Congenital Heart Disease Subjects Research Articles

Paediatrics congenital heart disease is associated with plasma miRNAs.

Congenital heart disease (CHD) are the most common malformations from birth. The severity of the different forms of CHD varies extensively from superficial mild lesions with follow-up for decades without any treatment to complex cyanotic malformations requiring urgent surgical intervention. microRNAs have been found to be crucial in cardiac development, giving rise to possible phenotypes in CHD. We aimed to evaluate the expression of miRNAs in 86 children with CHD and divided into cyanotic and non-cyanotic heart defects and 110 controls. The miRNAs expression of miR-21-5p, miR-155-5p, miR-221-3p, miR-26a-5p, and miR-144-3p were analyzed by RT-qPCR. In addition, the expressions of the miRNAs studied were correlated with the clinical characteristics of both the children and the mothers. The expression levels of miR-21-5-5p, miR-15-5p5, miR-221-3p, and miR-26-5p significantly differed between CHD and control subjects. Moreover, miR-21-5p levels were higher in patients with cyanotic versus non-cyanotic CHD patients. The expression levels of miRNAs of pediatric patients with CHD could participating in the development of cardiac malformations. Additionally, the high expression of miR-21-5p in cyanotic CHD children may be related to greater severity of illness relative to non-cyanotic CHD. This study adds to knowledge of the association between microRNAs and congenital heart disease in children. The expression levels of miR-21-5-5p, miR-15-5p5, miR-221-3p, and miR-26-5p of pediatric patients with CHD could be involved in the development and phenotype present in pediatric patients. miR-21-5p may help to discriminate between cyanotic and non-cyanotic CHD. In the future, the miRNAs studied could have applications as clinical biomarkers.

Increased Cerebello-Prefrontal Connectivity Predicts Poor Executive Function in Congenital Heart Disease.

Children and adolescents with congenital heart disease (CHD) are at risk for cognitive impairments, such as executive function deficits and motor delays, which can impact their academic and adaptive functioning as well as their quality of life. We investigated whether alterations in connectivity between the prefrontal and cerebellar brain structures exist between CHD and control cohorts and if these alterations could predict cognitive or motor impairment among youths with CHD. 53 participants with CHD and 73 healthy control participants completed multi-modal magnetic resonance imaging (MRI) of the brain, including high-resolution diffusion tensor imaging at 3T. We measured connectivity from masked regions of interest in the cerebellum to the frontal cortex using a probabilistic tractography method. Participants also completed neuropsychological tests of cognitive and motor skills using the NIH Toolbox. In the CHD group, fractional anisotropy (FA) was increased in the cognitive loop connectivity pathways, including from the right cerebellum to the left thalamus (p = 0.0002) and from the left thalamus to the left medial frontal gyrus (MFG) (p = 0.0048) compared with the healthy control group. In contrast, there were no differences between CHD and controls in motor loop connectivity pathways. An increase in FA from the right thalamus to the MFG tract in the cognitive loop (posterior subdivision) predicted (p = 0.03) lower scores on the NIHTB tests, including those of executive functioning. A transient increase in connectivity of the cognitive loop in the adolescent group was observed relative to the child and adult groups. Our results suggest that selective alteration of cerebellum-cerebral connectivity circuitry within the cognitive loops predicts cognitive dysfunction in CHD youth. Our study suggests a critical period of cerebellar circuitry plasticity in the adolescent period in CHD subjects that drives neurocognitive function. Further replication and validation in other pediatric CHD cohorts is warranted for future work.

Respiratory Microbiome Profile of Pediatric Pulmonary Hypertension Patients Associated With Congenital Heart Disease.

