Brain MRI Radiomics Analysis of School-Aged Children with Tetralogy of Fallot.

INTRODUCTION: Radiomics could be potential imaging biomarkers by capturing and analyzing the features. Children and adolescents with CHD have worse neurodevelopmental and functional outcomes compared with their peers. Early diagnosis and intervention are the necessity to improve neurological outcomes in CHD patients. METHODS: School-aged TOF patients and their healthy peers were recruited for MRI and neurodevelopmental assessment. LASSO regression was used for dimension reduction. ROC curve graph showed the performance of the model. RESULTS: Six related features were finally selected for modeling. The final model AUC was 0.750. The radiomics features can be potential significant predictors for neurodevelopmental diagnoses. CONCLUSION: The radiomics on the conventional MRI can help predict the neurodevelopment of school-aged children and provide parents with rehabilitation advice as early as possible.

Abnormal Right-Hemispheric Sulcal Patterns Correlate with Executive Function in Adolescents with Tetralogy of Fallot.

Neurodevelopmental disabilities are the most common noncardiac conditions in patients with congenital heart disease (CHD). Executive function skills have been frequently observed to be decreased among children and adults with CHD compared with peers, but a neuroanatomical basis for the association is yet to be identified. In this study, we quantified sulcal pattern features from brain magnetic resonance imaging data obtained during adolescence among 41 participants with tetralogy of Fallot (ToF) and 49 control participants using a graph-based pattern analysis technique. Among patients with ToF, right-hemispheric sulcal pattern similarity to the control group was decreased (0.7514 vs. 0.7553, P = 0.01) and positively correlated with neuropsychological testing values including executive function (r = 0.48, P < 0.001). Together these findings suggest that sulcal pattern analysis may be a useful marker of neurodevelopmental risk in patients with CHD. Further studies may elucidate the mechanisms leading to different alterations in sulcal patterning.

Association Between Tetralogy of Fallot and Psychiatric Disorders: A Nationwide Cohort Study.

OBJECTIVE: The tetralogy of Fallot (TOF) has been reported to be associated with some neurodevelopmental impairment and psychiatric disorders. Nevertheless, a nationwide study to clarify the risk between TOF and comorbid psychiatric disorders is lacking. Using a nationwide database in Taiwan, this study aimed to explore the role of TOF in various psychiatric disorders and analyze whether there are patient-related risk factors. METHODS: A total of 16,824 enrolled patients, including 4,206 study subjects who were diagnosed with TOF and 12,618 controls with TOF matched (1:3) for sex, age, hospital visits, and index year, were randomly selected from the Taiwanese National Health Insurance Research Database (NHIRD) between 2000 and 2015. Patients' diagnoses in the NHIRD were encoded using International Classification of Diseases, 9th Revision, Clinical Modification codes. RESULTS: Of patients with TOF, 256 (6.09%) developed psychiatric disorders compared to 394 (3.12%) in the control group. After adjusting for covariates, the adjusted hazard ratio of psychiatric disorders for patients with TOF was 3.192 (95% CI, 2.683-3.798; P < .001). After exclusion of psychiatric diagnoses within the first 5 years, TOF was associated with an increased risk of anxiety (P < .001), depression (P < .001), bipolar disorder (P < .001), and sleep disorders (P = .005). CONCLUSIONS: This study revealed that TOF patients have a nearly 3-fold higher risk of psychiatric disorders, including anxiety, depressive, bipolar, and sleep disorders, than the general population. Therefore, continued mental health screening and surveillance are warranted in TOF patients.

Implementation of Quality-of-Life Assessment Increases Referrals for Intervention in Patients with Tetralogy of Fallot.

Mortality from surgical repair of tetralogy of Fallot (TOF) has decreased dramatically over the last several decades. Despite excellent surgical outcomes, studies reveal that patients with TOF continue to have decreased physical functioning, academic difficulties, and psychosocial impairments. We hypothesized that administering a validated quality-of-life assessment to patients with TOF during routine cardiology follow-up visits would help identify deficits and increase referrals to appropriate interventional programs. Between May 2017 and November 2018, TOF patients (5-20 years) and/or their families completed a standardized quality-of-life assessment (PedsQL 4.0) during cardiology clinic visits. Providers were encouraged to refer patients with abnormal PedsQL 4.0 scores to appropriate services including cardiovascular rehabilitation, psychological evaluation, neurodevelopmental testing, and school intervention. Referrals for the intervention group were compared to those of a control group using χ2 analysis. The PedsQL 4.0 was completed by 79 patients at 90 clinic visits. At least one abnormal PedsQL 4.0 score was identified in 58% (52/90) of patient encounters, and of those 52 encounters, 38% (20/52) received at least one referral for intervention. The most commonly placed referrals were for neurodevelopmental testing (16) and school intervention (11). When comparing the number of referrals from the intervention group to those of the control group, referrals to all intervention services were statistically significant (p < 0.05). Our quality improvement initiative successfully utilized a quality-of-life assessment to detect deficits and subsequently increased the number of referrals to intervention services. Future studies will address barriers that prevent completion of the PedsQL and assess how interventions impact quality-of-life scores.

