White matter microstructure is differently associated with executive functioning in youth born with congenital heart disease and youth born preterm.

INTRODUCTION: Executive function deficits and adverse psychological outcomes are common in youth with congenital heart disease (CHD) or born preterm. Association white matter bundles play a critical role in higher order cognitive and emotional functions and alterations to their microstructural organization may result in adverse neuropsychological functioning. This study aimed to examine the relationship of myelination and axon density and orientation alterations within association bundles with executive functioning, psychosocial well-being, and resilience in youth with CHD or born preterm. METHODS: Youth aged 16 to 26 years born with complex CHD or preterm at ≤33 weeks of gestational age and healthy controls completed a brain MRI and self-report assessments of executive functioning, psychosocial well-being, and resilience. Multicomponent driven equilibrium single-pulse observation of T1 and T2 and neurite orientation dispersion and density imaging were used to calculate average myelin water fraction (MWF), neurite density index (NDI), and orientation dispersion index values for eight bilateral association bundles. The relationships of bundle-average metrics with neuropsychological outcomes were explored with linear regression and mediation analyses. RESULTS: In the CHD group, lower MWF in several bundles was associated with poorer working memory and behavioral self-monitoring and mediated self-monitoring deficits relative to controls. In the preterm group, lower NDI in several bundles was associated with poorer emotional control and lower MWF in the left superior longitudinal fasciculus III mediated planning/organizing deficits relative to controls. No significant relationships were observed for psychosocial well-being or resilience. CONCLUSION: The findings of this study suggest that microstructural alterations to association bundles, including lower myelination and axon density, have different relationships with executive functioning in youth with CHD and youth born preterm. Future studies should aim to characterize other neurobiological, social, and environmental influences that may interact with white matter microstructure and neuropsychological functioning in these at-risk individuals.

Psychological Well-Being, Everyday Functioning, and Autonomy In Emerging Adults with a Congenital Heart Defect.

OBJECTIVE: To characterize the psychological well-being, everyday functioning, and autonomy of emerging adults with congenital heart disease (CHD) and explore how they relate to the executive function (EF) deficits commonly observed in this population. STUDY DESIGN: Questionnaires assessing psychological well-being (encompassing psychosocial functioning and resilience), EF, and age-appropriate indicators of everyday function and autonomy (eg, housing, education, employment, relationship status) were completed by participants with CHD (16-26 years) who underwent open-heart surgery during infancy and age- and sex-matched controls. RESULTS: A total of 58 emerging adults with CHD and 57 controls participated in this study. Mean scores on the resilience and psychosocial functioning questionnaires were not significantly different between CHD and control participants. Emerging adults with CHD also did not differ from controls in terms of holding a driver's license, involvement in a romantic relationship, or current employment status. Multiple linear regression identified that better EF was associated with better psychological well-being. CONCLUSIONS: This study supports the need for systematic screening for EF deficits during adolescence and early adulthood to promote optimal well-being in this population. Further research is required to continue to document the everyday experiences of adolescents and young adults with CHD to identify protective factors associated with a successful and satisfying transition to adult life.

Sex-Specific Cerebral Blood Flow Alterations in Youth Operated for Congenital Heart Disease.

Background Lower cerebral blood flow (CBF) has previously been documented preoperatively in neonates with congenital heart disease (CHD). However, it remains unclear if these CBF deficits persist over the life span of CHD survivors following heart surgery. When exploring this question, it is critical to consider the sex differences in CBF that emerge during adolescence. Therefore, this study aimed to compare global and regional CBF between postpubertal youth with CHD and healthy peers and examine if such alterations are related to sex. Methods and Results Youth aged 16 to 24 years who underwent open heart surgery for complex CHD during infancy and age- and sex-matched controls completed brain magnetic resonance imaging, including T1-weighted and pseudo-continuous arterial spin labeling acquisitions. Global gray matter CBF and regional CBF in 9 bilateral gray matter regions were quantified for each participant. Compared with female controls (N=27), female participants with CHD (N=25) presented with lower global and regional CBF. In contrast, there were no differences in CBF between male controls (N=18) and males with CHD (N=17). Concurrently, female controls had higher global and regional CBF compared with male controls, with no differences in CBF between female and male participants with CHD. CBF was lower in individuals with a Fontan circulation. Conclusions This study provides evidence of altered CBF in postpubertal female participants with CHD despite undergoing surgical intervention during infancy. Alterations to CBF could have implications for later cognitive decline, neurodegeneration, and cerebrovascular disease in women with CHD.

A comparison of altered white matter microstructure in youth born with congenital heart disease or born preterm.

