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BACKGROUND: Known genetic causes of congenital heart disease (CHD) explain METHODS: We tested de novo variants from trio studies of 2649 CHD probands and their parents, as well as rare (allele frequency, − 6 ) variants from 4472 CHD probands in the Pediatric Cardiac Genetics Consortium through a combined computational and in vitro approach. RESULTS: We identified 53 de novo and 74 rare variants in CHD cases that alter splicing and thus are loss of function. Of these, 77 variants are in known dominant, recessive, and candidate CHD genes, including KMT2D and RBFOX2 . In 1 case, we confirmed the variant’s predicted impact on RNA splicing in RNA transcripts from the proband’s cardiac tissue. Two probands were found to have 2 loss-of-function variants for recessive CHD genes HECTD1 and DYNC2H1 . In addition, SpliceAI—a predictive algorithm for altered RNA splicing—has a positive predictive value of ≈93% in our cohort. CONCLUSIONS: Through assessment of RNA splicing, we identified a new loss-of-function variant within a CHD gene in 78 probands, of whom 69 (1.5%; n=4472) did not have a previously established genetic explanation for CHD. Identification of splice-altering variants improves diagnostic classification and genetic diagnoses for CHD. REGISTRATION: URL: https://clinicaltrials.gov ; Unique identifier: NCT01196182.

Recent large-scale sequencing efforts have shed light on the genetic contribution to the etiology of congenital heart defects (CHD); however, the relative impact of genetics on clinical outcomes remains less understood. Outcomes analyses using genetic data are complicated by the intrinsic severity of the CHD lesion and by interactions with conditionally dependent clinical variables. Here we apply Bayesian Networks, an explainable Artificial Intelligence solution, to describe the intertwined relationships between clinical variables, demography, and genetics in a cohort of children with single ventricle CHD. As isolated variables, a damaging genetic variant in a gene related to abnormal heart morphology and prolonged ventilator support following stage I palliative surgery increased the probability of having a low Mental Developmental Index (MDI) score at 14 months of age by 1.9- and 5.8-fold, respectively. However, in combination, these variables acted synergistically to further increase the probability of a low MDI score by 10-fold. Likewise, genetic information was predictive of a favorable neurodevelopmental outcome. For example, the absence of a damaging variant in a known syndromic CHD gene and a shorter post-operative ventilator support increased the probability of a normal MDI score 1.7- and 2.4-fold, respectively, but in combination increased the probability of a good outcome by 59-fold. Our analyses suggest a modest genetic contribution to neurodevelopmental and growth outcomes as isolated variables, similar to known clinical predictors. By contrast, genetic, demographic, and clinical variables interact synergistically to markedly impact clinical outcomes. These findings underscore the importance of capturing and quantifying the impact of damaging genomic variants in the context of multiple, conditionally dependent variables, such as pre- and post-operative factors, and demography.

Summary Background Little is known about geographical variation in infant mortality due to congenital heart disease (CHD) and the social determinants of health that might mediate such variation. We aimed to examine US county-level estimates of infant mortality due to CHD to understand geographical patterns and factors that might influence variation in mortality. Methods This US population-based cohort study used linked livebirth–infant death cohort files from the US National Center for Health Statistics from Jan 1, 2006, to Dec 31, 2015. All deaths attributable to congenital heart disease in infants in a given year were included. We used hierarchical Bayesian models to estimate rates of infant mortality due to congenital heart disease for all US counties. We mapped model-based estimates to explore geographical patterns. Covariates included infant sex, gestational age, maternal race and ethnicity, percentage of the county population below the poverty level, and proximity of the county to a US News & World Report 2015 top-50 ranked paediatric cardiac centre. Findings From 2006 to 2015, 40 847 089 livebirths occurred, of which there were 13 988 infant deaths attributed to congenital heart disease, with an unadjusted infant mortality rate due to CHD of 0·34 per 1000 livebirths (95% CI 0·34–0·35). Kentucky and Mississippi had the greatest proportions of counties with a predicted rate of infant mortality due to CHD above the 95th percentile. All counties in Connecticut, Massachusetts, and Rhode Island had a predicted rate below the fifth percentile. In the model, lower mortality risk correlated with closer proximity to a top-50 ranked paediatric cardiac centre (odds ratio [OR] 0·890, 95% credible interval [CrI] 0·840–0·942), whereas higher mortality risk correlated with higher levels of poverty (OR 1·181, 95% CrI 1·125–1·239). Interpretation Substantial geographical variation exists in infant mortality due to CHD in the USA, highlighting the potential importance of bolstering care delivery for infants from economically deprived communities and areas remote from top-performing paediatric cardiac centres. Funding None.

The well-established manifestation of mitochondrial mutations in functional cardiac disease (e.g., mitochondrial cardiomyopathy) prompted the hypothesis that mitochondrial DNA (mtDNA) sequence and/or copy number (mtDNAcn) variation contribute to cardiac defects in congenital heart disease (CHD). MtDNAcns were calculated and rare, non-synonymous mtDNA mutations were identified in 1,837 CHD-affected proband-parent trios, 116 CHD-affected singletons, and 114 paired cardiovascular tissue/blood samples. The variant allele fraction (VAF) of heteroplasmic variants in mitochondrial RNA from 257 CHD cardiovascular tissue samples was also calculated. On average, mtDNA from blood had 0.14 rare variants and 52.9 mtDNA copies per nuclear genome per proband. No variation with parental age at proband birth or CHD-affected proband age was seen. mtDNAcns in valve/vessel tissue (320 ± 70) were lower than in atrial tissue (1,080 ± 320, p= 6.8E-21), which were lower than in ventricle tissue (1,340 ± 280, p= 1.4E-4). The frequency of rare variants in CHD-affected individual DNA was indistinguishable from the frequency in an unaffected cohort, and proband mtDNAcns did not vary from those of CHD cohort parents. In both the CHD and the comparison cohorts, mtDNAcns were significantly correlated between mother-child, father-child, and mother-father. mtDNAcns among people with European (mean= 52.0), African (53.0), and Asian haplogroups (53.5) were calculated and were significantly different for European and Asian haplogroups (p= 2.6E-3). Variant heteroplasmic fraction (HF) in blood correlated well with paired cardiovascular tissue HF (r= 0.975) and RNA VAF (r= 0.953), which suggests blood HF is a reasonable proxy for HF in heart tissue. We conclude that mtDNA mutations and mtDNAcns are unlikely to contribute significantly to CHD risk.

