion/ablation, VO2 max ≤65% of predicted). A normal stress response was defined as a decrease in end-systolic volume (ESV) and increase in ejection fraction. The relative parameter change during stress was calculated as relative parameter change = [(parameterstress - parameterrest)/parameterrest] * 100. The predictive value of dobutamine stress CMR for the composite endpoint was determined using time-to-event analyses (Kaplan-Meier) and Cox proportional hazard analysis. We studied 100 patients [67 (67%) male, median age at baseline CMR 17.8 years (interquartile range 13.5-34.0), age at TOF repair 0.9 years (0.6-2.1)]. After a median follow-up of 8.6 years (6.7-14.1), 10 patients reached the composite endpoint. An abnormal stress response (30% vs. 4.4%, P = 0.021) was more frequently observed in composite endpoint patients. Also in endpoint patients, the relative decrease in right ventricular ESV decreased less during stress compared with the patients without an endpoint (-17 ± 15 vs. -26 ± 13 %, P = 0.045). Multivariable analyses identified an abnormal stress response (hazard ratio 10.4; 95% confidence interval 2.5-43.7; P = 0.001) as predictor for the composite endpoint. CONCLUSION: An abnormal ventricular response to dobutamine stress is associated with adverse outcome in patients with repaired TOF.

Does functional health status predict health-related quality of life in children after Fontan operation?

PURPOSE: It is important to identify those children with a Fontan circulation who are at risk for impaired health-related quality of life. We aimed to determine the predictive value of functional health status - medical history and present medical status - on both physical and psychosocial domains of health-related quality of life, as reported by patients themselves and their parents. METHODS: We carried out a prospective cross-sectional multi-centre study in Fontan patients aged between 8 and 15, who had undergone staged completion of total cavopulmonary connection according to a current technique before the age of 7 years. Functional health status was assessed as medical history - that is, age at Fontan, type of Fontan, ventricular dominance, and number of cardiac surgical procedures - and present medical status - assessed with magnetic resonance imaging, exercise testing, and rhythm assessment. Health-related quality of life was assessed with The TNO/AZL Child Questionnaire Child Form and Parent Form. RESULTS: In multivariate prediction models, several medical history variables, such as more operations post-Fontan completion, lower age at Fontan completion, and dominant right ventricle, and present medical status variables, such as smaller end-diastolic volume, a higher score for ventilatory efficiency, and the presence of sinus node dysfunction, predicted worse outcomes on several parent-reported and self-reported physical as well as psychosocial health-related quality of life domains. CONCLUSIONS: Medical history and worse present medical status not only predicted worse physical parent-reported and self-reported health-related quality of life but also worse psychosocial health-related quality of life and subjective cognitive functioning. These findings will help in identifying patients who are at risk for developing impaired health-related quality of life.

Does exercise training improve cardiopulmonary fitness and daily physical activity in children and young adults with corrected tetralogy of Fallot or Fontan circulation? A randomized controlled trial.

BACKGROUND: Many patients with congenital heart disease do not meet current public health guidelines to participate in moderate-to-vigorous physical activity for ≥60 minutes per day. They are less fit than their healthy peers. We hypothesized that exercise training would increase cardiopulmonary fitness and daily physical activity in these patients. We therefore assessed effects of an exercise training program on cardiopulmonary fitness and daily physical activity in patients with corrected tetralogy of Fallot (ToF) or Fontan circulation. METHODS: In a multicenter prospective controlled trial, patients with ToF or Fontan circulation (age 10-25 years) were randomized, 56 patients to the exercise group and 37 to the control group. The exercise group participated in a 12-week standardized aerobic exercise training program. The control group continued lifestyle as usual. Cardiopulmonary exercise testing and activity measurements were performed before and after 12 weeks. RESULTS: Peak oxygen uptake increased in the exercise group by 5.0% (1.7 ± 4.2 mL/kg per minute; P = .011) but not in the control group (0.9 ± 5.2 mL/kg per minute; P = not significant). Workload increased significantly in the exercise group compared with the control group (6.9 ± 11.8 vs 0.8 ± 13.9 W; P = .047). Subgroup analysis showed a significant increase in pre-to-post peak oxygen uptake in the exercise group of ToF patients but not in the exercise group of Fontan patients. Percentage of measured time spent in moderate-to-vigorous activity at baseline was 13.6% ± 8.6%, which did not significantly change after training. CONCLUSIONS: Aerobic exercise training improved cardiopulmonary fitness in patients with ToF but not in patients with Fontan circulation. Exercise training did not change daily physical activity.