Introduction: Alterations to white matter microstructure as detected by diffusion tensor imaging have been documented in both individuals born with congenital heart disease (CHD) and individuals born preterm. However, it remains unclear if these disturbances are the consequence of similar underlying microstructural disruptions. This study used multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) and neurite orientation dispersion and density imaging (NODDI) to characterize and compare alterations to three specific microstructural elements of white matter - myelination, axon density, and axon orientation - in youth born with CHD or born preterm. Methods: Participants aged 16 to 26 years with operated CHD or born ≤33 weeks gestational age and a group of healthy peers of the same age underwent a brain MRI including mcDESPOT and high angular resolution diffusion imaging acquisitions. Using tractometry, average values of myelin water fraction (MWF), neurite density index (NDI), and orientation dispersion index (ODI) were first calculated and compared between groups for 30 white matter bundles. Afterwards, bundle profiling was performed to further characterize the topology of the detected microstructural alterations. Results: The CHD and preterm groups both presented with widespread bundles and bundle segments with lower MWF, accompanied by some occurrences of lower NDI, relative to controls. While there were no differences in ODI between the CHD and control groups, the preterm group presented with both higher and lower ODI compared to the control group and lower ODI compared to the CHD group. Discussion: While youth born with CHD or born preterm both presented with apparent deficits in white matter myelination and axon density, youth born preterm presented with a unique profile of altered axonal organization. Future longitudinal studies should aim to better understand the emergence of these common and distinct microstructural alterations, which could orient the development of novel therapeutic approaches.

Altered myelination in youth born with congenital heart disease.

Brain injury and dysmaturation is common in fetuses and neonates with congenital heart disease (CHD) and is hypothesized to result in persistent myelination deficits. This study aimed to quantify and compare myelin content in vivo between youth born with CHD and healthy controls. Youth aged 16 to 24 years born with CHD and healthy age- and sex-matched controls underwent brain magnetic resonance imaging including multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT). Average myelin water fraction (MWF) values for 33 white matter tracts, as well as a summary measure of average white matter MWF, the White Matter Myelination Index, were calculated and compared between groups. Tract-average MWF was lower throughout the corpus callosum and in many bilateral association tracts and left hemispheric projection tracts in youth with CHD (N = 44) as compared to controls (N = 45). The White Matter Myelination Index was also lower in the CHD group. As such, this study provides specific evidence of widespread myelination deficits in youth with CHD, likely representing a long-lasting consequence of early-life brain dysmaturation in this population. This deficient myelination may underlie the frequent neurodevelopmental impairments experienced by CHD survivors and could eventually serve as a biomarker of neuropsychological function.

Altered resting state functional connectivity in youth with congenital heart disease operated during infancy.

Congenital heart disease (CHD) has been associated with structural brain growth and long-term developmental impairments, including deficits in learning, memory, and executive functions. Altered functional connectivity has been shown to be altered in neonates born with CHD; however, it is unclear if these early life alterations are also present during adulthood. Therefore, this study aimed to compare resting state functional connectivity networks associated with executive function deficits between youth (16 to 24 years old) with complex CHD (mean age = 20.13; SD = 2.35) who underwent open-heart surgery during infancy and age- and sex-matched controls (mean age = 20.41; SD = 2.05). Using the Behavior Rating Inventory of Executive Function-Adult Version questionnaire, we found that participants with CHD presented with poorer performance on the inhibit, initiate, emotional control, working memory, self-monitor, and organization of materials clinical scales than healthy controls. We then compared the resting state networks theoretically corresponding to these impaired functions, namely the default mode, dorsal attention, fronto-parietal, fronto-orbital, and amygdalar networks, between the two groups. Participants with CHD presented with decreased functional connectivity between the fronto-orbital cortex and the hippocampal regions and between the amygdala and the frontal pole. Increased functional connectivity was observed within the default mode network, the dorsal attention network, and the fronto-parietal network. Overall, our results suggest that youth with CHD present with disrupted resting state functional connectivity in widespread networks and regions associated with altered executive functioning.

Associations Between Postoperative Management in the Critical Care Unit and Adolescent Developmental Outcomes Following Cardiac Surgery in Infancy: An Exploratory Study.