Impaired exercise following Fontan is a surrogate of morbidity. Single-center longitudinal data exist, but there is a lack of contemporary multi-center data. Ramp cycle ergometry was re-performed in consented participants who had originally participated in the Pediatric Heart Network’s Fontan cross-sectional study. Annualized change was evaluated at maximal and submaximal exercise. Associations between these outcomes and patient characteristics were analyzed. There were 336 participants in Fontan 3, mean age 23.2 years. Paired measurements of peak oxygen consumption (peak VO(2)) were available for 95; peak exercise data at Fontan 3 were available for 275. Percent-predicted peak VO(2) declined by 0.8 ± 1.7% per year (p < 0.001). At Fontan 3, the lowest performing peak VO(2) tertile had the highest rate of overweight and obesity (p < 0.001). Female gender was more prevalent in the highest performing tertile (p = 0.004). Paired data at the ventilatory anaerobic threshold (VO(2) at VAT) were available for 196; VAT data at Fontan 3 were available for 311. Percent-predicted VO(2) at VAT decreased by 0.8 ± 2.6% per year (p < 0.001). At Fontan 3, VO(2) at VAT was better preserved than peak VO(2) across all tertiles, with higher rates of overweight and obesity in the lower performing group (p = 0.001). Female gender (p < 0.001) and left ventricular morphology (p = 0.03) were associated with better performance. Submaximal exercise is better preserved than maximal in the Fontan population, but declined at the same rate over the study period. The overall longitudinal rate of decline in exercise performance is slower than what has been described previously.

A genetic etiology is identified for one-third of patients with congenital heart disease (CHD), with 8% of cases attributable to coding de novo variants (DNVs). To assess the contribution of noncoding DNVs to CHD, we compared genome sequences from 749 CHD probands and their parents with those from 1,611 unaffected trios. Neural network prediction of noncoding DNV transcriptional impact identified a burden of DNVs in individuals with CHD (n = 2,238 DNVs) compared to controls (n = 4,177; P = 8.7 × 10-4). Independent analyses of enhancers showed an excess of DNVs in associated genes (27 genes versus 3.7 expected, P = 1 × 10-5). We observed significant overlap between these transcription-based approaches (odds ratio (OR) = 2.5, 95% confidence interval (CI) 1.1-5.0, P = 5.4 × 10-3). CHD DNVs altered transcription levels in 5 of 31 enhancers assayed. Finally, we observed a DNV burden in RNA-binding-protein regulatory sites (OR = 1.13, 95% CI 1.1-1.2, P = 8.8 × 10-5). Our findings demonstrate an enrichment of potentially disruptive regulatory noncoding DNVs in a fraction of CHD at least as high as that observed for damaging coding DNVs.

Objective:To evaluate the association of systolic blood pressure percentile, race, and body mass index with left ventricular hypertrophy on electrocardiogram and echocardiogram to define populations at risk.Study design:This is a retrospective cross-sectional study design utilising a data analytics tool (Tableau) combining electrocardiogram and echocardiogram databases from 2003 to 2020. Customized queries identified patients aged 2–18 years who had an outpatient electrocardiogram and echocardiogram on the same date with available systolic blood pressure and body measurements. Cases with CHD, cardiomyopathy, or arrhythmia diagnoses were excluded. Echocardiograms with left ventricle mass (indexed to height2.7) were included. The main outcome was left ventricular hypertrophy on echocardiogram defined as Left ventricle mass index greater than the 95th percentile for age.Results:In a cohort of 13,539 patients, 6.7% of studies had left ventricular hypertrophy on echocardiogram. Systolic blood pressure percentile >90% has a sensitivity of 35% and specificity of 82% for left ventricular hypertrophy on echocardiogram. Left ventricular hypertrophy on electrocardiogram was a poor predictor of left ventricular hypertrophy on echocardiogram (9% sensitivity and 92% specificity). African American race (OR 1.31, 95% CI = 1.10, 1.56, p = 0.002), systolic blood pressure percentile >95% (OR = 1.60, 95% CI = 1.34, 1.93, p < 0.001), and higher body mass index (OR = 7.22, 95% CI = 6.23, 8.36, p < 0.001) were independently associated with left ventricular hypertrophy on echocardiogram.Conclusions:African American race, obesity, and hypertension on outpatient blood pressure measurements are independent risk factors for left ventricular hypertrophy in children. Electrocardiogram has little utility in the screening for left ventricular hypertrophy.

Reproducibility in medical research has been a long-standing issue. More recently, the COVID-19 pandemic has publicly underlined this fact as the retraction of several studies reached out to general media audiences. A significant number of these retractions occurred after in-depth scrutiny of the methodology and results by the scientific community. Consequently, these retractions have undermined confidence in the peer-review process, which is not considered sufficiently reliable to generate trust in the published results. This partly stems from opacity in published results, the practical implementation of the statistical analysis often remaining undisclosed. We present a workflow that uses a combination of informatics tools to foster statistical reproducibility: an open-source programming language, Jupyter Notebook, cloud-based data repository, and an application programming interface can streamline an analysis and help to kick-start new analyses. We illustrate this principle by (1) reproducing the results of the ORCHID clinical trial, which evaluated the efficacy of hydroxychloroquine in COVID-19 patients, and (2) expanding on the analyses conducted in the original trial by investigating the association of premedication with biological laboratory results. Such workflows will be encouraged for future publications from National Heart, Lung, and Blood Institute-funded studies.