Impact of congenital heart surgery on quality of life in children and adolescents with surgically corrected Ventricular Septal Defect, Tetralogy of Fallot, and Transposition of the Great Arteries.

OBJECTIVE: To describe the impact of CHD surgery in early childhood on quality of life in children aged 10-16 years with surgically corrected Ventricular Septal Defect, Transposition of the Great Arteries, and Tetralogy of Fallot. METHOD: A cross-sectional survey study of quality of life survey on 161 children and adolescents aged 10-16 years with surgically corrected Ventricular Septal Defect, Transposition of the Great Arteries, and Tetralogy of Fallot. The international Paediatric Quality of Life 4.0 quality of life questionnaires were applied and collected for assessment from patients and parents. The endpoints were total, physical, emotional, social, and school quality of life scores. RESULTS: The quality of life total and school scores was significantly lower in children with CHD than their healthy peers. There was no significant difference in quality of life between the three CHD groups. All three CHD groups had a significantly lower total (7.7-13.2%, p<0.001) and school scores (21.1-31.6%, p<0.001) than the control group. The tetralogy of Fallot group was the only group that had significantly lower scores in the physical subscale (p<0.001) than the controls. CONCLUSION: Children and adolescents with surgically corrected CHD show losses in quality of life in total and school scores compared to healthy controls. The tetralogy of Fallot group was the only CHD group that had significantly lower physical score than the controls.

Quality of Life is Diminished in Patients with Tetralogy of Fallot with Mild Residual Disease: A Comparison of Tetralogy of Fallot and Isolated Valvar Pulmonary Stenosis.

The objective of this study is to compare quality of life (QOL) in patients with mild pulmonary insufficiency (PI) after Tetralogy of Fallot (TOF) repair or after balloon dilation for isolated valvar pulmonary stenosis (VPS). A cross-sectional study of patients with TOF (n = 12) and VPS (n = 19), ages 8-18 years, who underwent cardiac magnetic resonance (CMR) and cardiopulmonary exercise test (CPET) was conducted. Patients with genetic syndromes were excluded. The groups were matched by severity and duration of PI using propensity scores. PI was greater than mild if the regurgitant fraction by CMR was >20%. Health status and QOL assessment included Child Health Questionnaire Child Self-Report (CHQ-CF87), Child Health Questionnaire Parent Report (CHQ-PF50), and Pediatric Cardiac QOL Instrument (parent and patient). QOL scores were compared between groups. Due to propensity matching, the groups had, at worst, mild PI and normal right ventricular ejection fraction on CMR. Parental perception of QOL was significantly worse in TOF as compared to VPS in the domains of general perception of health (P = 0.03), physical functioning (PF; P = 0.004), and family cohesion (P = 0.048). There were no differences in self-reported QOL between groups. There was no association between QOL and right ventricular function on CMR or percent-predicted maximal oxygen consumption on CPET in both groups. Parent-perceived QOL, in the domains of general health perception, PF, and family cohesion, is significantly reduced in patients with TOF with mild residual disease suggesting that the psychosocial impact of congenital heart disease may be significant even with successful repair and satisfactory medical status.

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.

An antenatal marker of neurodevelopmental outcomes in infants with congenital heart disease.