OBJECTIVES: Children with congenital heart disease are at high risk for developmental sequelae. Most studies focus on preoperative and intraoperative predictors of developmental impairment, with less attention to the postoperative period. The relationship between patient-related factors specific to the postoperative course in the PICU following cardiac surgery with long-term neurodevelopmental outcomes in adolescence was examined. DESIGN: Retrospective chart review of patients previously recruited to a study describing their developmental outcomes in adolescence. SETTING: Single tertiary care pediatric hospital in Canada. PATIENTS: Eighty adolescents, born between 1991 and 1999, with congenital heart disease who required open-heart surgery before 2 years old. MEASUREMENTS AND MAIN RESULTS: Several variables related to acuity of illness and complexity of postoperative course in the PICU were collected. Outcome measures included the Movement-Assessment Battery for Children-2 (motor), Leiter Brief Intelligence Quotient (cognition), and Strength and Difficulties Questionnaire (behavior). Analyses examined associations between PICU variables and long-term outcomes. Longer mechanical ventilation (ß = -0.49; p = 0.013) and dopamine use (ß = -14.41; p = 0.012) were associated with lower motor scores. Dopamine use was associated with lower cognitive scores (ß = -14.02; p = 0.027). Longer PICU stay (ß = 0.18; p = 0.002), having an open chest postoperatively (ß = 3.83; p = 0.017), longer mechanical ventilation (ß = 0.20; p = 0.001), longer inotrope support (ß = 0.27; p = 0.002), hours on dopamine (ß = 0.01; p = 0.007), days to enteral feeding (ß = 0.22; p = 0.012), lower hemoglobin (ß = -0.11; p = 0.004), and higher creatinine (ß = 0.05; p = 0.014) were all associated with behavioral difficulties. CONCLUSIONS: Several important developmental outcomes in adolescents were associated with factors related to their postoperative course in the PICU as infants. Findings may highlight those children at highest risk for neurodevelopmental sequelae and suggest new approaches to critical care management following open-heart surgery, with the aim of mitigating or preventing adverse long-term outcomes.

Quantification of apparent axon density and orientation dispersion in the white matter of youth born with congenital heart disease.

BACKGROUND: White matter alterations have previously been demonstrated in adolescents born with congenital heart disease (CHD) using diffusion tensor imaging (DTI). However, due to the non-specific nature of DTI metrics, it is difficult to interpret these findings in terms of their microstructural implications. This study investigated the use of neurite orientation dispersion and density imaging (NODDI), which involves the acquisition of advanced multiple b-value data over two shells and provides proxy measures of apparent axon density and orientation dispersion within white matter, as a complement to classic DTI measures. STUDY DESIGN: Youth aged 16 to 24 years born with complex CHD and healthy peers underwent brain magnetic resonance imaging. White matter tract volumes and tract-average values of DTI and NODDI metrics were compared between groups. Tract-average DTI and NODDI results were spatially confirmed using tract-based spatial statistics. RESULTS: There were widespread regions of lower tract-average neurite density index (NDI) in the CHD group as compared to the control group, particularly within long association tracts and in regions of the corpus callosum, accompanied by smaller white matter tract volumes and isolated clusters of lower fractional anisotropy (FA). There were no significant differences in orientation dispersion index (ODI) between groups. CONCLUSION: Lower apparent density of axonal packing, but not altered axonal orientation, is a key microstructural factor in the white matter abnormalities observed in youth born with CHD. These impairments in axonal packing may be an enduring consequence of early life brain injury and dysmaturation and may explain some of the long-term neuropsychological difficulties experienced by this at-risk group.

Participation in leisure activities in adolescents with congenital heart defects.

AIM: To describe leisure participation in adolescents with congenital heart defects (CHD) and identify factors associated with intensity of participation. METHOD: Eighty adolescents with CHD were recruited (39 males, 41 females; mean age [SD] 15y 8mo [1y 8mo] range 11y 5mo-19y 11mo) of whom 78 completed the Children's Assessment of Participation and Enjoyment (CAPE) outcome measure of leisure participation. The measure has five subscales: recreational, active-physical, social, skill-based, and self-improvement. Associations between the CAPE and age, sex, and development were examined. Motor ability (Movement Assessment Battery for Children, Second Edition), cognition (Leiter International Performance Scale-Revised), behavior (Strengths and Difficulties Questionnaire), and motivation (Dimensions of Mastery Questionnaire) were assessed. RESULTS: Participants exhibited impaired motor (43.5%), behavioral (23.7%), and cognitive (29.9%) development. The most intense participation was in social (mean [SD] 3.3 [0.99]) and recreational (2.9 [0.80]) activity types on the CAPE. Male sex (p<0.05) and younger age were associated with greater physical activity (<15y: 1.87; ≥15y: 1.31, p<0.05). Greater engagement in social activities was related to better cognition (r=0.28, p<0.05), higher motor function (r=0.30-0.36, p<0.01), and fewer behavioral difficulties (r=-0.32 to -0.47, p<0.01). Cognitive ability (r=0.27, p<0.05), dexterity and aiming/catching (r=0.27-0.33, p<0.05), and behavior problems (r=0.38-0.49, p=0.001) were correlated with physical activity participation. Persistence in tasks, an aspect of motivation, correlated with physical (r=0.45, p<0.001) and social activity involvement (r=0.28, p<0.05). INTERPRETATION: Ongoing developmental impairments in adolescents with CHD are associated with decreased active-physical and social engagement, putting them at risk of poor physical and mental health. Health promotion strategies should be considered. WHAT THIS PAPER ADDS: Adolescents with congenital heart defects (CHD) have limited engagement in active-physical leisure activities. Cognitive, motor, and behavioral impairments are associated with decreased participation in leisure in children with CHD. Female sex and older age are associated with less engagement in leisure. Mastery motivation correlates with participation, suggesting an avenue for intervention.