Recent years have seen an exponential increase in the variety of healthcare data captured across numerous sources. However, mechanisms to leverage these data sources to support scientific investigation have remained limited. In 2013 the Pediatric Heart Network (PHN), funded by the National Heart, Lung, and Blood Institute, developed the Integrated CARdiac Data and Outcomes (iCARD) Collaborative with the goals of leveraging available data sources to aid in efficiently planning and conducting PHN studies; supporting integration of PHN data with other sources to foster novel research otherwise not possible; and mentoring young investigators in these areas. This review describes lessons learned through the development of iCARD, initial efforts and scientific output, challenges, and future directions. This information can aid in the use and optimisation of data integration methodologies across other research networks and organisations.

Optimising short- and long-term outcomes for children and patients with CHD depends on continued scientific discovery and translation to clinical improvements in a coordinated effort by multiple stakeholders. Several challenges remain for clinicians, researchers, administrators, patients, and families seeking continuous scientific and clinical advancements in the field. We describe a new integrated research and improvement network – Cardiac Networks United – that seeks to build upon the experience and success achieved to-date to create a new infrastructure for research and quality improvement that will serve the needs of the paediatric and congenital heart community in the future. Existing gaps in data integration and barriers to improvement are described, along with the mission and vision, organisational structure, and early objectives of Cardiac Networks United. Finally, representatives of key stakeholder groups – heart centre executives, research leaders, learning health system experts, and parent advocates – offer their perspectives on the need for this new collaborative effort.

Background Many factors affect outcomes after congenital cardiac surgery. Objectives The RLS (Residual Lesion Score) study explored the impact of severity of residual lesions on post-operative outcomes across operations of varying complexity. Methods In a prospective, multicenter, observational study, 17 sites enrolled 1,149 infants undergoing 5 common operations: tetralogy of Fallot repair (n = 250), complete atrioventricular septal defect repair (n = 249), arterial switch operation (n = 251), coarctation or interrupted arch with ventricular septal defect (VSD) repair (n = 150), and Norwood operation (n = 249). The RLS was assigned based on post-operative echocardiography and clinical events: RLS 1 (trivial or no residual lesions), RLS 2 (minor residual lesions), or RLS 3 (reintervention for or major residual lesions before discharge). The primary outcome was days alive and out of hospital within 30 post-operative days (60 for Norwood). Secondary outcomes assessed post-operative course, including major medical events and days in hospital. Results RLS 3 (vs. RLS 1) was an independent risk factor for fewer days alive and out of hospital (p ≤ 0.008) and longer post-operative hospital stay (p ≤ 0.02) for all 5 operations, and for all secondary outcomes after coarctation or interrupted arch with VSD repair and Norwood (p ≤ 0.03). Outcomes for RLS 1 versus 2 did not differ consistently. RLS alone explained 5% (tetralogy of Fallot repair) to 20% (Norwood) of variation in the primary outcome. Conclusions Adjusting for pre-operative factors, residual lesions after congenital cardiac surgery impacted in-hospital outcomes across operative complexity with greatest impact following complex operations. Minor residual lesions had minimal impact. These findings may provide guidance for surgeons when considering short-term risks and benefits of returning to bypass to repair residual lesions.

Background: Prior ECG standards in children have largely been defined without echo confirmation of normal anatomy. The Pediatric Heart Network Normal Echocardiogram Z-score Project provides a racially diverse age/sex classified group of healthy children with normal echos that included 2170 matched contemporaneous digitally acquired ECGs. We hypothesized that ECG measures and z-scores of left ventricular (LV) dimensions are correlated in healthy children. Methods: This was a secondary analysis of the previously described cohort. Six ECG measures historically associated with LV size (R V5, R V6, S V1, Q III, axis, R V6+S V1), and 13 paired echo measures were identified a-priori with LV Mass (LVMass-z) and left ventricular end diastolic volume (LVEDV-z) z-scores serving as primary echo measurement predictors. Pearson or Spearman correlations were calculated for each of the 78 ECG- echo pairs. Regression analyses were performed to assess how much variance in ECG measures was explained by variation in LV dimensions and by demographic variables (age, sex, race). Results: ECG and echo measurement correlations were significant and concordant in 41/78 (53%), though many were significant and discordant in 13, (17%) or not correlated in 24 (31%). Of the 6 ECG measures of LV size, 5 correlated in the clinically predicted direction for LV Mass-z and LVEDV-z. While many of the correlations were statistically significant, the correlations were weak (0.05-0.25). R 2 was higher for demographic variables than for echo measures in all pairs, but even with demographic variables included, the overall R 2 was < 0.17. Conclusions: In a large, diverse cohort of healthy children, there was a positive association between echo measures of LV dimension and mass and the most commonly used ECG measures of LVH. However, these correlations were weak and most of the variability in ECG measures was explained by factors other than echo derived mass or volume or measured patient demographic variables. These data question the utility of traditional ECG measurements of LV size as standalone indications for further cardiac evaluation in healthy children.

Background: Geographic variation in ischemic heart disease and stroke mortality is well-known and likely mediated by health care access, environmental, and sociodemographic factors. Little is known, however, about geographic variation in infant mortality due to congenital heart disease (CHD-IM). This study examines county-level estimates of CHD-IM to understand geographic patterns and factors that may influence variation in mortality. Methods: In this cross-sectional population-based study, we used linked live birth-infant death cohort files from the National Center for Health Statistics containing live births from 2006 to 2015 with cause of death attributed to congenital heart disease. Hierarchical Bayesian models were used to estimate CHD-IM rate for all US counties (N=3,142). Model based estimates were mapped to explore geographic patterns. Covariates included sex, maternal race and ethnicity, percentage of the county population below the poverty level, and proximity of the county to a US News and World Report top 50 ranked pediatric cardiac center (PCC). Results: From 2006 to 2015, there were 13,987 infant deaths due to congenital heart disease and 40,847,089 live births, giving an unadjusted CHD-IM rate of 0.34/1,000 live births. In our model, decreased mortality risk correlated with close proximity to a top 50 PCC, while increased mortality risk correlated with higher level of poverty. The figure shows predicted CHD-IM rates by county. Kentucky and Mississippi had the greatest proportion of counties with a predicted CHD-IM rate > 95th percentile. All counties in Connecticut, Massachusetts, and Rhode Island had a predicted CHD-IM rate < 5th percentile. Conclusion: Analyzing county-level variation of CHD-IM reveals patterns that can help to identify health care disparities and inform local efforts to understand and address variation in outcomes of infants born with congenital heart disease.