OBJECTIVE: Prenatal exposures are known to alter fetal neurodevelopment and autonomic control. We aimed to explore the correlation between fetal autonomic activity, measured by fetal heart rate variability, and 18-month developmental outcome in subjects with congenital heart disease. STUDY DESIGN: From 2010 to 2013, 5 fetuses with hypoplastic left heart syndrome, 9 with transposition of the great arteries and 9 with tetralogy of Fallot were included in this prospective cohort study. A maternal abdominal fetal electrocardiogram monitor recorded fetal heart rate at 34 to 38 weeks gestational age. We assessed associations between fetal heart rate parameters including interquartile range and s.d. of the fetal RR intervals and 18-month Bayley Scales of Infant Development-III scores using Pearson's correlation coefficient. Multivariable regression modeling identified predictors of neurodevelopmental scores. RESULTS: Fetal heart rate variability parameters at 34 to 38 weeks gestational age correlated with 18-month Cognition (r=0.47, P=0.03) and Motor scores (r=0.66, P=0.001). The interquartile range of the fetal RR intervals predicted Cognition (ß=0.462, P=0.028, R2=0.282) and Motor (ß=0.637, P<0.001, R2=0.542) scores. CONCLUSIONS: In fetuses with congenital heart disease, low heart rate variability at 34 to 38 weeks gestational age predicts diminished 18-month Cognitive and Motor performance. Prenatal autonomic activity may serve as a marker of early childhood development in these high-risk patients.

Psychiatric Disorders and Function in Adolescents with Tetralogy of Fallot.

OBJECTIVES: To assess psychiatric disorders and function in adolescents with repaired tetralogy of Fallot (TOF) without and with a genetic diagnosis and to evaluate associations of functioning with medical factors, IQ, and demographics. STUDY DESIGN: Adolescents with TOF (n = 91) and 87 healthy referents completed a clinician-rated structured psychiatric interview, parent-/self-report measures of psychopathology, and brain magnetic resonance imaging. Twenty-three of the adolescents with TOF had a known genetic diagnosis. RESULTS: The prevalence of anxiety disorders did not differ significantly between adolescents with TOF without genetic diagnosis (n = 68) and referents. Adolescents with TOF and a genetic diagnosis showed an increased lifetime prevalence of anxiety disorder (43%) and lower global psychosocial functioning (median, 70; IQR, 63-75) compared with adolescents with TOF without genetic diagnosis (15% and 83; IQR, 79-87, respectively; P = .04 and <.001, respectively) and referents (6% and 85; IQR, 76-90, respectively; P = .001 and <.001, respectively). Adolescents with TOF without and with a genetic diagnosis had a higher lifetime prevalence of attention deficit-hyperactivity disorder (ADHD) than referents (19% and 39%, respectively, vs 5%; P = .04 and .002, respectively) and worse outcomes on parent-/self-report ratings of anxiety and disruptive behavior compared with referents. Risk factors for anxiety, ADHD, and lower psychosocial functioning for adolescents with TOF without a genetic diagnosis included older age, male sex, and low IQ. Medical variables were not predictive of psychiatric outcomes. CONCLUSION: Adolescents with TOF, particularly those with a genetic diagnosis, show increased rates of psychiatric disorder and dysfunction. Continued mental health screening and surveillance into young adulthood is warranted for adolescents with TOF.

Cognitive and attentional functioning in adolescents and young adults with Tetralogy of Fallot and d-transposition of the great arteries.

The objective of this study is to investigate cognitive and attentional function in adolescents and young adults with operated congenital heart disease. Previous research has indicated that children with congenital heart disease have deficits in broad areas of cognitive function. However, less attention has been given to survivors as they grow into adolescence and early adulthood. The participants were 18 non-syndromic adolescents and young adults with tetralogy of Fallot and d-transposition of the great arteries that required cardiac surgery before the age of 5 years, and 18 healthy, unaffected siblings (11-22 years of age for both groups). Cases with congenital heart disease and their siblings were administered Wechsler Intelligence scales and reported attention problems using the Achenbach System of Empirically Based Assessments. Cases were compared to both healthy siblings and established norms. Cases performed significantly lower than siblings on full scale IQ and processing speed, and significantly lower than norms on perceptual reasoning. Cases also reported more attention problems compared to both siblings and norms. Effect sizes varied with medium-to-large effects for processing speed, perceptual reasoning, working memory, and attention problems. Findings suggest that neurocognitive function may continue to be affected for congenital heart disease survivors in adolescence and young adulthood, and that comparisons to established norms may underestimate neurocognitive vulnerabilities.

Fetal Growth and Neurodevelopmental Outcome in Congenital Heart Disease.

