Congenital Heart Defects Patients Research Articles

The efficacy and safety of patent ductus arteriosus stent versus surgical aortopulmonary shunt in the management of babies with duct dependent circulation: a meta-analysis and review of literature

This meta-analysis aims to comprehensively assess the efficacy and safety of both patent ductus arteriosus (PDA) stents and surgical aortopulmonary shunt (APS) as the initial palliative measures in babies relying on ductal-dependent circulation. This review is essential to compare the outcome of relatively newer catheter-based PDA stent procedure with a surgical APS. By synthesizing existing literature, this review aims to provide insights to inform clinical practice and enhance patient care in this challenging clinical scenario. The methodology involved an extensive search of PubMed and Embase databases using specific keywords and terminology related to mortality, procedural outcomes, and postprocedural complications following PDA stent and APS in cyanotic congenital heart defects (CHD) patients. Six retrospective observational studies met the criteria, with 757 patients included. The analysis showed comparable mortality rates between PDA stents and APS. However, PDA stents were associated with decreased risks of mechanical circulatory support, postprocedural complications, and shorter hospital stays, mechanical ventilation, and intensive care unit stays compared to APS. Notably, patients with pulmonary atresia scheduled for biventricular surgery were more prevalent among those receiving PDA stents. In conclusion, while the risk of mortality is similar between PDA stents and APS, PDA stents offer advantages such as shorter hospital stays and reduced complications. Patient characteristics also vary, with a higher prevalence of intact ventricular septum among those receiving PDA stents.

Pathology of explanted pediatric hearts: An 11-year study. Population characteristics and implications for outcomes.

As more pediatric patients become candidates for heart transplantation (HT), understanding pathological predictors of outcome and the accuracy of the pretransplantation evaluation are important to optimize utilization of scarce donor organs and improve outcomes. The authors aimed to investigate explanted heart specimens to identify pathologic predictors that may affect cardiac allograft survival after HT. Explanted pediatric hearts obtained over an 11-year period were analyzed to understand the patient demographics, indications for transplant, and the clinical-pathological factors. In this study, 149 explanted hearts, 46% congenital heart defects (CHD), were studied. CHD patients were younger and mean pulmonary artery pressure and resistance were significantly lower than in cardiomyopathy patients. Twenty-one died or underwent retransplantation (14.1%). Survival was significantly higher in the cardiomyopathy group at all follow-up intervals. There were more deaths and the 1-, 5- and 7-year survival was lower in patients ≤10 years of age at HT. Early rejection was significantly higher in CHD patients exposed to homograft tissue, but not late rejection. Mortality/retransplantation rate was significantly higher and allograft survival lower in CHD hearts with excessive fibrosis of one or both ventricles. Anatomic diagnosis at pathologic examination differed from the clinical diagnosis in eight cases. Survival was better for the cardiomyopathy group and patients >10 years at HT. Prior homograft use was associated with a higher prevalence of early rejection. Ventricular fibrosis (of explant) was a strong predictor of outcome in the CHD group. We presented several pathologic findings in explanted pediatric hearts.

Use of polygenic and clinical risk scores in wide spectrum congenital heart malformations: a diagnostic and therapeutic perspective