Introduction: Childhood hypertension, obesity, and left ventricular hypertrophy (LVH) are risk factors for premature cardiovascular events in adulthood, particularly among minorities. In children, race and body mass index (BMI) have been shown to be independently associated with LVH, with conflicting data on the association of systolic blood pressure (SBP) level with risk of LVH and utility of ECG in assessing LVH. This study looks at the association of SBP percentile, race, and BMI with LVH on electrocardiogram (ECG) and echocardiogram (echo) to define populations at risk. Methods: This is a retrospective cross-sectional study design utilizing a data analytics tool (Tableau) combining ECG and echo databases from 2003-2020. Customized queries identified patients ages 2-18 years old who had an outpatient ECG and echo on the same date with available SBP and body measurements. Cases with congenital heart disease, cardiomyopathy, or arrhythmia diagnoses were excluded. Echos with left ventricle mass (indexed to height 2.7 ) were included. The main outcome was LVH on echo defined as LV mass index greater than the 95 th percentile for age. Results: In a cohort of 13,926 patients, 6.9% of studies had LVH on echo. SBP percentile > 90% has a sensitivity of 36% and specificity of 82% for LVH on echo. LVH on ECG was a poor predictor of LVH on echo (9% sensitivity and 92% specificity). African American race (OR 1.31, 95% CI = 1.11, 1.55, p=.001), SBP percentile > 95% (OR=1.64, 95% CI = 1.37, 1.95, p Conclusions: African American race, obesity, and hypertension are independent risk factors for LVH in children. Outpatient ECG has low utility in screening for LVH.

Supplemental Digital Content is available in the text., Background: De novo genic and copy number variants are enriched in patients with congenital heart disease, particularly those with extra-cardiac anomalies. The impact of de novo damaging variants on outcomes following cardiac repair is unknown. Methods: We studied 2517 patients with congenital heart disease who had undergone whole-exome sequencing as part of the CHD GENES study (Congenital Heart Disease Genetic Network). Results: Two hundred ninety-four patients (11.7%) had clinically significant de novo variants. Patients with de novo damaging variants were 2.4 times more likely to have extra-cardiac anomalies (P=5.63×10−12). In 1268 patients (50.4%) who had surgical data available and underwent open-heart surgery exclusive of heart transplantation as their first operation, we analyzed transplant-free survival following the first operation. Median follow-up was 2.65 years. De novo variants were associated with worse transplant-free survival (hazard ratio, 3.51; P=5.33×10−04) and longer times to final extubation (hazard ratio, 0.74; P=0.005). As de novo variants had a significant interaction with extra-cardiac anomalies for transplant-free survival (P=0.003), de novo variants conveyed no additional risk for transplant-free survival for patients with these anomalies (adjusted hazard ratio, 1.96; P=0.06). By contrast, de novo variants in patients without extra-cardiac anomalies were associated with worse transplant-free survival during follow-up (hazard ratio, 11.21; P=1.61×10−05) than that of patients with no de novo variants. Using agnostic machine-learning algorithms, we identified de novo copy number variants at 15q25.2 and 15q11.2 as being associated with worse transplant-free survival and 15q25.2, 22q11.21, and 3p25.2 as being associated with prolonged time to final extubation. Conclusions: In patients with congenital heart disease undergoing open-heart surgery, de novo variants were associated with worse transplant-free survival and longer times on the ventilator. De novo variants were most strongly associated with adverse outcomes among patients without extra-cardiac anomalies, suggesting a benefit for preoperative genetic testing even when genetic abnormalities are not suspected during routine clinical practice. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01196182.

Background/Aims:Registry-based trials have emerged as a potentially cost-saving study methodology. Early estimates of cost savings, however, conflated the benefits associated with registry utilisation and those associated with other aspects of pragmatic trial designs, which might not all be as broadly applicable. In this study, we sought to build a practical tool that investigators could use across disciplines to estimate the ranges of potential cost differences associated with implementing registry-based trials versus standard clinical trials.Methods:We built simulation Markov models to compare unique costs associated with data acquisition, cleaning, and linkage under a registry-based trial design versus a standard clinical trial. We conducted one-way, two-way, and probabilistic sensitivity analyses, varying study characteristics over broad ranges, to determine thresholds at which investigators might optimally select each trial design.Results:Registry-based trials were more cost effective than standard clinical trials 98.6% of the time. Data-related cost savings ranged from $4300 to $600,000 with variation in study characteristics. Cost differences were most reactive to the number of patients in a study, the number of data elements per patient available in a registry, and the speed with which research coordinators could manually abstract data. Registry incorporation resulted in cost savings when as few as 3768 independent data elements were available and when manual data abstraction took as little as 3.4 seconds per data field.Conclusions:Registries offer important resources for investigators. When available, their broad incorporation may help the scientific community reduce the costs of clinical investigation. We offer here a practical tool for investigators to assess potential costs savings.

Objective: To describe epidemiologic data from the Sudden Death in the Young (SDY) Case Registry. Understanding the scope of SDY may optimize prevention efforts. Study design: We analyzed sudden, unexpected deaths of infants (

Introduction Genetic testing for congenital long-QT syndrome (LQTS) has become common. Recent studies have shown that some variants labelled as pathogenic might be misclassified due to sparse case reports and relatively common allele frequencies in the general population. This study aims to evaluate the presence of LQTS-associated variants in the Genome Aggregation Database (gnomAD) population, and assess the functional impact of these variants. Methods and results Variants associated with LQTS from the Human Gene Mutation Database were extracted and matched to the gnomAD to evaluate population-based allele frequencies (AF). We used MetaSVM to predict the function of LQTS variants. Allele distribution by protein topology in KCNQ1, KCNH2, and SCN5A was compared between gnomAD (n = 123,136) and a cohort of LQTS patients aggregated from 8 published studies (n = 2,683). Among the 1,415 LQTS-associated single nucleotide variants in 30 genes, 347 (25%) are present in gnomAD; 24% of the 347 variants were predicted as functionally tolerated compared with 4% of variants not present in gnomAD (p

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ∼3% of isolated CHD patients and ∼28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70% probability of being disease related. DNMs in ∼440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.