Participación en actividades recreativas en adolescentes con cardiopatías congénitas OBJETIVO: Describir la participación en el tiempo libre en adolescentes con defectos cardíacos congénitos (CHD) e identificar los factores asociados con la intensidad de la participación. MÉTODO: Ochenta adolescentes con CHD fueron reclutados (39 varones, 41 mujeres; edad media [DE] 15 años 8 meses [1 año 8 meses] rango 11 año 5 meses- 19 año 11 meses) de los cuales 78 completaron la medida de resultado de la Evaluación de la Participación y el Disfrute de los Niños (Children's Assessment of Participation and Enjoyment [CAPE]) del ocio participación. La medida tiene cinco subescalas: recreación, actividad física, social, basada en habilidades y mejoría personal. Se examinaron las asociaciones entre el CAPE y la edad, el sexo y el desarrollo. Se evaluó la capacidad motora con la Batería de Evaluación de Movimiento para Niños (Movement Assessment Battery for Children, Segunda edición), la cognición (Leiter International Performance Scale-Revised), el comportamiento con el Cuestionario de Fortalezas y Dificultades (Strengths and Difficulties Questionnaire) y la motivación usando el cuestionario Dimensiones del Dominio (Dimensions of Mastery Questionnaire). RESULTADOS: Los participantes exhibieron problemas en el desarrollo motor (43.5%), conducta (23.7%) y en el desarrollo cognitivo (29.9%). La participación más intensa fue en los tipos de actividad social (media [DE] 3.3 [0.99]) y recreativa (2.9 [0.80]) en el CAPE. El sexo masculino (p <0.05) y la edad más joven se asociaron con una mayor actividad física (<15 años: 1.87; ≥15 años: 1.31, p <0.05). Una mayor participación en actividades sociales se relacionó con una mejor cognición (r = 0.28, p <0.05), una función motora más alta (r = 0.30-0.36, p <0.01) y menos dificultades en el comportamiento (r = -0.32 a -0.47, p < 0,01). La capacidad cognitiva (r = 0.27, p <0.05), la destreza manual y la habilidad para apuntar y atajar (r = 0.27-0.33, p <0.05) y los problemas de comportamiento (r = 0.38-0.49, p = 0.001) se correlacionaron con la participación en la actividad física. La capacidad de persistir en las tareas, un aspecto de la motivación se correlacionó con la participación física (r = 0.45, p <0.001) y la actividad social (r = 0.28, p <0.05). INTERPRETACIÓN: Los problemas de desarrollo en los adolescentes con CHD están asociados con una disminución de la participación física y social, lo que los pone a riesgo de una pobre salud física y mental. Deben buscarse estrategias para la promoción de la salud de esta población.

Participação em atividades de lazer em adolescentes com defeitos cardíacos congênitos OBJETIVO: Descrever a participação em lazer de adolescentes com defeitos cardíacos congênitos (DCC) e identificar fatores associados com a intensidade de participação. MÉTODO: Oitenta adolescentes com DCC foram recrutados (39 do sexo masculino, 41 do sexo feminino; média de idade [DP] 15a 8m [1a 8m] variação 11a 5m-19a 11m), dos quais 78 completaram a medida de participação em lazer Avaliação da participação e diversão das crianças (APDC). A medida tem cinco subescalas: recreacional, ativa-física, social, baseada em habilidades, e auto-aprimoramento. Associações entre a APDC e idade, sexo e desenvolvimento foram examinadas. A capacidade motora (Bateria de avaliação do movimento para crianças, segunda edição), cognição (Escala internacional de desempenho de Leiter- Revisada), comportamento (Questionário de capacidades e dificuldades), e motivação (Questionário de Dimensões do Domínio) foram avaliados. RESULTADOS: Os participantes exibiram comprometimento do desenvolvimento motor (43,5%), comportamental (23,7%), e cognitivo (29,9%). A participação mais intensa segundo a APDC foi nos tipos social (média [DP] 3,3 [0,99]) e recreacional (2.9 [0,80]). O sexo masculino (p<0,05) e menor idade foram associados com maior nível de atividade física (<15a: 1,87; ≥15a: 1,31, p<0,05). Um maior engajamento em atividades sociais foi relacionado com uma melhor cognição (r=0,28, p<0,05), maior função motora (r=0,30-0,36, p<0,01), e menos dificuldades comportamentais (r=-0,32 a -0,47, p<0,01). A capacidade cognitiva (r=0,27, p<0,05), destreza e mirar/apreender (r=0,27-0,33, p<0,05), e problemas comportamentais (r=0,38-0,49, p=0,001) foram correlacionadas com a participação em atividades físicas. A persistência nas tarefas, um aspecto da motivação, se correlacionou com o envolvimento em atividades físicas (r=0,45, p<0,001) e sociais (r=0,28, p<0,05). INTERPRETAÇÃO: Alterações persistentes do desenvolvimento de adolescentes com DCC são associadas com engajamento ativo-físico e social reduzidos, o que os coloca em risco para sua saúde física e mental. Estratégias de promoção de saúde deveriam ser consideradas.