Regional ventricular performance and exercise training in children and young adults after repair of tetralogy of Fallot: randomized controlled pilot study.

BACKGROUND: Public-health guidelines recommend patients with congenital heart disease to exercise. Studies have shown that patients with congenital heart disease can improve physical exercise capacity. The effect of training on regional ventricular performance has hardly been studied. We performed a pilot study to assess whether an exercise training program would result in adverse changes of regional ventricular performance in patients with corrected tetralogy of Fallot. METHODS AND RESULTS: Multicenter prospective randomized controlled pilot study in patients with tetralogy of Fallot aged 10 to 25 years. A 12-week standardized aerobic dynamic exercise training program (3 one-hour sessions per week) was used. Pre- and post-training cardiopulmonary exercise tests, MRI, and echocardiography, including tissue-Doppler imaging, were performed. Patients were randomized to the exercise group (n=28) or control group (n=20). One patient in the exercise group dropped out. Change in tissue-Doppler imaging parameters was similar in the exercise group and control group (change in right ventricle free wall peak velocity E' exercise group, 0.8±2.6 cm/s; control group, 0.9±4.1; peak velocity A' exercise group, 0.4±2.4 m/s; control group 4.6±18.1 cm/s). CONCLUSIONS: This randomized controlled pilot study provides preliminary data suggesting that regional ventricular performance is well maintained during 3-month aerobic dynamic exercise training in children and young adults with repaired tetralogy of Fallot. This information might help patients adhere to current public-health guidelines. CLINICAL TRIAL REGISTRATION: URL: http//:www.trialregister.nl. Unique identifier: NTR2731.

Comprehensive rhythm evaluation in a large contemporary Fontan population.

OBJECTIVES: Rhythm disturbances are an important cause of morbidity in Fontan patients. Currently, the total cavopulmonary connection is performed by using the intra-atrial lateral tunnel (ILT) ('baffle ILT' or 'prosthetic ILT'), or the extracardiac conduit (ECC). The aim of the study was to evaluate rhythm abnormalities and compare the surgical techniques in a contemporary cohort. METHODS: In a cross-sectional multicentre study, 115 patients (age 12.5 ± 3.1 years) underwent rhythm evaluation using ECG, exercise testing and Holter, including heart rate variability. Medical history was reviewed for episodes of arrhythmia. RESULTS: Sinus node dysfunction (SND) was found in 29%, 3 of whom required pacemaker therapy. No difference was found in the incidence of SND between ILT and ECC patients. Sinus pauses occurred only in the ILT group. Exercise testing showed no difference in peak heart rate between the groups. Heart rate reserve (P = 0.023) and heart rate recovery (HRrecovery) (P < 0.001) were lower in ILT patients. Atrial arrhythmias were more common in ILT patients (15 vs 1%, P = 0.004), but only in those with a baffle ILT. One patient had symptomatic ventricular tachycardia (VT). Holter recordings showed sub-clinical VT in 6% of patients, which was associated with larger end-diastolic (P = 0.035) and end-systolic volumes (P = 0.029). CONCLUSIONS: The overall incidence of arrhythmia was low, although SND was frequently present in both Fontan groups. ILT patients had slower HRrecovery, and ILT patients with the more extensive baffle technique had more atrial arrhythmias and more sinus pauses. The significance of asymptomatic ventricular arrhythmias in this young population remains to be determined.

Parental mental health moderates the efficacy of exercise training on health-related quality of life in adolescents with congenital heart disease.