Pulmonary hypertension (PH) associated with congenital heart disease (CHD) is the most common type of PH in pediatric patients. The airway microbiome profile in CHD-PH patients remains rarely studied. A total of 158 children were recruited for collection of oropharyngeal swabs to sequence the 16S ribosomal RNA (16S rRNA) V3-V4 region of respiratory microbiome, to establish a correlation between these bacterial groups and echocardiography indicators in CHD-PH patients. Bacterial α- and β-diversity of the airway microbiome indicated a significantly lower richness in the CHD-PH group and compositional differences associated with the specific taxa and their relative abundances in the upper respiratory tract. Principal coordinate analysis showed that the pharynx microbiota composition in the CHD-PH group varied from that in the CHD or control group. The linear discriminant analysis effect size also highlighted an increased presence of Streptococcus and Rothia in pediatric CHD-PH patients. Comparison of microbial composition between pediatric and adult PH patients showed significant differences and separation of microbiota. The correlation between bacterial abundance and transthoracic echocardiography indexes in CHD-associated PH indicated that different groups of microbiomes may be related to different PH grades. In summary, our study reported the systematic definition and divergent profile of the upper respiratory tract microbiota in pediatric PH patients, CHD and reference subjects, as well as between pediatric and adult PH patients.

Mutation spectrum of congenital heart disease in a consanguineous Turkish population.

BackgroundsWhile many studies agree that consanguinity increases the rate of congenital heart disease (CHD), few genome analyses have been conducted with consanguineous CHD cohorts.MethodsWe recruited 73 CHD probands from consanguineous families in Turkey and used whole‐exome sequencing (WES) to identify genetic lesions in these patients.ResultsOn average, each patient had 6.95 rare damaging homozygous variants, 0.68 of which are loss‐of‐function (LoF) variants. Seven patients (9.6%) carried damaging homozygous variants in five causal CHD genes. Six of those patients exhibited laterality defects (six HTX and one D‐TGA). Three additional patients (4.1%) harbored other types of CHD‐associated genomic alterations, which overall explained 13.7% (10/73) of the cohort. The contribution from recessive variants in our cohort is higher than 1.8% reported from a cohort of 2871 CHD subjects where 5.6% of subjects met the criteria for consanguinity.ConclusionsOur WES screen of a Turkish consanguineous population with structural CHD revealed its unique genetic architecture. Six of seven damaging homozygous variants in CHD causal genes occur in the setting of laterality defects implies a strong contribution from consanguinity to these defects specifically. Our study thus provided valuable information about the genetic landscape of CHD in consanguineous families in Turkey.

Free-running cardiac and respiratory motion-resolved 5D whole-heart coronary cardiovascular magnetic resonance angiography in pediatric cardiac patients using ferumoxytol

BackgroundCoronary cardiovascular magnetic resonance angiography (CCMRA) of congenital heart disease (CHD) in pediatric patients requires accurate planning, adequate sequence parameter adjustments, lengthy scanning sessions, and significant involvement from highly trained personnel. Anesthesia and intubation are commonplace to minimize movements and control respiration in younger subjects. To address the above concerns and provide a single-click imaging solution, we applied our free-running framework for fully self-gated (SG) free-breathing 5D whole-heart CCMRA to CHD patients after ferumoxytol injection. We tested the hypothesis that spatial and motion resolution suffice to visualize coronary artery ostia in a cohort of CHD subjects, both for intubated and free-breathing acquisitions.MethodsIn 18 pediatric CHD patients, non-electrocardiogram (ECG) triggered 5D free-running gradient echo CCMRA with whole-heart 1 mm3 isotropic spatial resolution was performed in seven minutes on a 1.5T CMR scanner. Eleven patients were anesthetized and intubated, while seven were breathing freely without anesthesia. All patients were slowly injected with ferumoxytol (4 mg/kg) over 15 minutes. Cardiac and respiratory motion-resolved 5D images were reconstructed with a fully SG approach. To evaluate the performance of motion resolution, visibility of coronary artery origins was assessed. Intubated and free-breathing patient sub-groups were compared for image quality using coronary artery length and conspicuity as well as lung-liver interface sharpness.ResultsData collection using the free-running framework was successful in all patients in less than 8 min; scan planning was very simple without the need for parameter adjustments, while no ECG lead placement and triggering was required. From the resulting SG 5D motion-resolved reconstructed images, coronary artery origins could be retrospectively extracted in 90% of the cases. These general findings applied to both intubated and free-breathing pediatric patients (no difference in terms of lung-liver interface sharpness), while image quality and coronary conspicuity between both cohorts was very similar.ConclusionsA simple-to-use push-button framework for 5D whole-heart CCMRA was successfully employed in pediatric CHD patients with ferumoxytol injection. This approach, working without any external gating and for a wide range of heart rates and body sizes provided excellent definition of cardiac anatomy for both intubated and free-breathing patients.