Hippocampal alterations and functional correlates in adolescents and young adults with congenital heart disease.

There is a high prevalence of neurodevelopmental impairments in individuals living with congenital heart disease (CHD) and the neural correlates of these impairments are not yet fully understood. Recent studies have shown that hippocampal volume and shape differences may provide unique biomarkers for neurodevelopmental disorders. The hippocampus is vulnerable to early life injury, especially in populations at risk for hypoxemia or hemodynamic instability such as in neonates with CHD. We compared hippocampal gray and white matter volume and morphometry between youth born with CHD (n = 50) aged 16-24 years and healthy peers (n = 48). We also explored whether hippocampal gray and white matter volume and morphometry are associated with executive function and self-regulation deficits. To do so, participants underwent 3T brain magnetic resonance imaging and completed the self-reported Behavior Rating Inventory of Executive Function-Adult version. We found that youth with CHD had smaller hippocampal volumes (all statistics corrected for false discovery rate; q < 0.05) as compared to controls. We also observed significant smaller surface area bilaterally and inward displacement on the left hippocampus predominantly on the ventral side (q < 0.10) in the CHD group that were not present in the controls. Left CA1 and CA2/3 were negatively associated with working memory (p < .05). Here, we report, for the first-time, hippocampal morphometric alterations in youth born with CHD when compared to healthy peers, as well as, structure-function relationships between hippocampal volumes and executive function. These differences may reflect long lasting alterations in brain development specific to individual with CHD.

A Comparison of Developmental Outcomes of Adolescent Neonatal Intensive Care Unit Survivors Born with a Congenital Heart Defect or Born Preterm.

OBJECTIVE: To compare cognitive, motor, behavioral, and functional outcomes of adolescents born with a congenital heart defect (CHD) and adolescents born preterm. STUDY DESIGN: Adolescents (11-19 years old) born with a CHD requiring open-heart surgery during infancy (n = 80) or born preterm ≤29 weeks of gestational age (n = 128) between 1991 and 1999 underwent a cross-sectional evaluation of cognitive (Leiter International Performance Scale-Revised), motor (Movement Assessment Battery for Children-II), behavioral (Strengths and Difficulties Questionnaire), and functional (Vineland Adaptive Behavior Scale-II) outcomes. Independent samples t tests and Pearson χ2 or Fisher exact tests were used to compare mean scores and proportions of impairment, respectively, between groups. RESULTS: Adolescents born with a CHD and adolescents born preterm had similar cognitive, motor, behavioral, and functional outcomes. Cognitive deficits were detected in 14.3% of adolescents born with a CHD and 11.8% of adolescents born preterm. Motor difficulties were detected in 43.5% of adolescents born with a CHD and 50% of adolescents born preterm. Behavioral problems were found in 23.7% of adolescents in the CHD group and 22.9% in the preterm group. Functional limitations were detected in 12% of adolescents born with a CHD and 7.3% of adolescents born preterm. CONCLUSIONS: Adolescents born with a CHD or born preterm have similar profiles of developmental deficits. These findings highlight the importance of providing long-term surveillance to both populations and guide the provision of appropriate educational and rehabilitation services to better ameliorate long-term developmental difficulties.

Educational and rehabilitation service utilization in adolescents born preterm or with a congenital heart defect and at high risk for disability.

AIM: This historical cohort study describes the use of educational and rehabilitation services in adolescents born preterm or with a congenital heart defect (CHD). METHOD: Parents of 76 young people (mean age 15y 8mo [SD 1y 8mo]) with CHD and 125 born ≤29 weeks gestational age (mean age 16y [SD 2y 5mo]) completed a demographics questionnaire including educational and rehabilitation resource utilization within the previous 6 months. Rehabilitation services included occupational therapy, physical therapy, speech language pathology, psychology. Developmental (Leiter Brief IQ, Movement-ABC, Strengths and Difficulties Questionnaire) and functional (Vineland) status of the young people was assessed. Pearson χ2 tests were used to perform simple pairwise comparisons of categorical outcomes across the two groups (CHD, preterm). Univariate logistic regression was used to examine predictors of service utilization. RESULTS: Developmental profiles of the two groups (CHD/preterm) were similar (29.9%/30% IQ<80; 43.5%/50.0% motor difficulties; 23.7%/22.9% behavior problems). One-third received educational supports or attended segregated schools. Only 16% (preterm) and 26.7% (CHD) were receiving rehabilitation services. Services were provided predominantly in the school setting, typically weekly. Few received occupational therapy or physical therapy (1.3-7.6%) despite functional limitations. Leiter Brief IQ<70 was associated with receiving educational supports (CHD: OR 5.53, 95% CI 1.29-23.68; preterm: OR 14.63, 3.10-69.08) and rehabilitation services (CHD: OR 4.46, 1.06-18.88; preterm: OR 5.11, 1.41-18.49). Young people with motor deficits were more likely to require educational (CHD: OR 5.72, 1.99-16.42; preterm: OR 3.11, 1.43-6.77) and rehabilitation services (preterm: OR 3.97, 1.21-13.03). INTERPRETATION: Although young people with impairments were more likely to receive educational and rehabilitation services, many may not be adequately supported, particularly by rehabilitation specialists. Rehabilitation services at this important transition phase could be beneficial in optimizing adaptive functioning in the home, school, and community.