We evaluated differences in growth between fetuses with and without congenital heart disease (CHD) and tested associations between growth and early childhood neurodevelopment (ND). In this prospective cohort study, fetuses with hypoplastic left heart syndrome (HLHS), transposition of the great arteries (TGA), and tetralogy of Fallot (TOF) and controls had biparietal diameter (BPD), head (HC) and abdominal circumference (AC), femur length (FL), and estimated fetal weight (EFW) recorded serially during pregnancy at 18-26 weeks GA (F1), at 27-33 weeks GA (F2), and at 34-40 weeks GA (F3). CHD subjects underwent Bayley Scales of Infant Development-III ND testing at 18 months. Differences between CHD fetuses and controls were assessed using t tests and generalized linear modeling. Correlations between biometry and ND informed regression modeling. We enrolled 41 controls and 68 fetuses with CHD (N = 24 HLHS, N = 21 TGA, N = 23 TOF), 46 of whom had ND scores available. At 18-26 weeks, CHD fetuses were smaller than controls in all biometric parameters. Differences in growth rates were observed for HC, BPD, and AC, but not for FL or EFW. Cognitive score correlated with HC/AC at F2 (r = -0.33, P = 0.04) and mean HC/AC across gestation (r = -0.35, P = 0.03). Language correlated with FL/BPD at F2 (r = 0.34, P = 0.04). In stepwise linear regression, mean HC/AC predicted Cognition (B = -102, P = 0.026, R (2) = 0.13) and FL/BPD at F2 predicted Language score (B = 127, P = 0.03, R (2) = 0.12). Differences in growth between CHD fetuses and controls can be measured early in pregnancy. In CHD fetuses, larger abdominal relative to head circumference is associated with better 18-month neurodevelopment.

Adolescents with tetralogy of Fallot: neuropsychological assessment and structural brain imaging.

BACKGROUND: Few data are available on the neuropsychological, behavioural, or structural brain imaging outcomes in adolescents who underwent corrective surgery in infancy for tetralogy of Fallot. METHODS: In this single-centre cross-sectional study, we enrolled 91 adolescents (13-16 years old) with tetralogy of Fallot and 87 referent subjects. Assessments included tests of academic achievement, memory, executive functions, visual-spatial skills, attention, and social cognition, as well as brain magnetic resonance imaging. RESULTS: Genetic abnormalities or syndromes were present in 25% of tetralogy of Fallot patients, who had markedly greater neuropsychological morbidities than did patients without a syndrome. However, even patients without a syndrome performed significantly worse than the referent group or population norms in all of the neuropsychological domains assessed. In multivariable regression in those without a genetic/phenotypic syndrome, the strongest predictors of adverse late neurodevelopmental outcomes included a greater number of complications at the first operation, more total surgical complications across all operations, and occurrence of post-operative seizures. The presence of at least one abnormality on structural magnetic resonance imaging was more frequent in tetralogy of Fallot patients than the referent group (42% versus 8%). CONCLUSIONS: Adolescents with tetralogy of Fallot are at increased neurodevelopmental risk and would benefit from ongoing surveillance and educational supports even after childhood.

Predictors of health-related quality of life in adolescents with tetralogy of Fallot.

OBJECTIVE: To assess health-related quality of life (HRQoL) of adolescents with repaired tetralogy of Fallot (TOF) and whether impairments in HRQoL domains are associated with neurocognitive and medical factors. STUDY DESIGN: Parents of subjects with TOF and healthy referents 13-16 years of age completed the Child Health Questionnaire-Parent Form 50, generating psychosocial (PsS) and physical (PhS) health summary scores. Adolescents completed the Child Health Questionnaire-Child Form 87 and concurrent in-person neurocognitive testing. We analyzed relationships of PsS and PhS scores with neurocognitive performance and medical factors. RESULTS: Compared with referents (n = 85), adolescents with TOF without a genetic diagnosis (n = 66) had lower PsS (50.9 ± 9.4 vs 57.2 ± 4.2, P < .001) and PhS scores (49.4 ± 9.5 vs 55.8 ± 4.9; P < .001). Compared with a normative sample, these adolescents with TOF had similar PsS scores (P = .52) but significantly lower PhS scores (P = .01). Within adolescents with TOF without genetic disorders, lower PsS scores were highly associated with worse neurocognitive measures, particularly the parent-reported Behavior Rating Inventory of Executive Function composite (r = -0.66, P < .001) and Parent Conners' attention deficit-hyperactivity disorder Index T score (r = -0.54, P < .001), whereas associations of PhS scores with neurocognitive measures were weaker. CONCLUSIONS: Psychosocial health status in adolescents with TOF without genetic disorders was worse than in healthy referents without risk factors for brain injury but similar to a normative sample; physical health status was worse in these adolescents than in either comparison group. Within these subjects with TOF, worse psychosocial health status was most highly associated with concurrent executive dysfunction and attention deficit-hyperactivity disorder. Optimizing HRQoL constitutes another indication for attention to neurodevelopment in children with congenital heart disease.

