Stress Markers, Executive Functioning, and Resilience Among Early Adolescents With Complex Congenital Heart Disease.

Importance: Infants with complex congenital heart disease (cCHD) may experience prolonged and severe stress when undergoing open heart surgery. However, little is known about long-term stress and its role in neurodevelopmental impairments in this population. Objective: To investigate potential differences between early adolescents aged 10 to 15 years with cCHD and healthy controls in physiological stress markers by hair analysis, executive function (EF) performance, and resilience. Design, Setting, and Participants: This single-center, population-based case-control study was conducted at the University Children's Hospital Zurich, Switzerland. Patients with different types of cCHD who underwent cardiopulmonary bypass surgery during the first year of life and who did not have a genetic disorder were included in a prospective cohort study between 2004 and 2012. A total of 178 patients were eligible for assessment at ages 10 to 15 years. A control group of healthy term-born individuals was cross-sectionally recruited. Data assessment was between 2019 and 2021. Statistical analysis was performed from January to April 2023. Exposure: Patients with cCHD who underwent infant open heart surgery. Main Outcomes and Measures: Physiological stress markers were quantified by summing cortisol and cortisone concentrations measured with liquid chromatography with tandem mass spectrometry in a 3-centimeter hair strand. EFs were assessed with a neuropsychological test battery to produce an age-adjusted EF summary score. Resilience was assessed with a standardized self-report questionnaire. Results: The study included 100 patients with cCHD and 104 controls between 10 and 15 years of age (mean [SD] age, 13.3 [1.3] years); 110 (53.9%) were male and 94 (46.1%) were female. When adjusting for age, sex, and parental education, patients had significantly higher sums of hair cortisol and cortisone concentrations (ß, 0.28 [95% CI, 0.12 to 0.43]; P < .001) and lower EF scores (ß, -0.36 [95% CI, -0.49 to -0.23]; P < .001) than controls. There was no group difference in self-reported resilience (ß, -0.04 [95% CI, -0.23 to 0.12]; P = .63). A significant interaction effect between stress markers and EFs was found, indicating a stronger negative association in patients than controls (ß, -0.65 [95% CI, -1.15 to -0.15]; P = .01). The contrast effects were not significant in patients (ß, -0.21 [95% CI, -0.43 to -0.00]; P = .06) and controls (ß, 0.09 [95% CI, -0.11 to 0.30]; P = .38). Conclusions and Relevance: This case-control study provides evidence for altered physiological stress levels in adolescents with cCHD and an association with poorer EF. These results suggest that future studies are needed to better understand the neurobiological mechanisms and timing of alterations in the stress system and its role in neurodevelopment.

Association of cerebellar volume with cognitive and motor function in adults with congenital heart disease.

INTRODUCTION: Patients with congenital heart disease (CHD) are at risk for cognitive and motor function impairments, brain injury, and smaller total brain volumes. The specific vulnerability of the cerebellum and its role in cognitive and motor functions in adults with congenital heart disease is not well defined. METHODS: Forty-three patients with CHD and 53 controls between 18 and 32 years underwent brain magnetic resonance imaging and cognitive, executive (EF), and motor function assessment. Cerebellar volumes were obtained using EasyMeasure and SUIT Toolbox. Associations between cerebellar volumes and cognitive and motor function were calculated using linear models. RESULTS: General cognitive and pure motor functions were lower in patients compared to controls (P < 0.05). Executive functions were within the normal range. While total cerebellar volumes and the anterior lobes were similar in patients and controls (P > 0.1), the posterior cerebellar lobe was smaller in patients with more complex CHD (P = 0.006). Smaller posterior cerebellar gray matter was not associated with cognitive functions. Smaller anterior cerebellar gray matter was not significantly related to motor functions (P > 0.1). CONCLUSION: In adults with CHD, cerebellar volume was largely unimpaired. Patients with more complex CHD may be vulnerable to changes in the posterior cerebellar gray matter. We found no significant contribution of cerebellar gray matter to cognitive and motor impairments. More advanced imaging techniques are necessary to clarify the contribution of the cerebellum to cognitive and motor functions.

White matter microstructure and executive functions in congenital heart disease from childhood to adulthood: A pooled case-control study.