Left Atrial Inexcitability in Children With Congenital Lupus-Induced Complete Atrioventricular Block.

BACKGROUND: Congenital atrioventricular block is a well-established immunologic complication of maternal systemic lupus erythematosus. We sought to further characterize the electrophysiological manifestations of maternal systemic lupus erythematosus on neonatal atria. METHODS AND RESULTS: Cases of isolated congenital atrioventricular block treated at our center over the past 41 years were identified. Data were extracted from clinical charts, pacemaker interrogations, ECGs, echocardiograms, and histopathological reports, when available. Of 31 patients with isolated congenital atrioventricular block, 18 were negative for maternal antibodies and had normal epicardial atrial sensing and pacing thresholds. In contrast, 12 of 13 patients with positive maternal antibodies had epicardial pacemakers, 5 (42%) of whom had left atrial (LA) inexcitability and/or atrial conduction delay. In 3 patients, the LA could not be captured despite high-output pacing. The fourth patient had acutely successful LA appendage and left ventricular lead placement. At early follow-up, an increased delay between the surface P-wave and intracardiac atrial depolarization was observed, indicative of atrial conduction delay. The fifth patient exhibited LA lead dysfunction, with atrial under-sensing and an increased capture threshold, 2 weeks after implantation. Biopsies of LA appendages performed in 2 patients showed no evidence of atrial fibrosis or loss of atrial myocytes. CONCLUSIONS: Herein, we report previously undescribed yet prevalent electrophysiological ramifications of maternal systemic lupus erythematosus, which extend beyond congenital atrioventricular block to encompass alterations in LA conduction, including LA inexcitability. These manifestations can complicate epicardial pacemaker implantation in newborns. In the absence of histological evidence of extensive atrial fibrosis, immune-mediated functional impairment of electrical activity is suspected.

Risk of congenital heart defects is influenced by genetic variation in folate metabolism.

Genetic disturbances in folate metabolism may increase risk for congenital heart defects. We examined the association of heart defects with four polymorphisms in folate-related genes (methylenetetrahydrofolate reductase (MTHFR) c.677C.T, MTHFR c.1298A.C, methionine synthase reductase (MTRR) c.66A.G, and reduced folate carrier (SLC19A1) c.80A.G) in a case-control study of children (156 patients, 69 controls) and mothers of children with heart defects (181 patients, 65 controls), born before folic acid fortification. MTRR c.66A.G in children modified odds ratios for overall heart defects, specifically ventricular septal defect and aortic valve stenosis (p-value below 0.05). The 66GG and AG genotypes were associated with decreased odds ratios for heart defects (0.42, 95% confidence interval (0.18-0.97) and 0.39 (0.18-0.84), respectively). This overall association was driven by decreased risk for ventricular septal defect for 66GG and AG (odds ratio 0.32 (0.11-0.91) and 0.25 (0.09-0.65)) and decreased odds ratio for aortic valve stenosis for 66AG (0.27 (0.09-0.79)). The association of ventricular septal defect and 66AG remained significant after correction for multiple testing (p = 0.0044, multiple testing threshold p = 0.0125). Maternal MTHFR 1298AC genotype was associated with increased odds ratio for aortic valve stenosis (2.90 (1.22-6.86), p = 0.0157), but this association did not meet the higher multiple testing threshold. No association between MTHFR c.677C.T or SLC19A1 c.80A.G and heart defect risk was found. The influence of folate-related polymorphisms may be specific to certain types of heart defects; larger cohorts of mothers and children with distinct sub-classes are required to adequately address risk.

Choices doctors would make if their infant had hypoplastic left heart syndrome: comparison of survey data from 1999 and 2007.