Mitochondrial Respiration Defects in Single-Ventricle Congenital Heart Disease.

Background: Congenital heart disease (CHD) with single-ventricle (SV) physiology is now survivable with a three-stage surgical course ending with Fontan palliation. However, 10-year transplant-free survival remains at 39–50%, with ventricular dysfunction progressing to heart failure (HF) being a common sequela. For SV-CHD patients who develop HF, undergoing the surgical course would not be helpful and could even be detrimental. As HF risk cannot be predicted and metabolic defects have been observed in Ohia SV-CHD mice, we hypothesized that respiratory defects in peripheral blood mononuclear cells (PBMCs) may allow HF risk stratification in SV-CHD.Methods: SV-CHD (n = 20), biventricular CHD (BV-CHD; n = 16), or healthy control subjects (n = 22) were recruited, and PBMC oxygen consumption rate (OCR) was measured using the Seahorse Analyzer. Respiration was similarly measured in Ohia mouse heart tissue.Results: Post-Fontan SV-CHD patients with HF showed higher maximal respiratory capacity (p = 0.004) and respiratory reserve (p < 0.0001), parameters important for cell stress adaptation, while the opposite was found for those without HF (reserve p = 0.037; maximal p = 0.05). This was observed in comparison to BV-CHD or healthy controls. However, respiration did not differ between SV patients pre- and post-Fontan or between pre- or post-Fontan SV-CHD patients and BV-CHD. Reminiscent of these findings, heart tissue from Ohia mice with SV-CHD also showed higher OCR, while those without CHD showed lower OCR.Conclusion: Elevated mitochondrial respiration in PBMCs is correlated with HF in post-Fontan SV-CHD, suggesting that PBMC respiration may have utility for prognosticating HF risk in SV-CHD. Whether elevated respiration may reflect maladaptation to altered hemodynamics in SV-CHD warrants further investigation.

Effects of Cardiopulmonary Rehabilitation on the Muscle Function of Children with Congenital Heart Disease: A Prospective Cohort Study.

Critical medical and surgical advances have led to a shift in the care and management of children with congenital heart disease (CHD). These patients present with muscle deconditioning, which negatively influences their response to exercise, functional capacities, and quality of life. This study evaluates the influence of a cardiopulmonary rehabilitation program (CPRP) on the function of peripheral musculature of children with CHD. A single-center prospective cohort study was designed. Fifteen CHD subjects, between 12 and 16 years of age, with reduced aerobic capacity on a cardiopulmonary exercise test, were included in a three-month, 24-session CPRP. Measurements of the subjects’ handgrip strength, biceps brachii and quadriceps femoris strength, and triceps surae fatigue process were collected at the beginning of the program, after completion, and six months after the end of the intervention. A substantial and statistically significant improvement was observed in the subjects’ handgrip strength (kg) (p < 0.001), biceps brachii and quadriceps femoris strength (N) (p < 0.001), as well as triceps surae fatigue process (repetitions) (p = 0.018), with a maintenance of the results six months after the intervention. These results suggest that a CPRP could potentially improve the peripheral muscle function of children with CHD. Additional research is needed to confirm and expand on this hypothesis.

Fick versus flow: a real-time invasive cardiovascular magnetic resonance (iCMR) reproducibility study