Worldwide, congenital heart defects (CHDs) are a leading cause of mortality and morbidity. Globally, the annual prevalence rate of CHDs is about 1.5 million. It is one of the most common life-threatening congenital malformations, with a visible difference between high-income countries (HICs) and developing countries. This difference may be attributed to the diagnostic facilities and interventions.1 Moreover, the use of genetic and clinical risk scores is less studied in this field compared to other diagnostic and therapeutic approaches. Thus, we comprehensively review the available literature on adult and pediatric syndromic or non-syndromic CHDs and propose limitations and future directions in this field. Risk factors for this fatal disease include genetic and environmental factors.2,3 Risk stratification based on prenatal diagnosis with genetic counseling has shown better clinical outcomes. The modified World Health Organization (mWHO) guidelines are among the first proposed for risk stratification based on clinical scores.4 The combination of polygenic risk scores (PRS) and clinical risk evaluation has been adopted in various populations as better diagnostic and therapeutic approaches for various diseases, including coronary artery disease,5 diabetes,6 obesity,7 and cancers.8,9 However, unlike these diseases, polygenic risk scores are rarely used for the genetic diagnosis of CHD patients. The clinical utility of polygenic risk scores for CHDs is still in the early stages and requires validation studies in different cohorts. Incorporating PRS into the clinical setting may improve CHD diagnosis and therapeutic strategies.10 Recently, an initial attempt was made to determine the clinical utility of polygenic risk scores in a large dataset of the European cohort. Data from this study suggested a high potential for PRS in distinguishing between clinical phenotypes (mild, moderate, and severe) of congenital heart malformations.11 Furthermore, this hypothesis was tested in patients with transposition of the great arteries (TGA) to assess the utility of risk stratification after arterial switch operation. The cumulative risk score was computed for single nucleotide polymorphisms (SNPs) that reached the threshold statistical significance of p<1×10−5 in the initial analysis. Combined clinical and polygenic risk scores showed improved risk stratification in mild, moderate, and severe TGA phenotypes.12 Similarly, in another European cohort, the risk allele frequency was higher in the diseased group compared to the control group. However, statistical analysis suggested a non-significant association with p>0.05. Interestingly, combined risk scores constructed for selected SNPs showed a significant association with the disease with a p-value of 0.002. This evidence further supports the hypothesis that the cumulative effect of polymorphisms has better diagnostic and therapeutic efficacy than individual SNPs.13 There are certain limitations to its clinical use. Firstly, social stigma and lack of awareness regarding this disease are major hurdles. Secondly, there is a need to recruit a large number of samples from different populations to validate the clinical utility of PRS. Additionally, a lack of resources in developing countries also contributes to fatal outcomes. We recommend conducting large cohort studies in different ethnic groups to predict better risk associations, develop better therapeutic strategies, and formulate management guidelines.

Congenital Heart Defects in Patients with Molecularly Confirmed Sotos Syndrome.

Sotos syndrome is an autosomal dominant condition characterized by overgrowth with advanced bone age, macrodolicocephaly, motor developmental delays and learning difficulties, and characteristic facial features caused by heterozygous pathogenetic variants in the NSD1 gene located on chromosome 5q35. The prevalence of heart defects (HDs) in individuals with Sotos syndrome is estimated to be around 15-40%. Septal defects and patent ductus arteriosus are the most commonly diagnosed malformations, but complex defects have also been reported. The aim of our study was to analyze the prevalence of HD, the anatomic types, and the genetic characteristics of 45 patients with Sotos syndrome carrying pathogenetic variants of NSD1 or a 5q35 deletion encompassing NSD1, who were followed at Bambino Gesù Children's Hospital in Rome. Thirty-nine of the forty-five patients (86.7%) had a mutation in NSD1, while six of the forty-five (13.3%) had a deletion. Most of the patients (62.2%, 28/45) were male, with a mean age of 14 ± 7 years (range 0.2-37 years). A total of 27/45 (60.0%) of the patients had heart defects, isolated or combined with other defects, including septal defects (12 patients), aortic anomalies (9 patients), mitral valve and/or tricuspid valve dysplasia/insufficiency (1 patient), patent ductus arteriosus (3 patients), left ventricular non-compaction/hypertrabeculated left ventricle (LV) (4 patients), aortic coarctation (1 patient), aortopulmonary window (1 patient), and pulmonary valve anomalies (3 patients). The prevalences of HD in the two subgroups (deletion versus intragenic mutation) were similar (66.7% (4/6) in the deletion group versus 58.91% (23/39) in the intragenic variant group). Our results showed a higher prevalence of HD in patients with Sotos syndrome in comparison to that described in the literature, with similar distributions of patients with mutated and deleted genes. An accurate and detailed echocardiogram should be performed in patients with Sotos syndrome at diagnosis, and a specific cardiological follow-up program is needed.