In an era of ongoing need for research to enable evidence-based care for the expanding population with congenital heart disease (CHD), economic fluctuations have impacted research funding. We characterize trends in NIH-funded CHD research from 2005 to 2015. We searched the NIH RePORTER database from 2005 to 2015 using the terms “congenital heart” and “cardiac morphogenesis”. Projects were characterized by year, institute, mechanism, costs, type and topic, and funding trends were analyzed. From 2005 to 2015, NIH funded 633 CHD research projects with total costs of $991 million. The National Heart, Lung, and Blood Institute funded 83% of CHD projects (528, $857 million). The R01 mechanism was used for 45% of projects (288, $421 million). Projects were 70% basic/early translational research, 27% clinical research, and 3% both. Cardiac developmental biology was the most common topic (52%), followed by technology/therapy development (15%), and diagnosis/management (12%). The total number of CHD projects ranged from 153 to 221 per year (30–58 new projects/year), and costs per year ranged from $58 to $116 million. The number of projects and total costs increased until 2012, but decreased again thereafter. CHD research did not experience as much erosion as overall NIH purchasing power; in constant dollars, CHD research funding levels in 2015 were $12 million higher than those in 2005. The NIH supported a diverse portfolio of CHD projects from 2005 to 2015. Support of CHD research projects trended upward until 2012, but declined thereafter due to fiscal austerity measures.

Background Data routinely captured in clinical registries may be leveraged to enhance efficiency of prospective research. The quality of registry data for this purpose has not been studied, however. We evaluated the completeness and accuracy of perioperative data within congenital heart centers' local surgical registries. Methods Within 12 Pediatric Heart Network (PHN) sites, we evaluated 31 perioperative variables (and their subcategories, totaling 113 unique fields) collected via sites' local clinical registries for submission to The Society of Thoracic Surgeons Database, compared with chart review by PHN research coordinators. Both used standard STS definitions. Data were collected on 10 subjects for 2 to 5 procedures/site and adjudicated by the study team. Completeness and accuracy (agreement of registry data with medical record review by PHN coordinator, adjudicated by the study team) were evaluated. Results A total of 56,500 data elements were collected on 500 subjects. With regard to data completeness, 3.1% of data elements were missing from the registry, 0.6% from coordinator-collected data, and 0.4% from both. Overall, registry data accuracy was 98%. In total, 94.7% of data elements were both complete/non-missing and accurate within the registry, although there was variation across data fields and sites. Mean total time for coordinator chart review per site was 49.1 hours versus 7.0 hours for registry query. Conclusions This study suggests that existing surgical registry data constitute a complete, accurate, and efficient information source for prospective research. Variability across data fields and sites also suggest areas for improvement in some areas of data quality.

The National Heart, Lung, and Blood Institute convened a working group in January 2015 to explore issues related to an integrated data network for congenital heart disease research. The overall goal was to develop a common vision for how the rapidly increasing volumes of data captured across numerous sources can be managed, integrated, and analyzed to improve care and outcomes. This report summarizes the current landscape of congenital heart disease data, data integration methodologies used across other fields, key considerations for data integration models in congenital heart disease, and the short- and long-term vision and recommendations made by the working group.

Children with long QT syndrome (LQTS) live with the risk of sudden death, activity restrictions, and the need for daily medications. We sought to evaluate the quality of life (QOL), self-perception, and behavior of patients with LQTS as perceived by both patients and their parents and identify predictors of lower QOL. QOL (Pediatric QOL Inventory [PedsQL] and Pediatric Cardiac Quality of Life Inventory [PCQLI]), self-perception, and behavioral inventories were completed by patients with LQTS and their parents. Comparison of PedsQL scores was made to published data for healthy children using t tests, and PCQLI scores were compared with those of patients with differing complexity of congenital heart disease. Mixed modeling was used for multivariable analysis. Sixty-one patients with LQTS were evaluated (age 13.6 ± 3.0 years; male 49%). Compared with healthy children, the PedsQL Total, Psychosocial, and Physical Health Summary scores were significantly lower for patients with LQTS and parent proxy reports (p ≤0.001). In general, PCQLI scores of patients with LQTS and parents were similar to those of patients with tetralogy of Fallot (p ≥0.2), lower than those of patients with bicuspid aortic valve (p ≤0.02), and higher than those of patients with single ventricle (p ≤0.03). Lower patient and parent PCQLI scores were associated with internalizing problems. For parents, the presence of a cardiac device and medication side effects were additionally associated with lower PCQLI scores. In conclusion, patients with LQTS and their parents report lower QOL than normal children secondary to physical and psychosocial factors. Increasing focus on the psychological well-being of these patients is needed in an effort to improve their QOL.

Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2% of patients with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, a regulator of mRNA splicing. Genes mutated in other cohorts examined for NDD were enriched in CHD cases, particularly those with coexisting NDD. These findings reveal shared genetic contributions to CHD, NDD, and CA and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients.