BackgroundCardiac catheterization and cardiovascular magnetic resonance (CMR) imaging have distinct diagnostic roles in the congenital heart disease (CHD) population. Invasive CMR (iCMR) allows for a more thorough assessment of cardiac hemodynamics at the same time under the same conditions. It is assumed but not proven that iCMR gives an incremental value by providing more accurate flow quantification.MethodsSubjects with CHD underwent real-time 1.5 T iCMR using a passive catheter tracking technique with partial saturation pulse of 40° to visualize the gadolinium-filled balloon, CMR-conditional guidewire, and cardiac structures simultaneously to aid in completion of right (RHC) and left heart catheterization (LHC). Repeat iCMR and catheterization measurements were performed to compare reliability by the Pearson (PCC) and concordance correlation coefficients (CCC).ResultsThirty CHD (20 single ventricle and 10 bi-ventricular) subjects with a median age and weight of 8.3 years (2–33) and 27.7 kg (9.2–80), respectively, successfully underwent iCMR RHC and LHC. No catheter related complications were encountered. Time taken for first pass RHC and LHC/aortic pull back was 5.1, and 2.9 min, respectively. Total success rate to obtain required data points to complete Fick principle calculations for all patients was 321/328 (98%). One patient with multiple shunts was an outlier and excluded from further analysis. The PCC for catheter-derived pulmonary blood flow (Qp) (0.89, p < 0.001) is slightly lower than iCMR-derived Qp (0.96, p < 0.001), whereas catheter-derived systemic blood flow (Qs) (0.62, p = < 0.001) was considerably lower than iCMR-derived Qs (0.94, p < 0.001). CCC agreement for Qp at baseline (C1-CCC = 0.65, 95% CI 0.41–0.81) and retested conditions (C2-CCC = 0.78, 95% CI 0.58–0.89) were better than for Qs at baseline (C1-CCC = 0.22, 95% CI − 0.15–0.53) and retested conditions (C2-CCC = 0.52, 95% CI 0.17–0.76).ConclusionThis study further validates hemodynamic measurements obtained via iCMR. iCMR-derived flows have considerably higher test–retest reliability for Qs. iCMR evaluations allow for more reproducible hemodynamic assessments in the CHD population.

Comparison of Economic Self-Sufficiency and Educational Attainment in Adults With Congenital Heart Disease Versus Siblings Without Heart Disease and to General Population

Among children with congenital heart disease (CHD), there is often neurodevelopmental and behavioral impairment with unclear implications regarding adult socioeconomic achievements. We aimed to compare economic self-sufficiency and educational attainment in CHD adults with sibling and general population controls. Using Danish population-based nationwide registries, this cohort study aimed to include all CHD subjects greater than 13 years born between 1963 and 1993. Comparison cohorts included: (1) sibling cohort and (2) general population cohort matched 10:1 on birth year and gender. We computed cumulative incidences of time to first full year of economic self-sufficiency, as well as educational attainment. We assessed the relative probability of self-sufficiency in all cohorts before 30 years of age, defined by Statistics Denmark federal standard. In total, we identified 7,019 CHD subjects, 6,257 full siblings, and 68,805 general population controls. The cumulative incidence of self-sufficiency by age 20 and 35 years for CHD subjects (49% and 84%, respectively) was lower than sibling (68% and 96%) and general population cohorts (67% and 95%). The relative probability of self-sufficiency for CHD subjects compared with siblings was 0.44 (95% confidence interval 0.39 to 0.49). By age 30, adults with CHD were less likely than their siblings to attain all levels of education. Among those achieving higher educational milestones, differences in self-sufficiency between cohorts were absent by age 35. In conclusion, CHD is associated with reduced adult economic self-sufficiency, and the relation between educational level attained and self-sufficiency may suggest that targeted interventions have the potential to improve adult self-sufficiency.

De novo damaging variants associated with congenital heart diseases contribute to the connectome

Congenital heart disease (CHD) survivors are at risk for neurodevelopmental disability (NDD), and recent studies identify genes associated with both disorders, suggesting that NDD in CHD survivors may be of genetic origin. Genes contributing to neurogenesis, dendritic development and synaptogenesis organize neural elements into networks known as the connectome. We hypothesized that NDD in CHD may be attributable to genes altering both neural connectivity and cardiac patterning. To assess the contribution of de novo variants (DNVs) in connectome genes, we annotated 229 published NDD genes for connectome status and analyzed data from 3,684 CHD subjects and 1,789 controls for connectome gene mutations. CHD cases had more protein truncating and deleterious missense DNVs among connectome genes compared to controls (OR = 5.08, 95%CI:2.81–9.20, Fisher’s exact test P = 6.30E-11). When removing three known syndromic CHD genes, the findings remained significant (OR = 3.69, 95%CI:2.02–6.73, Fisher’s exact test P = 1.06E-06). In CHD subjects, the top 12 NDD genes with damaging DNVs that met statistical significance after Bonferroni correction (PTPN11, CHD7, CHD4, KMT2A, NOTCH1, ADNP, SMAD2, KDM5B, NSD2, FOXP1, MED13L, DYRK1A; one-tailed binomial test P ≤ 4.08E-05) contributed to the connectome. These data suggest that NDD in CHD patients may be attributable to genes that alter both cardiac patterning and the connectome.