Body plethysmography - additional information on exercise capacity in patients with congenital heart disease?

In each cardiopulmonary exercise test (CPET), resting spirometry is performed in advance. In patients with a congenital heart defect (CHD), lung volumes are often impaired. This study investigates correlations between lung volumes and CPET parameters and determines, whether body plethysmography provides substantial additional information for these patients. Data from 102 patients (23.8 ± 10.4years of age, 39 female) with various forms of CHD were examined from April 2018 to October 2022. All patients underwent spirometry (measuring forced vital capacity, FVC and forced expiratory volume in 1s, FEV1), body plethysmography (measuring total lung capacity, TLC) and an exhausting CPET. Data is presented as the median and interquartile range (z-scores) and correlated with Spearman's rho. Fifty-five% of all patients had normal results in lung function and 45% had normal peak oxygen uptake (≥ 80% predicted in peak VO2). Patients with impaired lung function were significantly more likely to have low exercise capacity (Fisher's exact test: p = 0.028). FVC z-values and %predicted peak VO2 (r = 0.365, p < 0.001) correlated significantly as well as FEV1_z and %predicted peak VO2 (r = 0.320, p = 0.001), and TLC z-values and %predicted peak VO2 (r = 0.249, p = 0.012). No correlation was found between FEV1/FVC z-values and %predicted peak VO2 (r = -0.043, p = 0.670). Spirometry and exercise capacity positively correlate, also in CHD patients. However, body plethysmography does not provide additional or improved prediction and is therefore only recommended in noteworthy results in spirometry to exclude further lung co-morbidities.

Predictors of in-ICU length of stay among congenital heart defect patients using artificial intelligence model: A pilot study

ObjectiveThis study aims to develop a predictive model using artificial intelligence to estimate the ICU length of stay (LOS) for Congenital Heart Defects (CHD) patients after surgery, improving care planning and resource management. DesignWe analyze clinical data from 2240 CHD surgery patients to create and validate the predictive model. Twenty AI models are developed and evaluated for accuracy and reliability. SettingThe study is conducted in a Brazilian hospital's Cardiovascular Surgery Department, focusing on transplants and cardiopulmonary surgeries. ParticipantsRetrospective analysis is conducted on data from 2240 consecutive CHD patients undergoing surgery. InterventionsNinety-three pre and intraoperative variables are used as ICU LOS predictors. Measurements and main resultsUtilizing regression and clustering methodologies for ICU LOS (ICU Length of Stay) estimation, the Light Gradient Boosting Machine, using regression, achieved a Mean Squared Error (MSE) of 15.4, 11.8, and 15.2 days for training, testing, and unseen data. Key predictors included metrics such as “Mechanical Ventilation Duration", “Weight on Surgery Date", and “Vasoactive-Inotropic Score". Meanwhile, the clustering model, Cat Boost Classifier, attained an accuracy of 0.6917 and AUC of 0.8559 with similar key predictors. ConclusionsPatients with higher ventilation times, vasoactive-inotropic scores, anoxia time, cardiopulmonary bypass time, and lower weight, height, BMI, age, hematocrit, and presurgical oxygen saturation have longer ICU stays, aligning with existing literature.

Modern risk scales in pediatrics and pediatric cardiac surgery as tools for assessing the quality of medical care