Congenital heart disease (CHD) is the most common birth defect and a leading cause of morbidity and mortality in patients with congenital malformations. The past 7 decades have witnessed dramatic advances in the medical, catheter, and surgical management of these patients. Clinical research has been a driving force to improve our understanding of the pathophysiology of disease and to refine therapy. Here, we identify some of the themes that have characterized the research process in the past and that have propelled the field to its present state. We discuss current research-related challenges and speculate about what trends may define the future of CHD research. The historical canon of congenital heart disease (CHD) is replete with dramatic triumphs: the first open heart surgery, the first use of cardiopulmonary bypass, the first transcatheter interventional cardiac procedure, and many others. In the years since these seminal events, progress has been made in all aspects of the care for patients with CHD. Prompt diagnosis is routine, surgical management of the most complex lesions is achievable, and acute and chronic care of patients has been refined. Important challenges remain, including persistent mortality for particular complex defects and long-term problems such as neurodevelopmental abnormalities, arrhythmias, and heart failure. Nevertheless, there are many reasons to be proud, and clinical research has been a foundational feature that has helped drive much of this progress. We describe some trends in research that have propelled the field to its current state and speculate about what trends may define the future of CHD research. ### Individual to Group Science A defining trend of the past 75 years of CHD research has been the change in focus from the individual to the group. Early CHD research was performed by individuals trying to solve problems, 1 child at a time. Innovative thinkers and doers—Gross, Lillehei, Rashkind, and Norwood—pushed …

OBJECTIVES: The Residual Lesion Score (RLS) was developed as a novel tool for assessing residual lesions after congenital heart operations based on widely available clinical and echocardiographic characteristics. The RLS ranks postoperative findings as follows: Class 1 (no/trivial residua), Class 2 (minor residua), or Class 3 (major residua or reintervention prior to discharge for residua). The multi-center prospective RLS study aims to analyze the impact of residual lesions on outcomes in common congenital cardiac operations. We hypothesize that RLS will predict postoperative adverse events, resource utilization, mortality and reinterventions by one year postoperatively. METHODS: The study cohort consists of infants ≤12 months of age undergoing definitive surgery for: (1) complete atrioventricular septal defect, (2) tetralogy of Fallot, (3) dextro-transposition of the great arteries with or without intact ventricular septum, (4) single ventricle (Norwood procedure), and (5) coarctation or interrupted/hypoplastic arch with ventricular septal defect. Subjects with major congenital or acquired extra-cardiac anomalies that could independently affect the primary endpoint, which is number of days alive and out of the hospital within 30 days of surgery (60 days for Norwood procedure), were excluded. Secondary outcomes include: ≥1 early major postoperative adverse event; days of intensive care unit and hospital stay, and initial and total ventilator time; mortality/transplant after discharge; unplanned reinterventions after discharge; and cost. All analyses will be performed separately by surgical operation. CONCLUSION: This is the first multi-center prospective validation of a tool for surgical outcome assessment and quality improvement specific to congenital heart surgery.

Background/Aims Identifying predictors of recruitment success in clinical trials, particularly prior to study launch, could contribute to higher study completion rates and improved scientific return on investment. This article evaluates the performance of clinical trials funded by the National Heart, Lung, and Blood Institute that began recruitment before and after implementation of National Heart, Lung, and Blood Institute’s 2009 Accrual Policy and identifies study-related factors that predict recruitment success. Methods A retrospective analysis of National Heart, Lung, and Blood Institute’s cardiovascular clinical trials with initial funding from 1996 to 2012 was performed to assess recruitment success. Success was defined as ≥100% enrollment of the proposed sample size within the duration initially proposed by investigators. Trials were assigned to categories (pre-policy vs post-policy) based on whether the first patient was enrolled before or after the 2009 Accrual Policy implementation. Potential determinants of successful recruitment were evaluated using multivariable logistic regression. Results Of 167 trials analyzed, 26.3% met the definition of success. Twenty-four trials (14.4%) were terminated early and 15 (62.5%) for insufficient recruitment. Trials failed due to Conclusion Enrollment success rates for National Heart, Lung, and Blood Institute’s clinical trials are concerning. The 2009 National Heart, Lung, and Blood Institute Accrual Policy did not significantly improve trial success. Clinical trials testing behavioral interventions, those conducted within networks, and those with normal controls were predictive of recruitment success. Components of networks may provide model practices to help other trials attain success, including close attention to oversight activities such as recruitment plans, real-time enrollment monitoring, corrective action plans to address shortfalls, and close sponsor-investigator collaborations.

Background: Interpretation of pediatric ECGs is limited by lack of accurate sex- and race-specific normal reference values obtained with modern technology for all ages. We sought to obtain contemporary digital ECG measurements in healthy children from North America, to evaluate the effects of sex and race, and to compare our results to commonly used published datasets. Methods: Digital ECGs (12-lead) were retrospectively collected for children ≤18 years old with normal echocardiograms at 19 centers in the Pediatric Heart Network. Patients were classified into 36 groups: 6 age, 2 sex, and 3 race (white, black, and other/mixed) categories. Standard intervals and amplitudes were measured; mean±SD and 2nd/98th percentiles were determined by age group, sex, and race. For each parameter, multivariable analysis, stratified by age, was conducted using sex and race as predictors. Parameters were compared with 2 large pediatric ECG data sets. Results: Among ECGs from 2400 children, significant differences were found by sex and race categories. The corrected QT interval in lead II was greater for girls compared with boys for age groups ≥3 years ( P ≤0.03) and for whites compared with blacks for age groups ≥12 years ( P P P ≤0.006), and greater compared with a commonly used public data set for age groups ≥12 years ( P Conclusions: In this large, diverse cohort of healthy children, most ECG intervals and amplitudes varied by sex and race. These differences have important implications for interpreting pediatric ECGs in the modern era when used for diagnosis or screening, including thresholds for left ventricular hypertrophy.

Congenital heart defects (CHDs) are the most common type of birth defect occurring in ≈1% of live births[1][1] and, if minor cardiac abnormalities such as bicuspid aortic valve are included, then the prevalence may be as high as 2% to 3%.[2][2] Advances in surgical and perioperative care and

We compared the incidence and 30-day mortality of myocardial infarction (MI) in adults with congenital heart disease (CHD) relative to the general population. This cohort study used nationwide population-based medical databases to identify individuals born before 1982 and diagnosed with CHD in Denmark between 1963 and 2012. Patients were followed for first-time MI using data from the Danish National Registry of Patients. For each subject with CHD, we identified 10 controls from the general population, matched by sex and birth year. A unique personal identifier enabled follow-up for migration, death, or MI. We computed cumulative incidences and hazard ratios (HR) adjusted for birth year and sex for MI and 30-day mortality after MI. We identified 10,501 CHD adults alive at 30 years. By 70 years of age, the cumulative incidence of MI was 10% versus 6.5% for controls. The overall HR of MI in subjects with CHD compared with controls was 2.0 (95% CI 1.7 to 2.3). The 30-day mortality was 18% for the 296 subjects with CHD experiencing an MI during follow-up. The overall HR comparing 30-day mortality after MI between subjects with CHD and controls was 1.4 (95% CI 1.0 to 1.8). The greatest mortality was observed in adults with severe CHD (HR 2.7 [95% CI 1.5 to 5.0]). In conclusion, the incidence of MI and the 30-day mortality after MI for severe CHD were increased in adults with CHD compared with the general population. Underlying mechanisms need to be clarified. (C) 2017 Elsevier Inc. All rights reserved.