Data suggest that despite improved surgical outcomes for infants with hypoplastic left heart syndrome (HLHS), the past two decades have seen little change in parents' decisions whether to choose surgery or palliative treatment without life-prolonging intervention. Data also suggest that doctors' predictions of the choices they would make if their own infant were diagnosed with HLHS do not correlate with their predictions of surgical outcomes. Although previous studies have compared rates of surgery and palliative treatment without life-prolonging intervention over time, no studies have assessed changes in doctors' attitudes. The current study used descriptive and quantitative statistics to compare responses from American pediatric cardiologists and congenital cardiac surgeons from studies conducted in 1999 and 2007. These doctors were asked what choice they believe they would make for their own affected infant. Comparison of responses from 1999 and 2007 showed no difference in the responses of cardiologists: 1999 (44 % surgery, 17 % palliative treatment, 40 % uncertain) versus 2007 (45 % surgery, 20 % palliative treatment, 35 % uncertain). Among surgeons, there was a non-statistically significant trend away from choosing surgery: 1999 (77 % surgery, 5 % palliative treatment, 18 % uncertain) versus 2007 (56 % surgery, 8 % palliative treatment, 36 % uncertain). In conclusion, these analyses suggest that despite improving surgical outcomes, doctors are no more likely to predict that they would choose surgery for their own hypothetical infant with HLHS. Further research is needed to determine what factors influence choice making in the care of infants with HLHS.

Gender differences in the developmental outcomes of children with congenital cardiac defects.

OBJECTIVE: This study compares the developmental and functional outcomes at school entry between boys and girls born with a congenital cardiac defect who required early surgical correction. STUDY DESIGN: A prospective cohort of 94 children, including 49 percent boys, were followed up to 5 years of age and assessed for developmental progress. Developmental measures included Wechsler Preschool and Primary Scale of Intelligence - cognitive; Peabody Picture Vocabulary Test - receptive language; Peabody Developmental Motor Scale - motor; and Child Behaviour Checklist - behaviour. Measures of function included the Vineland Adaptive Behavior Scale and Functional Independence Measure for Children (WeeFIM). RESULTS: The mean scores of the boys on the WeeFIM subscales, such as self-care, mobility, cognition, were significantly lower than that of the girls. There was a trend for a greater proportion of boys to have abnormalities on neurological examination (boys 37.5 percent abnormal, girls 19.5 percent abnormal). Verbal, performance, and full scale Intellectual Quotients were 5-7 points lower in boys but did not reach significance (full scale Intellectual Quotient: boys 87.7 plus or minus 22.2; girls 93.9 plus or minus 19.3). Boys were more likely to have fine motor delays (50 percent, 82.7 plus or minus 16.5) compared with girls (28.2 percent, 87.0 plus or minus 15.8). There were no gender differences in receptive language or behavioural difficulties. CONCLUSIONS: Boys born with congenital heart disease requiring early surgical repair appear to be at enhanced risk for neuromotor impairments and activity limitations. Findings support gender differences in the pathogenesis of early brain injury following hypoxic-ischaemic insults. This has implications for neuroprotective strategies to prevent brain injury.

Hypoxia in early life is associated with lasting changes in left ventricular structure and function at maturity in the rat.

BACKGROUND: There is a growing population of adults with repaired cyanotic congenital heart disease. These patients have increased risk of impaired cardiac health and premature death. We hypothesized that hypoxia in early life before surgical intervention causes lasting changes in left ventricular structure and function with physiological implications in later life. METHODS: Sprague-Dawley rats reared initially hypoxic conditions (FiO(2)=0.12) for days 1-10 of life were compared to rats reared only in ambient air. Cellular morphology and viability were compared among LV cardiomyocytes and histological analyses were performed on LV myocardium and arterioles. Intracellular calcium transients and cell shortening were measured in freshly-isolated cardiomyocytes, and mitochondrial hexokinase 2 (HK2) expression and activity were determined. Transthoracic echocardiography was used to assess LV function in anesthetized animals. RESULTS: Cardiomyocytes from adult animals following hypoxia in early life had greater cellular volumes but significantly reduced viability. Echocardiographic analyses revealed LV hypertrophy and diastolic dysfunction, and alterations in cardiomyocyte calcium transients and cell shortening suggested impaired diastolic calcium reuptake. Histological analyses revealed significantly greater intima-media thickness and decreased lumen area in LV arterioles from hypoxic animals. Alterations in mitochondrial HK2 protein distribution and activity were also observed which may contribute to cardiomyocyte fragility. CONCLUSIONS: Hypoxia in early life causes lasting changes in left ventricular structure and function that may negatively influence myocardial and vascular responses to physiological stress in later life. These data have implications for the growing population of adults with repaired or palliated cyanotic congenital heart disease.

Design and rationale of a genetic cohort study on congenital cardiac disease: experiences from a multi-institutional platform in Quebec.