Introduction. The review presents the characteristics of modern risk scales in pediatrics. A comparative analysis of the advantages and disadvantages of risk scales in pediatric cardiac surgery has been carried out. Early detection of high-risk patients was shown to be the basis for the prevention of adverse outcomes after cardiac surgery. The capabilities of the Aristotle School (Aristotle Basic Complexity (ABC) Score have been established as a tool for assessing the quality of surgical treatment of children with congenital heart defects (CHD). Its determinants are mortality, the complexity of the postoperative period, and the technical complexity of the operation. The correlation between the values of the ABC scale and its determinants was evaluated. If the values of all three determinants exceeded the upper limit of the 95% confidence interval (CI), the patient was included in the high-risk group. The quality of treatment was assessed by the performance index (IP). A close correlation between ABC and its determinants has been revealed. For the ABC school, a high accuracy of the prognosis of death, complications, and technical complexity was established with an optimal threshold value of 6.5 points. Patients with ABC above the threshold were more likely to die. The IP was 0.56, similar indicators of foreign clinics ranged from 0.46 to 0.62 points. &#x0D; Conclusion. The basic Aristotle scale and new risk stratification scales after cardiac surgery in children are effective systems for evaluating the results of surgical treatment of CHD patients of different levels of complexity can be used to determine the quality of surgical treatment and identify high-risk groups.

Tissue inhibitor of metalloproteinase-2 in patients aged 1 month to 1 year with and without cardiac surgery-associated acute kidney injury in congenital heart disease surgery with cardiopulmonary bypass: a single-center retrospective study

Introduction: Acute kidney injury is a common complication of cardiac surgery after management of congenital heart defects. Cardiac surgery-associated acute kidney injury (CS-AKI) results in longer stays of patients in the intensive care unit and hospital. However, using an increase in postoperative creatinine as a means of detecting AKI has some limitations, since significant changes occur after the loss of more than 50% of renal function. In children, the creatinine level is influenced by various factors such as muscle mass, cardiac output, etc. These factors vary significantly among young children and complicate the early diagnosis of AKI. Recent studies have explored biomarkers as potential predictors for the early detection of CS-AKI after cardiac surgery for management of congenital heart disease in children.Objective: To evaluate the urinary tissue inhibitor of metalloproteinase-2 (TIMP2) as a predictor of CS-AKI following management of congenital heart defects in children aged 1 month to 1 year who underwent cardiopulmonary bypass.Methods: A single-center retrospective study included patients aged 1 month to 1 year who underwent cardiopulmonary bypass for the correction of congenital heart defects. The groups were formed based on the presence of CS-AKI. The study group comprised of patients who had CS-AKI (group 1, n = 52), while those without CC-AKI constituted the control group (group 2, n = 98). To ensure minimal systematic errors and comparability between two groups, propensity score matching analysis was performed (52 patients in groups 1 and 2). Preoperative, intraoperative, and postoperative parameters and characteristics were compared.Results: The results showed no differences in baseline or demographic characteristics between the patients. In the study group, 34.6% of patients were diagnosed with CS-AKI. Among them, 67.4% (n = 35) were stage 1, 28.8% (n = 15) were stage 2, and 3.8% (n = 2) were stage 3. The results of the regression analysis show a decrease by 24% and an increase by 9 and 16% in CS-AKI respectively, with an increase in creatinine levels by 1 µmol/l, at baseline and on days 3 and 4. Additionally, male patients have a 76% lower likelihood to develop CS-AKI. It was observed that there was no significant difference in the tissue inhibitor of metalloprotease-2 levels between the groups with and without CS-AKI.Conclusion: Urinary TIMP2 levels were found to be unable to predict the early onset of CS-AKI in congenital heart defect patients ages 1 month to 1 year who underwent cardiopulmonary bypass surgery. Received 24 April 2023. Revised 27 November 2023. Accepted 28 November 2023. Funding: The study did not have sponsorship. Conflict of interest: The authors declare no conflict of interest. Contribution of the authors: The authors contributed equally to this article.

Are congenital heart defects connected to more severe attention-deficit/hyperactivity disorder?: A systematic review and meta-analysis.