Congenital Heart Disease and Risk of Central Nervous System Infections: A Nationwide Cohort Study.

Congenital heart disease (CHD) is associated with risk factors of central nervous system (CNS) infections including infective endocarditis, cardiac shunt physiology, and immune deficiencies. We aimed to investigate the risk of CNS infections in the CHD population compared to the general population. In this cohort study, we used Danish nationwide medical registries to identify individuals diagnosed with CHD at any age, born between 1977 and 2012. For each CHD individual, we matched 10 individuals on sex and birth year from the general population. Subjects were followed until first-time hospital diagnosis of CNS infection, death, emigration, or end of study. We computed cumulative incidences of CNS infections with death as a competing risk, as well as hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) adjusted for birth year and sex. We identified 17,550 individuals with CHD (50% male). Among subjects with CHD, the cumulative incidence of CNS infection at age 30years was 1.0% compared to 0.6% in the general population. The overall HR of CNS infections in CHD subjects relative to the general population was 2.1 (95% CI 1.6-2.7). The HR was 1.9 (95% CI 1.4-2.7) for mild to moderate CHD, 2.1 (95% CI 1.3-3.3) for severe CHD and 3.0 (95% CI 1.1-8.2) for univentricular physiology. The HR for CHD subjects without record of infective endocarditis was 2.0 (95% CI 1.5-2.5). The risk of CNS infections was increased among individuals with CHD compared to the general population, and the risk was not limited to individuals with infective endocarditis.

P2740Quantitative assessment of the entire right ventricle from one acoustic window: an attractive approach in patients with congenital heart disease

Abstract Background Right ventricular (RV) function is recognized as a prognostic factor in congenital heart disease (CHD). The accuracy of established parameters as tricuspid annular plane systolic excursion (TAPSE), right ventricular fractional area change (RVFAC) and tissue Doppler imaging (TDI S') are limited as the parameters reflect only a limited region of the RV. We previously introduced a novel four-view approach with different RV walls visualized in their long axis from one apical view using 2D-transthoracic echocardiographic (TTE) iRotate mode. Aims To extensive evaluate the entire RV function using iRotate echocardiography in a whole spectrum of CHD patients with abnormally loaded RV; both feasibility and RV echocardiographic parameters as comparison with healthy subjects is evaluated. Methods and results One hundred and forty-two CHD patients with abnormally loaded RV and 89 healthy subjects were included. All subjects underwent complete TTE with evaluation of TAPSE, TDI S' and peak systolic global longitudinal RV strain (RV-GLS) from the RV walls using the four-view iRotate model. The feasibility of TAPSE and RV S' ranged between 94% and 100%. The feasibility of RV-GLS in CHD was 98%, 69%, 87% and 72% respectively in the lateral, anterior, inferior and inferior coronal view walls. With the exception of RV S' in the inferior coronal view, all parameters were significantly lower in the CHD vs healthy subjects (p&lt;0.001) (Table). i-Rotate RV wall GLS (%) RV wall GLS (%) Measurement Feasibility Congenital (n=142) Controls (n=89) P-value Lateral 97.9 −17.6±5.0 −25.4±4.5 &lt;0.001 Anterior 69.0 −15.9±4.9* −24.2±4.5 &lt;0.001 Inferior 88.7 −17.2±4.7 −23.3±4.4 &lt;0.001 Inferior coronal view 72.5 −15.1±4.5* ** −20.8±5.2 &lt;0.001 Data expressed as mean ± SD or %. p&lt;0.05 for *Lateral vs Anterior and vs Inferior CV; **Inferior vs Inferior CV. Conclusion The feasibility of all RV parameters in the four-axis iRotate model is excellent in CHD and represents a reproducible, easily applicable and complete RV assessment in daily practice. RV function is significantly decreased in the CHD group using both load dependent and independent parameters. Complete RV strain analysis reveals regional differences in patients with CHD.