BACKGROUND: Congenital cardiac disease is the most common malformation, and a substantial source of mortality and morbidity in children and young adults. A role for genetic factors is recognised for these malformations, but overall few predisposing loci have been identified. Here we report the rationale, design, and first results of a multi-institutional congenital cardiac disease cohort, assembled mainly from the French-Canadian population of the province of Quebec and centred on families with multiple affected members afflicted by cardiac malformations. METHODS: Families were recruited into the study, phenotyped and sampled for DNA in cardiology clinics over the first 3 years of enrolment. We performed segregation analysis and linkage simulations in the subgroup of families with left ventricular outflow tract obstruction (LVOTO). RESULTS: A total of 1603 participants from 300 families were recruited, with 169 out of 300 (56.3%) families having more than one affected member. For the LVOTO group, we estimate heritability to be 0.46-0.52 in our cohort. Simulation analysis demonstrated sufficient power to carry out linkage analyses, with an expected mean log-of-odds (LOD) score of 3.8 in 67 pedigrees with LVOTO. CONCLUSION: We show feasibility and usefulness of a population-based biobank for genetic investigations into the causes of congenital cardiac disease. Heritability of LVOTO is high and could be accounted for by multiple loci. This platform is ideally suited for multiple analysis approaches, including linkage analysis and novel gene sequencing approaches, and will allow to establish segregation of risk alleles at family and population levels.

Long-term pediatric outcome of isolated discrete subaortic stenosis.

BACKGROUND: The management of pediatric discrete subaortic stenosis remains controversial. OBJECTIVES: Document the natural history and surgical outcomes for discrete subaortic stenosis to adolescence. METHODS: Retrospective review of clinical and echocardiographic findings in 74 patients diagnosed in childhood between 1985 and 1998. RESULTS: Twenty-five patients were followed only medically for 9.4 ± 0.9 years to 15.9 ± 0.6 years of age. Their echocardiographic left ventricular outflow peak gradient did not progress, 19 ± 1.4 (SEM) vs 20 ± 2.3 mm Hg. The proportion with aortic insufficiency (AI) increased (4% to 52%). Forty-nine patients were operated for discrete subaortic stenosis at 7.8 ± 0.6 years. Their peak gradient at diagnosis was 36 ± 3 mm Hg with AI in 33%. Preoperatively their peak gradient progressed to 60 ± 5 mm Hg with AI in 82%. Assessment 6.2 ± 0.5 years postoperativly showed a peak gradient of 14 ± 2 mm Hg with AI in 88%. Ten patients required reoperation for recurrent discrete subaortic stenosis, 3 acquired complete heart block, and 1 developed endocarditis. There was no mortality. At diagnosis, surgical patients were younger, had greater peak gradients, and greater incidence of AI, than those followed only medically. The progression of discrete subaortic stenosis was positively associated with severity of obstruction and negatively associated with older age at diagnosis. The risk of having surgery over time was associated with greater preoperative obstruction and presence of AI. CONCLUSIONS: Many pediatric patients with mild discrete subaortic stenosis exhibit little progression of obstruction and need not undergo immediate surgery. Others with more severe stenosis may progress precipitously and will benefit from early resection.

Nuclear ß-adrenergic receptors modulate gene expression in adult rat heart.

Both ß(1)- and ß(3)-adrenergic receptors (ß(1)ARs and ß(3)ARs) are present on nuclear membranes in adult ventricular myocytes. These nuclear-localized receptors are functional with respect to ligand binding and effector activation. In isolated cardiac nuclei, the non-selective ßAR agonist isoproterenol stimulated de novo RNA synthesis measured using assays of transcription initiation (Boivin et al., 2006 Cardiovasc Res. 71:69-78). In contrast, stimulation of endothelin receptors, another G protein-coupled receptor (GPCR) that localizes to the nuclear membrane, resulted in decreased RNA synthesis. To investigate the signalling pathway(s) involved in GPCR-mediated regulation of RNA synthesis, nuclei were isolated from intact adult rat hearts and treated with receptor agonists in the presence or absence of inhibitors of different mitogen-activated protein kinase (MAPK) and PI3K/PKB pathways. Components of p38, JNK, and ERK1/2 MAP kinase cascades as well as PKB were detected in nuclear preparations. Inhibition of PKB with triciribine, in the presence of isoproterenol, converted the activation of the ßAR from stimulatory to inhibitory with regards to RNA synthesis, while ERK1/2, JNK and p38 inhibition reduced both basal and isoproterenol-stimulated activity. Analysis by qPCR indicated an increase in the expression of 18S rRNA following isoproterenol treatment and a decrease in NFκB mRNA. Further qPCR experiments revealed that isoproterenol treatment also reduced the expression of several other genes involved in the activation of NFκB, while ERK1/2 and PKB inhibition substantially reversed this effect. Our results suggest that GPCRs on the nuclear membrane regulate nuclear functions such as gene expression and this process is modulated by activation/inhibition of downstream protein kinases within the nucleus.