Congenital heart defects (CHDs) are the most common cause of birth defect-related infant morbidity and mortality, affecting 1% of 40,000 births per year in the United States. On the other side, the etiology of attention-deficit/hyperactivity disorder (ADHD) is multifactorial. Multiple studies have found that cardiac surgery patients have higher morbidity of having this disorder. Many studies have investigated the prevalence of ADHD in different subtypes of CHD, but few have focused on the severity of ADHD symptoms. Thus, we conducted this systematic review and meta-analysis to investigate the severity of ADHD symptoms in CHD patients. We searched PubMed, Embase, Scopus, and Web of Science were searched from inception to March 6, 2023 without any restrictions. We included observational studies published in English language that evaluated burden of symptom of ADHD in CHD patients. Moreover, the standardized mean difference (SMD) for continuous outcomes with 95% confidence interval (CI) was pooled. P-values <.05 are considered as significant, and we performed all statistical analyses using RevMan software Version 5.4.1. Eight studies were included in our review with a total number of 120,158 patients. CHD was associated with a statistically significant increase in both ADHD index T score and ADHD Hyperactivity-Impulsivity Subscale (informant) with (SMD = 0.65, 95% CI [0.40, 0.90], P < .00001, I2 = 81%) and (SMD = 0.16, 95% CI [0.04, 0.28], P = .008, I2 = 0%). Regarding ADHD Inattention Subscale (informant), the pooled data showed that a significant increase of this score in the CHD group (SMD = 0.25, 95% CI [0.13, 0.37], P < .001, I2 = 0%), and ADHD Combined Score (informant) showed a significant increase of this score in the CHD group (SMD = 0.23, 95% CI [0.11, 0.35], P = .0002, I2 = 0%). Our study revealed a strong association between CHD and not only ADHD, but also the severity of ADHD, making early diagnosis of ADHD in children with CHD a mandatory step in the clinical evaluation practice to improve these children on both clinical and psychological aspects.

Noncardiac anomalies in children with congenital heart disease.

Noncardiac anomalies (NCAs) in patients with congenital heart defects (CHDs) are crucial for perioperative management and etiology studies. This study aimed to investigate NCAs in Chinese children with CHDs. Medical records for CHD-diagnosed children hospitalized from 1 January 2015 to 31 December 2019 were collected and subjected to retrospective analyses to excavate potential association rules between CHDs and noncardiac malformations. A total of 3,788 CHD patients were included in this study. The main phenotypes of CHD were Ventricular Septal Defect (VSD, 33.69%), Atrial Septal Defect (ASD, 12.72%), and Tetralogy of Fallot (TOF, 5.54%). A total of 887 (23.42%) cases showed noncardiac anomalies, which were mainly associated with the central nervous system (34.61%), nose/ear/mandibular/face (19.39%), genitourinary system (15.78%), and musculoskeletal system (15.56%). Compared to other CHD subtypes, septal defects had a lower percentage of associated NCAs (P = 3.7 × 10-9) while AVSD had a higher percentage (P = 0.0018). NCAs are prevalent among CHD-diagnosed children in China, and the spectrums of NCAs in different CHD subcategories were different.

Abstract 18813: Economic Burden of Pregnancy Among Privately Insured Women With Congenital Heart Disease

Background: Women with congenital heart defects (CHD) are increasingly reaching childbearing age. Understanding their healthcare costs in pregnancy may inform resource allocation, financial planning, and pre-conception counseling. Methods: We used 2010-2016 US commercially insured beneficiaries’ data within the IBM ® MarketScan® database to identify pregnancies among 18-55-year-old women with CHD and matched controls without CHD. We assessed baseline characteristics, cardiac and noncardiac conditions, pregnancy related conditions, birth outcomes, and cesarean section. We estimated total and out-of-pocket (OOP) costs, compiled and adjusted to 2016 medical component of the consumer price index. Negative binomial mixed model was used. Results: There were 6385 pregnancies in 5077 women with CHD (672 pregnancies among severe and 5713 among nonsevere) and 9438 pregnancies in 7737 controls. Compared to controls, pregnancies with CHD were more likely to be 35+ years of age at delivery, resided in the Northeast and West regions, had flexible insurance plans, cardiac conditions, noncardiac conditions, birth outcomes, pregnancy related conditions and cesarean sections, while there was no difference in the year of delivery and gestational diabetes rates. After adjusting for all covariates, having CHD was an independent predictor of higher adjusted pregnancy-related cost ratio for total (1.49, 95% confidence interval [CI] 1.40, 1.59) and OOP costs (1.27, 95% CI 1.19, 1.35). The adjusted mean total and OOP cost difference for pregnancy per patient for any CHD, severe CHD, and nonsevere CHD was significantly higher than controls (Figure). Total expenditure and OOP cost of CHD pregnancies during the study period were $162.5 and $15.7 million dollars respectively. Conclusions: We provide novel estimates of economic burden of pregnancy among privately insured CHD patients for clinical and financial counseling and planning for patients, payors and policymakers.