Abnormal Left-Hemispheric Sulcal Patterns Correlate with Neurodevelopmental Outcomes in Subjects with Single Ventricular Congenital Heart Disease.

Neurodevelopmental abnormalities are the most common noncardiac complications in patients with congenital heart disease (CHD). Prenatal brain abnormalities may be due to reduced oxygenation, genetic factors, or less commonly, teratogens. Understanding the contribution of these factors is essential to improve outcomes. Because primary sulcal patterns are prenatally determined and under strong genetic control, we hypothesized that they are influenced by genetic variants in CHD. In this study, we reveal significant alterations in sulcal patterns among subjects with single ventricle CHD (n= 115, 14.7 ± 2.9years [mean ± standard deviation]) compared with controls (n= 45, 15.5 ± 2.4years) using a graph-based pattern-analysis technique. Among patients with CHD, the left hemisphere demonstrated decreased sulcal pattern similarity to controls in the left temporal and parietal lobes, as well as the bilateral frontal lobes. Temporal and parietal lobes demonstrated an abnormally asymmetric left-right pattern of sulcal basin area in CHD subjects. Sulcal pattern similarity to control was positively correlated with working memory, processing speed, and executive function. Exome analysis identified damaging de novo variants only in CHD subjects with more atypical sulcal patterns. Together, these findings suggest that sulcal pattern analysis may be useful in characterizing genetically influenced, atypical early brain development and neurodevelopmental risk in subjects with CHD.

Health-related quality of life (HRQOL) in children and adolescents with congenital heart disease: a cross-sectional survey from South India

ObjectiveThere are limited data on health-related quality of life (HRQOL) for children and adolescents with uncorrected congenital heart disease (CHD) from low-income and middle-income countries where late presentation is common....

Incidence and Mortality of Adults With Pulmonary Hypertension and Congenital Heart Disease

Reports on pulmonary hypertension (PH) in the aging congenital heart disease (CHD) population are few and focused on arterial PH and patients with systemic-to-pulmonary shunts. Our objective was to estimate incidence and mortality of adult-onset PH in the CHD population. Using Danish nationwide registries, we identified all patients diagnosed with CHD from 1963 to 1974 and 1977 to 2012. Patients were matched 1:10 by birth year and gender with general population subjects. Between 1977 and 2013 adults >18 years of age were followed up until PH diagnosis, death, or emigration, whichever came first, using data from the Danish National Registry of Patients. We computed cumulative incidences of PH. Using Cox regression, we compared the mortality rate between CHD subjects with and without PH matched by gender and birth year. We identified 14,860 patients with CHD. At 70 years of age, their overall cumulative incidence of PH was 7.2% (8.3% in those with systemic-to-pulmonary shunts and 5.3% in those without) compared with 0.4% in the general population. The 1-, 5-, and 10-year mortality for adults with CHD and PH was 24%, 44%, and 52%, respectively. This represented a 4-fold (95% confidence interval 3.3 to 5.6) increase in mortality compared with adults with CHD without PH after adjusting for gender, birth year, CHD severity, and presence of extracardiac defects. In conclusion the incidence of PH was substantially increased in adults with CHD relative to the general population. Of note, the increased incidence was not limited to those with a history of systemic-to-pulmonary shunts. PH was associated with increased mortality.

Congenital heart disease and the prevalence of underweight and obesity from age 1 to 15 years: data on a nationwide sample of children

ObjectiveWe examined the prevalence of underweight and obesity in children with congenital heart disease (CHD) compared with the general population.MethodsUsing the Danish National Patient Registry, we identified individuals born and...

Health-related quality of life in infants and toddlers with congenital heart disease: a cross-sectional survey from South India

ObjectiveThere are limited data on health-related quality of life (HRQOL) for infants and toddlers with congenital heart disease (CHD). We sought to compare generic HRQOL of infants and toddlers between...

Additive effect of congenital heart disease and early developmental disorders on attention-deficit/hyperactivity disorder and autism spectrum disorder: a nationwide population-based longitudinal study.