Congenital heart disease (CHD) patients are at risk for alterations in the cerebral white matter microstructure (WMM) throughout development. It is unclear whether the extent of WMM alterations changes with age, especially during adolescence when the WMM undergoes rapid maturation. We investigated differences in WMM between patients with CHD and healthy controls from childhood until early adulthood in a pooled sample of children, adolescents, and young adults. The association between WMM and EF was assessed. Patients with CHD (N=78) and controls (N=137) between 9 and 32 years of age underwent diffusion tensor imaging and an executive function test-battery. Mean fractional anisotropy (FA) was calculated for each white matter tract. Linear regression tested age and group effects (CHD vs control) and their interaction on FA. Relative Variable Importance (RI) estimated the independent contribution of tract FA, presence of CHD, CHD complexity, and parental education to the variability in EF. Mean FA was lower in patients compared to controls in almost all tracts (p between 0.057 and <0.001). WMM alterations in patients were not different depending on age (all interaction effects p>0.074). Predictors of EF were CHD group (RI=43%), parental education (RI=23%), CHD complexity (RI=10%), FA of the hippocampal cingulum (RI=6%) and FA of the corticospinal tract (RI=6%). The lack of group-FA-interactions indicates that the extent of altered FA remains similar across age. Altered FA is associated with EF impairments. CHD is a chronic disease with cerebral and neurocognitive impairments persisting into adulthood and, thus, long-term follow-up programs may improve overall outcome for this population.

Brain volumes in adults with congenital heart disease correlate with executive function abilities.

Congenital heart disease is the most common birth defect, and patients are at risk for neurodevelopmental impairment and brain abnormalities. Yet, little is known about the link between brain volumes and cognitive function in adults with congenital heart disease. Forty-four patients and 53 controls between 18 and 32 years underwent brain magnetic resonance imaging and cognitive testing, assessed with an intelligence quotient and executive function global score. Associations between brain volumes and cognitive function were calculated using linear models. Cognitive function in patients was within the normal range (intelligence quotient: 97.74 (10.76)). Total brain volume was significantly smaller in patients compared to controls (1067.26 (113.53) vs 1113.04 (97.88) cm3, P < 0.01), irrespective of cardiac factors (heart defect complexity, cyanosis, cardiopulmonary bypass: all P > 0.4). After adjusting for total brain volume, only corpus callosum volume remained significantly smaller (P = 0.03). Smaller total brain volume was associated with poorer overall executive functioning (P = 0.02) and inhibition (P < 0.01), in both patients and controls. The association between total brain volume and overall executive functioning was moderated by parental socioeconomic status (lower socioeconomic status was associated with a stronger association between brain volume and EF; interaction P = 0.03). In adults with congenital heart disease, despite normal intelligence quotient, brain volume alterations persist into adulthood and are related to executive functioning, in particular inhibitory control. Adults coming from low socioeconomic background and with altered brain volumes are especially vulnerable and should thus be followed-up during adulthood to ensure optimal social and educational support.

Long-term neuroprotective effect of erythropoietin on executive functions in very preterm children (EpoKids): protocol of a prospective follow-up study.

INTRODUCTION: Premature infants are particularly vulnerable to brain injuries with associated cognitive and behavioural deficits. The worldwide first randomised interventional multicentre trial investigating the neuroprotective effects of erythropoietin (entitled 'Does erythropoietin improve outcome in very preterm infants?' (NCT00413946)) included 450 very preterm infants in Switzerland. MRI at term equivalent age showed less white matter (WM) injury in the erythropoietin group compared with the placebo group. Despite these promising imaging findings, neurodevelopmental outcome at 2 years showed no beneficial effect of early erythropoietin. One explanation could be that the assessment of more complex cognitive functions such as executive functions (EFs) is only possible at a later age. We hypothesise that due to improved WM development and fewer WM injuries, children born preterm treated with early erythropoietin will have better EF abilities at 7-12 years than those treated with placebo. METHODS AND ANALYSIS: 365 children who were included into the primary analysis of the original trial (NCT00413946) will be eligible in this prospective follow-up study at the age of 7-12 years. 185 children born at term will be control children. Primary outcome measures are EF abilities and processing speed, while secondary outcomes are academic performance, IQ, fine motor abilities and global brain connectivity. A comprehensive test battery will be applied to assess EFs. MRI will be performed to assess global brain connectivity. Cognitive scores and MRI measures will be compared between both groups using the Wilcoxon test. Propensity score matching will be used to balance gender, age, socioeconomic status and other potentially unbalanced variables between the children born preterm and the healthy control children. ETHICS AND DISSEMINATION: The cantonal ethical committee granted ethical approval for this study (KEK 2017-00521). Written consent will be obtained from the parents. Findings from this study will be disseminated via international and national conference presentations and publications in peer-reviewed journals.