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.

Long-term psychosocial outcome of adults with tetralogy of Fallot and transposition of the great arteries: a historical comparison.

OBJECTIVE: To make a historical comparison on the long-term psychosocial outcome of cardiothoracic surgery during childhood. METHODS: Adult patients operated for tetralogy of Fallot or transposition of the great arteries between 1980 and 1990 (recent sample) were compared with patients who underwent surgery and were investigated 10 years earlier (historical sample). In addition, atrial switch and arterial switch patients within the recent sample were compared. Psychosocial functioning was measured using standardised, validated psychological questionnaires. RESULTS: Although the recent sample of patients overall shows a favourable quality of life, impairments were found in income, living conditions, relationships, offspring, and occupational level. Compared with the historical sample, the recent sample showed no significant improvements on psychosocial functioning, except for a better educational level. The amount of educational problems, such as learning difficulties, was still high compared with normative data. Recently operated patients with transposition of the great arteries (arterial switch) scored significantly better on the Short Form-36 vitality scale (p = 0.02) compared with historical patients with transposition of the great arteries (atrial switch). CONCLUSIONS: Despite improvements in medical treatment over the past few decades, hardly any change was found in the psychosocial outcome of the recent patient sample compared with the historical patient sample. In particular, the percentage of patients needing special education and showing learning problems remained high, whereas income was low compared with normative data.

Exercise capacity, quality of life, and resilience after repair of tetralogy of Fallot: a cross-sectional study of patients operated between 1964 and 2009.

INTRODUCTION: Patients with repaired tetralogy of Fallot have good long-term survival but less is known about the subjectively assessed quality of life or objectively measured functional status of those who have not required subsequent pulmonary valve replacement. We assessed these parameters in a group of children and adults free from pulmonary valve replacement after tetralogy of Fallot repair. METHODS AND RESULTS: A random sample of 50 subjects--16 children and 34 adults, aged 4.1-56.7 years---who had undergone tetralogy of Fallot repair and were free from subsequent pulmonary valve replacement underwent cardiopulmonary exercise testing and completed standardised questionnaires assessing health-related quality of life and resilience. Patients were generally asymptomatic (median New York Heart Association class = I). Exercise capacity was within two standard deviations of normal for most children and adults (mean z VO2max: 0.20 ± 1.5; mean z VE/VCO2: -0.9 ± 1.3). Children reported a total health-related quality of life score similar to healthy norms (78 ± 10 versus 84 ± 1, p = 0.73). Adult survivors also reported quality of life scores comparable to healthy norms. Resilience was highly correlated with all domains of health-related quality of life (r = 0.713, p < 0.0001). CONCLUSIONS: Patients who have undergone tetralogy of Fallot repair in childhood and have not required pulmonary valve replacement have a good long-term health-related quality of life. The finding that patients with greater resilience had better health-related quality of life suggests that it may be beneficial to implement interventions to foster resilience.

Functional health status of adults with tetralogy of Fallot: matched comparison with healthy siblings.

BACKGROUND: Survival prospects for adults with repaired tetralogy of Fallot (TOF) are now excellent. Attention should therefore shift to assessing and improving functional health status and quality of life. We aimed to assess late functional health status of adults surviving TOF repair by matched comparison to their healthy siblings. METHODS: All 1,693 TOF repairs performed at our institution between 1946 and 1990 were reviewed. A matched comparison was undertaken whereby presumed survivors and their healthy sibling were contacted and asked to complete the Ontario Health Survey 1990 and the 36-Item Short Form Health Survey (SF-36) questionnaire. RESULTS: Both questionnaires were completed by 224 adult survivors and their sibling closest in age. Adults with repaired TOF had lower scores for self-perceived general health status (p < 0.001), were less likely to rate their health as good or excellent (p < 0.001), and had lower SF-36 scores for physical functioning and general health (p = 0.001) than their siblings. However, patients reported similar satisfaction with their lives, similar levels of social participation and support, and were as likely to be in long-term partnerships. Worse physical and mental health scores were associated with older age at surgery and at time of questionnaire completion and recent requirement for noncardiac medication. CONCLUSIONS: Although reporting lower functional health status then their siblings, quality of life and life satisfaction for adults who underwent surgery for TOF during childhood is comparable to that of their siblings without heart defects. Follow-up of younger adults is required to understand current health outcomes attributable to improvements in the management of TOF.