High-quality cardiopulmonary resuscitation (CPR) may improve survival. The quality of CPR performed during pediatric out-of-hospital cardiac arrest (p-OHCA) is largely unknown. The main objective of this study was to describe the quality of CPR performed during p-OHCA resuscitation attempts.Prospective observational multi-center cohort study of p-OHCA patients ≥ 1 and19 years of age registered in the Resuscitation Outcomes Consortium (ROC) Epistry database. The primary outcome was an a priori composite variable of compliance with American Heart Association (AHA) guidelines for both chest compression (CC) rate and CC fraction (CCF). Event compliance was defined as a case with 60% or more of its minute epochs compliant with AHA targets (rate 100-120 min(-1); depth ≥ 38 mm; and CCF ≥ 0.80). In a secondary analysis, multivariable logistic regression was used to evaluate the association between guideline compliance and return of spontaneous circulation (ROSC).Between December 2005 and December 2012, 2564 pediatric events were treated by EMS providers, 390 of which were included in the final cohort. Of these events, 22% achieved AHA compliance for both rate and CCF, 36% for rate alone, 53% for CCF alone, and 58% for depth alone. Over time, there was a significant increase in CCF (p0.001) and depth (p = 0.03). After controlling for potential confounders, there was no significant association between AHA guideline compliance and ROSC.In this multi-center study, we have established that there are opportunities for professional rescuers to improve prehospital CPR quality. Encouragingly, CCF and depth both increased significantly over time.

Prevention of mother to child HIV transmission (MTCT) has been a resounding public health success story. In the past 20 years, the rate of MTCT in the US has been reduced from 26% to under 1% using potent combination antiretroviral (cARV) regimens [1-4]. As the use of cARV regimens in pregnancy has increased, concerns have been raised regarding the potential risk of in utero cARV exposure on long-term outcomes among HIV-exposed but uninfected (HEU) children, including mitochondrial toxicity which has also been associated with cardiomyopathy in HIV-unexposed children [5-12]. Among HIV-infected children, cardiomyopathy was common prior to widespread use of cARV and was associated with high mortality [13]. However, a study of both HEU and HIV-infected children in the National Heart, Lung, and Blood Institute (NHLBI) Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study (P2C2) born between 1990-1994 found no association between perinatal exposure to zidovudine (ZDV) monotherapy and abnormalities of left ventricular (LV) structure or function [14]. In another report, compared to the subset of ARV-unexposed HEU children in the P2C2 study, 136 children (96% exposed to cARV in utero) born between 2003-2006 in the NHLBI-funded Cardiovascular Status of Highly Active Antiretroviral Therapy (HAART) in HIV-Exposed Infants and Children cohort study (CHAART I) had significantly lower LV mass, septal wall thickness, and LV diameter, and higher LV contractility at age 2 years [15]. Since these prior studies were limited by their small sample size and/or they were conducted during an earlier era when there were fewer antiretroviral (ARV) options compared to the contemporary era which has more robust combination ARV combination therapy options, we evaluated the relationship between perinatal ARV drug exposure and echocardiographic measurements from the Pediatric HIV/AIDS Cohort Study (PHACS) Surveillance Monitoring for ART Toxicities (SMARTT) study.

Ectopic atrial tachycardia (EAT) is common in surgically repaired congenital heart disease (CHD) and carries the potential for significant hemodynamic compromise. Our objective was to determine the incidence, and risk factors of EAT after CHD surgery. Prospective study of patients that underwent surgery for CHD from February to October 2016 was performed. Demographic, perioperative and electrophysiologic data were collected. Sustained EAT (> 30 s) was documented by telemetry or electrocardiogram and confirmed by a pediatric electrophysiologist. All patients were followed through index hospitalization. During the study period, 17/204 (8%) of patients developed EAT with median time-to-event of 14 days. 15/17 (88%) received anti-arrhythmic therapy for sustained EAT. By univariate analysis, younger age (5 vs. 284 days, P

Cardiac pacing and defibrillation in paediatric and congenital heart disease / , Cardiac pacing and defibrillation in paediatric and congenital heart disease / , کتابخانه دیجیتال جندی شاپور اهواز

Knowledge gaps persist about the incidence of and risk factors for sudden death in the young (SDY). The SDY Case Registry is a collaborative effort between the National Institutes of Health, the Centers for Disease Control and Prevention, and the Michigan Public Health Institute. Its goals are to: (1) describe the incidence of SDY in the United States by using population-based surveillance; (2) compile data from SDY cases to create a resource of information and DNA samples for research; (3) encourage standardized approaches to investigation, autopsy, and categorization of SDY cases; (4) develop partnerships between local, state, and federal stakeholders toward a common goal of understanding and preventing SDY; and (5) support families who have lost loved ones to SDY by providing resources on bereavement and medical evaluation of surviving family members. Built on existing Child Death Review programs and as an expansion of the Sudden Unexpected Infant Death Case Registry, the SDY Case Registry achieves its goals by identifying SDY cases, providing guidance to medical examiners/coroners in conducting comprehensive autopsies, evaluating cases through child death review and an advanced review by clinical specialists, and classifying cases according to a standardized algorithm. The SDY Case Registry also includes a process to obtain informed consent from next-of-kin to save DNA for research, banking, and, in some cases, diagnostic genetic testing. The SDY Case Registry will provide valuable incidence data and will enhance understanding of the characteristics of SDY cases to inform the development of targeted prevention efforts.