To evaluate the moderating influence of parental variables on changes in health-related quality of life (HRQoL) in adolescents with Tetralogy of Fallot (ToF) or a Fontan circulation after participation in standardized exercise training. A multicenter randomized controlled trail in which 56 patients, aged 10-15, were randomly allocated (stratified by age, gender, and congenital heart disease) to a 12-week period with either: (a) 3 times per week standardized exercise training or (b) care-as-usual (randomization ratio 2:1). Adolescents and their parents filled in online questionnaires at baseline and at 12-week follow-up. In this randomized controlled trail, primary analyses involved influence of parental mental health and parental social support for exercise on changes in the TNO/AZL Child Quality of Life Questionnaire Child Form at follow-up. Secondary analyses concerned comparing levels of parental characteristics with normative data. Compared with controls, adolescents in the exercise group reported a decrease in social functioning when their parents had more anxiety/insomnia or severe depression themselves. Adolescents also reported a decrease in social functioning when their parents showed poorer overall mental health themselves. Parents reported comparable or even better mental health compared with normative data. The effect of a standardized exercise program on HRQoL changes in adolescents with ToF or a Fontan circulation is moderated by parental mental health, more specifically by parental anxiety/insomnia and severe depression. The trial registration number of this article is NTR2731 ( www.trialregister.nl ).

Long-term outcomes of transatrial-transpulmonary repair of tetralogy of Fallot.

OBJECTIVES: The surgical approach to repair of tetralogy of Fallot (ToF) has shifted over the years. We aimed to report the long-term follow-up after ToF repair with the transatrial-transpulmonary approach and to determine predictors of long-term outcomes. METHODS: Retrospective analysis of patients operated on in two tertiary referral centres. Primary outcome measures were: death, pulmonary valve replacement (PVR), reintervention for other reasons, internal cardiodefibrillator and/or pacemaker placement. Kaplan-Meier assessment of overall and event-free survival as well as uni- and multivariate analyses of risk factors for outcomes were performed. RESULTS: Four hundred and fifty-three patients were included. Median age at operation was: 0.6 years (range 0-19.6) and median age at the last follow-up was 14.3 years (range 0.1-42.1). Median age at repair decreased from 1.2 years (range 0.6-5.8) (1970-80) to 0.3 years (range 0-4.7) (2000-12). A transannular patch (TP) was used in 65% of all patients. The use of a TP showed a decline from 89% in the initial years of the cohort to 64% in 2000-12. Early mortality was 1.1% (5 patients) for the entire cohort and late mortality 2.4% (11 patients). Overall survival for the entire cohort was 97.3% (95% CI 95.7-98.8) and 91.8% (95% CI 85.9-97.7) at 10 and 25 years, respectively. For patients with a TP (n = 294) vs non-TP (n = 159), this was 97.2% (95% CI 95.2-99.2) vs 97.5% (95% CI 95.1-99.9) at 10-year and 91.0% (95% CI 83.9-98.1) vs 96.3% (95% CI 93.0-99.6) at 25-year follow-up (P = 0.958). Fifty-two patients underwent PVR, and in 5 a pacemaker was inserted. Event-free survival for TP versus non-TP patients was 80.2% (95 CI% 75.5-84.9) vs 81.7% (95% CI 75.2-88.2) at 10-year and 27.9% (95% CI 17.7-38.1) vs 78.5% (95% CI 71.4-85.6) at 25-year follow-up (P = 0.016). In multivariate analysis, both the use of a TP (HR 1.705, 95% CI 1.023-2.842) and the year of surgical repair of tetralogy of Fallot (HR 1.039, 95% CI 1.006-1.073) were associated with a higher probability of an event. CONCLUSIONS: ToF patients corrected with the transatrial-transpulmonary approach have good long-term survival. PVR is a frequent event at longer follow-up, and other events are limited. The use of a TP is a predictor for poorer event-free outcomes, increasing the risk of the composite endpoint 1.7 times.

Exercise capacity in children after total cavopulmonary connection: lateral tunnel versus extracardiac conduit technique.