In this retrospective nationwide population-based case-control study, we investigated the impact of congenital heart disease (CHD) on the development of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), which remains unclear. Children aged <18years that were diagnosed with CHD (n=3552) between January 1, 1997 and December 31, 2009 were identified from the National Health Insurance Research Database in Taiwan. Non-CHD controls (n=14,208) matched for age and sex (1:4) were selected from the same dataset. All subjects were observed until December 31, 2011 or their death. Comorbid perinatal conditions and early developmental disorders (EDD) that were diagnosed before ADHD and ASD diagnosis were also analyzed. The incidence rates of perinatal comorbidities, EDD, ADHD, and ASD were higher in the CHD group than in the control group. Multivariate Cox regression analysis revealed that the CHD group had an increased risk of developing ADHD (adjusted hazard ratio [aHR] 2.52, 95% confidence interval CI 1.96-3.25) and ASD (aHR 1.97, 95% CI 1.11-3.52) after adjusting for confounding comorbidities. EDD, but not perinatal comorbidities were also independent risk factors for ADHD and ASD after adjustment. Subgroup analysis indicated that the risk for ADHD (HR 16.59, 95% CI 12.17-22.60) and ASD (HR 80.68, 95% CI 39.96-176.12) was greatly increased in CHD subjects with EDD than in non-CHD subjects without EDD. These findings suggested that CHD at birth and EDD during early childhood were two independent risk factors for ADHD and ASD and that concurrent CHD and EDD might additively increase these risks.

Predictors of Memory Deficits in Adolescents and Young Adults with Congenital Heart Disease Compared to Healthy Controls.

Adolescents and young adults with congenital heart disease (CHD) show a range of memory deficits, which can dramatically impact their clinical outcomes and quality of life. However, few studies have identified predictors of these memory changes. The purpose of this investigation was to identify predictors of memory deficits in adolescents and young adults with CHD after surgical palliation compared to healthy controls. One hundred fifty-six adolescents and young adults (80 CHD and 76 controls; age 14-21 years) were recruited and administered an instrument to assess memory [Wide Range Assessment of Memory and Learning Second Edition - general memory index (GMI) score] and completed questionnaires that measure anxiety, depression, sleepiness, health status, and self-efficacy. Descriptive and non-parametric statistics were used to assess group differences, and logistic regression to identify predictors of memory deficits. CHD subjects consisted of 58% males, median age 17 years, 43% Hispanic, and medians of 2 previous heart surgeries and 14 years since last surgery. Memory deficits (GMI ≤ 85) were identified in 50% CHD compared to 4% healthy controls (median GMI 85 vs. 104, p < 0.001). Of GMI subscale medians, CHD subjects had significantly worse memory performance vs. healthy controls (verbal 88 vs. 105, p < 0.001; attention 88 vs. 109, p < 0.001; working memory 86 vs. 108, p < 0.001). No significant differences appeared between groups for visual memory. Multiple clinical and psychosocial factors were identified which were statistically different on bivariate analyses between the subjects with and without memory deficits. By multivariate analysis, male gender, number of surgeries, anxiety, and self-efficacy emerged as independent predictors of memory deficits. Adolescents and young adults with CHD, more than a decade since their last surgery, show significant verbal, attention, and working memory deficits over controls. To enhance patient memory/self-care, clinicians should explore ways to reduce anxiety, improve self-efficacy, and increase use of visual patient education material, especially in CHD males.

Loss of RNA expression and allele-specific expression associated with congenital heart disease.

Congenital heart disease (CHD), a prevalent birth defect occurring in 1% of newborns, likely results from aberrant expression of cardiac developmental genes. Mutations in a variety of cardiac transcription factors, developmental signalling molecules and molecules that modify chromatin cause at least 20% of disease, but most CHD remains unexplained. We employ RNAseq analyses to assess allele-specific expression (ASE) and biallelic loss-of-expression (LOE) in 172 tissue samples from 144 surgically repaired CHD subjects. Here we show that only 5% of known imprinted genes with paternal allele silencing are monoallelic versus 56% with paternal allele expression—this cardiac-specific phenomenon seems unrelated to CHD. Further, compared with control subjects, CHD subjects have a significant burden of both LOE genes and ASE events associated with altered gene expression. These studies identify FGFBP2, LBH, RBFOX2, SGSM1 and ZBTB16 as candidate CHD genes because of significantly altered transcriptional expression.