The Infant Jarvik ventricular assist device (VAD; Jarvik Heart, Inc., New York, NY) has been developed to support the circulation of infants and children with advanced heart failure. The first version of the device was determined to have elevated hemolysis under certain conditions. The objective of this work was to determine appropriate modifications to the Infant Jarvik VAD that would result in acceptably low hemolysis levels. In vitro hemolysis testing revealed that hemolysis was related to the shape of the pump blade tips and a critical speed over which hemolysis would occur. Various design modifications were tested and a final design was selected that met the hemolysis performance goal. The new version was named the Jarvik 2015 VAD. Chronic in vivo tests, virtual fit studies, and a series of other performance tests were carried out to assess the device's performance characteristics. In vivo test results revealed acceptable hemolysis levels in a series of animals and virtual fit studies showed that the device would fit into children 8 kg and above, but could fit in smaller children as well. Additional FDA-required testing has been completed and all of the data are being submitted to the FDA so that a clinical trial of the Jarvik 2015 VAD can begin. Development of a Jarvik VAD for use in young children has been challenging for various reasons. However, with the hemolysis issue addressed in the Jarvik 2015 VAD, the device is well-poised for the start of the PumpKIN clinical trial in the near future.

Rationale : Congenital heart disease (CHD) is among the most common birth defects. Most cases are of unknown pathogenesis. Objective : To determine the contribution of de novo copy number variants (CNVs) in the pathogenesis of sporadic CHD. Methods and Results : We studied 538 CHD trios using genome-wide dense single nucleotide polymorphism arrays and whole exome sequencing. Results were experimentally validated using digital droplet polymerase chain reaction. We compared validated CNVs in CHD cases with CNVs in 1301 healthy control trios. The 2 complementary high-resolution technologies identified 63 validated de novo CNVs in 51 CHD cases. A significant increase in CNV burden was observed when comparing CHD trios with healthy trios, using either single nucleotide polymorphism array ( P =7×10 −5 ; odds ratio, 4.6) or whole exome sequencing data ( P =6×10 −4 ; odds ratio, 3.5) and remained after removing 16% of de novo CNV loci previously reported as pathogenic ( P =0.02; odds ratio, 2.7). We observed recurrent de novo CNVs on 15q11.2 encompassing CYFIP1, NIPA1 , and NIPA2 and single de novo CNVs encompassing DUSP1, JUN, JUP, MED15, MED9, PTPRE SREBF1, TOP2A , and ZEB2 , genes that interact with established CHD proteins NKX2-5 and GATA4 . Integrating de novo variants in whole exome sequencing and CNV data suggests that ETS1 is the pathogenic gene altered by 11q24.2-q25 deletions in Jacobsen syndrome and that CTBP2 is the pathogenic gene in 10q subtelomeric deletions. Conclusions : We demonstrate a significantly increased frequency of rare de novo CNVs in CHD patients compared with healthy controls and suggest several novel genetic loci for CHD.

Background Adolescents and young adults with congenital heart disease (CHD) are often restricted from physical activity and sports participation, which may have adverse effects. Objectives To determine the amount of physical activity, type of sports participation, and reasons for sports restrictions, and to evaluate the effect of sports participation on quality of life (QoL) in a cohort of patients with CHD. Methods Individuals with CHD aged 13–30 years were recruited at outpatient visits or via mailings. They completed a questionnaire addressing physical activity, sports participation, sports restrictions, and QoL (Pediatric Quality of Life Inventory). We also reviewed the patient's medical record. Results Of the 177 patients who responded (mean age 20 years), 31% have mild CHD, 40% have moderate CHD, and 29% have severe CHD. In the cohort, 52% participate in competitive sports, 25% recreational sports, and 23% no sports. Among patients with severe CHD, 29% participate in competitive sports that would be restricted by published guidelines (36th Bethesda Conference). After controlling for age, sex, CHD severity, residual hemodynamic disease, and comorbidities, participation in competitive sports and increased frequency of physical activity are independently associated with a higher QoL (P = .003 and P = .001, respectively). In an identical model, competitive sports participation and frequency of physical activity are associated with higher maximum predicted oxygen consumption (VO2) (n = 40; P = .002 and .02) and slightly lower body mass index (BMI) (P = .02 and .01). All findings were similar when analyses were stratified by recruitment method. Conclusions Patients with CHD commonly participate in competitive sports, and such participation is associated with higher QoL, improved exercise capacity, and lower BMI.

Objective To determine if the incidence of maternal diabetes mellitus or neonatal macrosomia is more frequent in fetuses and neonates with atrial arrhythmias than the general population. Methods Fetuses and neonates

Background Postoperative (PO) junctional ectopic tachycardia (JET) can be a life-threatening arrhythmia that follows surgical repair of congenital heart disease (CHD) and results in PO morbidity. Methods We reviewed 750 open heart surgeries (OHS) for CHD performed between January 2005 and February 2009. Kaplan-Meier and Cox proportional hazards model analyses were used to estimate the frequency and evaluate risk factors that might predict JET occurrence. Results The patients ranged in age from 1 day to 36.6 years; half were less than 4.8 months at the time of OHS. JET occurred in 115 of 750 (15.3%) OHS. JET was bimodally distributed by age with a peak incidence between 1–2 weeks and 1–3 years. JET occurred more commonly: (1) in specific types of OHS (single ventricle [19.5%] and cono-truncal defects [19.3%]) (P = 0.03); (2) with increased total surgical time (P = 0.001), aortic cross-clamp time (P < 0.001), cardiopulmonary bypass time (P < 0.001); and (3) followed use of inotropic agents (dopamine or milrinone, P < 0.001). JET lengthened intensive care stay by 3 days (P = 0.0001) and increased mortality (+JET [9.6%] vs –JET [4.6%], P = 0.03). In a multiple variable Cox regression model, total surgical time and PO use of milrinone were the best predictors for JET risk. PO administration of nitroprusside decreased risk of JET. Conclusions JET occurred more commonly following OHS associated with prolonged surgical times and PO use of inotropic medications. In contrast to previous reports, our results suggest that mechanical injury to the atrioventricular node area is not strongly associated with JET.