OBJECTIVES: In patients with univentricular heart disease, the total cavopulmonary connection (TCPC) is the preferred treatment. TCPC can be performed using the intra-atrial lateral tunnel (ILT) or extracardiac conduit (ECC) technique. The purpose of the present study was to evaluate exercise capacity in contemporary TCPC patients and compare the results between the 2 techniques. METHODS: A total of 101 TCPC patients (ILT, n=42; ECC, n=59; age, 12.2±2.6 years; age at TCPC completion, 3.2±1.1 years) underwent cardiopulmonary exercise testing. The patients were recruited prospectively from 5 tertiary referral centers. RESULTS: For the entire group, the mean peak oxygen uptake was 74%±14%, peak heart rate was 90%±8%, peak workload was 62%±13%, and slope of ventilation versus carbon dioxide elimination (VE/VCO2 slope) was 127%±30% of the predicted value. For the ILT and ECC groups, patient age, age at TCPC completion, body surface area, peak workload, and peak heart rate were comparable. The percentage of predicted peak oxygen uptake was lower in the ILT group (70%±12% vs 77%±15%; P=.040), and the percentage of predicted VE/VCO2 slope was greater in the ILT group (123%±36% vs 108%±14%; P=.015). In a subgroup analysis that excluded ILT patients with baffle leak, these differences were not statistically significant. CONCLUSIONS: Common exercise parameters were impaired in contemporary Fontan patients. Chronotropic incompetence was uncommon. The peak oxygen uptake and VE/VCO2 slope were less favorable in ILT patients, likely related to baffle leaks in some ILT patients. These results have shown that a reduced exercise capacity in Fontan patients remains an important issue in contemporary cohorts. The ECC had a more favorable exercise outcome at medium-term follow-up.

Aerobic exercise influences quality of life of children and youngsters with congenital heart disease: a randomized controlled trial.

PURPOSE: To evaluate effects of an exercise program on health-related quality of life (HRQoL) in children and adolescents with tetralogy of Fallot (ToF) or a Fontan circulation. METHODS: Stratified, randomized, controlled intervention study conducted in five participating centers of pediatric cardiology in The Netherlands. In total, 93 patients, aged 10-25 years, with surgical repair for tetralogy of Fallot or with a Fontan circulation for single-ventricle physiology were included. They were randomly allocated with a ratio of 2:1 to: (1) a 12-week period with an exercise program for 3 times per week or (2) to a control group. Randomization was stratified by age, gender, and cardiac diagnosis. At baseline and follow-up after 12 weeks, all participants completed Web-based age-appropriate HRQoL questionnaires. Primary analyses involved change in HRQoL during follow-up. Secondary analyses concerned influence of cardiac diagnosis and comparison with normative data. RESULTS: Forty-eight (86%) and 32 (86%) patients in the exercise-group and control-group respectively completed all questionnaires at baseline and follow-up. Compared with the control-group, children, aged 10-15 years, in the exercise-group improved significantly on self-reported cognitive functioning, p < .05, r = .30, and parent-reported social functioning, p < .05, r = .30. Youngsters aged 16-25 years did not change their HRQoL. Cardiac diagnosis had no influence on pre/post changes. Children and youngsters in this study reported comparable or better HRQoL than norm groups. CONCLUSIONS: Participation in an exercise program improved HRQoL of children with ToF or a Fontan circulation, especially in those with low baseline QoL.

Effect of exercise training on sports enjoyment and leisure-time spending in adolescents with complex congenital heart disease: the moderating effect of health behavior and disease knowledge.

OBJECTIVE: The aim of this study was to evaluate the effects of a standardized exercise program on sports enjoyment and leisure-time spending in adolescents with congenital heart disease and to know what the moderating impact of their baseline health behavior and disease knowledge is. METHODS: Included were 93 patients, aged 10 to 25, with surgical repair for tetralogy of Fallot or with a Fontan circulation for single-ventricle physiology, of 5 participating centers of pediatric cardiology in The Netherlands. They were randomly allocated, stratified for age, gender, and type of congenital heart disease to a 12-week period with either: (1) three times per week standardized exercise training or (2) care as usual (randomization ratio 2:1). At baseline and after 12 weeks, participants completed Web-based questionnaires and were interviewed by phone. OUTCOME MEASURES: Primary analyses tested changes from baseline to follow-up in sports enjoyment and leisure-time spending in the exercise group vs. control group. Secondary analyses concerned the moderating influence of baseline health behavior and disease knowledge on changes from baseline to follow-up, and comparison with normative data. RESULTS: At follow-up, the exercise group reported a decrease in passive leisure-time spending (watching television and computer usage) compared with controls. Exercise training had no effect on sports enjoyment and active leisure-time spending. Disease knowledge had a moderating effect on improvement in sports enjoyment, whereas health behavior did not. Compared with normative data, patients obtained similar leisure time scores and lower frequencies as to drinking alcohol and smoking. CONCLUSIONS: Exercise training decreased passive, but not active, leisure-time spending. It did not influence sports enjoyment.

Associations between exercise capacity, physical activity, and psychosocial functioning in children with congenital heart disease: a systematic review.

BACKGROUND: Children and adolescents operated upon for congenital heart disease (ConHD) may show reduced exercise capacity and physical activity, possibly associated with lowered self-esteem and quality of life (QoL). The studies into associations between these parameters have not been reviewed before. OBJECTIVE: Review of studies into associations between exercise capacity, physical activity, respectively exercise training, and psychosocial functioning of ConHD youngsters. DATA SOURCES: PubMed, Embase and reference lists of related articles. STUDY SELECTION: Articles published between January 2000 and December 2012 into exercise capacity and/or physical activity, and a measure of psychosocial functioning in children with ConHD. DATA EXTRACTION: Two investigators independently reviewed the identified articles for eligibility, and one author extracted the data. RESULTS: Although exercise capacity was strongly related to physical domains of parent-reported and self-reported QoL, it was almost never associated with psychosocial domains of QoL. Physical activity was rarely associated with physical or psychosocial domains of QoL. Remarkably, self-reported depressive symptoms were associated with both physical and psychosocial QoL. The few studies into exercise-training programmes showed promising results in QoL and emotional and behavioral problems, but they contained methodological flaws. CONCLUSIONS: No clear relationships were found between exercise capacity, physical activity, and QoL in children and adolescents with ConHD. Therefore we recommend assessing QoL separately, preferably both self-reported and parent-reported. Since depressive symptoms were associated with reduced physical and psychosocial QoL, screening on these symptoms is also recommended.

[A neonate without anus]. / Een neonaat zonder anus.

A male neonate presented with an anal atresia and a rectoperineal fistula. The fistula was dilated which made a temporary colostomy unnecessary. A posterior sagittal anorectoplasty was conducted successfully.

Physical activity in adolescents with juvenile idiopathic arthritis.

OBJECTIVE: To explore physical activity (PA) in adolescents with juvenile idiopathic arthritis (JIA) compared with a healthy population and to examine associations between PA and disease-related factors. METHODS: Total energy expenditure (TEE), activity-related energy expenditure (AEE), PA level, and PA pattern were assessed with a 3-day activity diary. Aerobic capacity was assessed using a Symptom Limited Bicycle Ergometry test. Functional ability was assessed with the Childhood Health Assessment Questionnaire. Disease activity was assessed using Paediatric Rheumatology International Trials Organisation core set criteria. Overall well-being was measured using a visual analog scale, and time since diagnosis was assessed by retrospective study from patients' charts. We used a cross-sectional study design. Reference data were collected from healthy Dutch secondary school children. RESULTS: Thirty patients and 106 controls were included (mean+/-SD age 17.0+/-0.6 and 16.7+/-0.9 years, respectively). TEE, AEE, and PA level were significantly lower in the JIA group. The JIA group spent more time in bed and less time on moderate to vigorous PA. Only 23% of the JIA patients met public health recommendations to perform >or=1 hour daily moderate to vigorous PA compared with 66% in the reference group. Higher PA was associated with higher levels of well-being and maximal oxygen consumption. CONCLUSION: Adolescents with JIA have low PA levels and are at risk of losing the benefits of PA. Low PA is not related to disease activity, and control over the disease does not restore previous PA levels. Interventions by pediatric rheumatologists are needed to increase PA levels in patients with JIA.