Serum Markers of Brain Injury in Pediatric Patients with Congenital Heart Defects Undergoing Cardiac Surgery: Diagnostic and Prognostic Role.

Introduction: The objectives of this study were to assess the role of neuromarkers like glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF), protein S100 (pS100), and neuron-specific enolase (NSE) as diagnostic markers of acute brain injury and also as prognostic markers for short-term neurodevelopmental impairment. Methods: Pediatric patients with congenital heart defects (CHDs) undergoing elective cardiac surgery were included. Neurodevelopmental functioning was assessed preoperatively and 4-6 months postoperatively using the Denver Developmental Screening Test II. Blood samples were collected preoperatively and postoperatively. During surgery, regional cerebral tissue oxygen saturation was monitored using near-infrared spectroscopy (NIRS). Results: Forty-two patients were enrolled and dichotomized into cyanotic and non-cyanotic groups based on peripheric oxygen saturation. Nineteen patients (65.5%) had abnormal developmental scores in the non-cyanotic group and eleven (84.6%) in the cyanotic group. A good diagnostic model was observed between NIRS values and GFAP in the cyanotic CHD group (AUC = 0.7). A good predicting model was observed with GFAP and developmental scores in the cyanotic CHD group (AUC = 0.667). A correlation was found between NSE and developmental quotient scores (r = 0.09, p = 0.046). Conclusions: From all four neuromarkers studied, only GFAP was demonstrated to be a good diagnostic and prognostic factor in cyanotic CHD patients. NSE had only prognostic value.

Functions of cilia in cardiac development and disease.

Errors in embryonic cardiac development are a leading cause of congenital heart defects (CHDs), including morphological abnormalities of the heart that are often detected after birth. In the past few decades, an emerging role for cilia in the pathogenesis of CHD has been identified, but this topic still largely remains an unexplored area. Mouse forward genetic screens and whole exome sequencing analysis of CHD patients have identified enrichment for de novo mutations in ciliary genes or non-ciliary genes, which regulate cilia-related pathways, linking cilia function to aberrant cardiac development. Key events in cardiac morphogenesis, including left-right asymmetric development of the heart, are dependent upon cilia function. Cilia dysfunction during left-right axis formation contributes to CHD as evidenced by the substantial proportion of heterotaxy patients displaying complex CHD. Cilia-transduced signaling also regulates later events during heart development such as cardiac valve formation, outflow tract septation, ventricle development, and atrioventricular septa formation. In this review, we summarize the role of motile and non-motile (primary cilia) in cardiac asymmetry establishment and later events during heart development.

Pattern of congenital heart defects among children in Jazan Region, Saudi Arabia: A five-year hospital-based study

ABSTRACT Background: Congenital heart defects (CHDs) are the leading cause of death and morbidity in children under one year around the world. This study explores the prevalence, patterns, and interventions of congenital heart defects in children in the Jazan region, Saudi Arabia. Methods: This was a descriptive cross-sectional study, conducted in the Jazan region, Saudi Arabia. We looked back at all of the CHD patients who went to the two tertiary hospitals in the Jazan region between January 2017 and December 2021 and collected and analyzed their background information and diagnosis. Results: During the study period, 1,275 CHD patients aged under 15 years old were identified. A total of 717 (56.24%) were males, while 558 (43.76%) were females. Acyanotic CHDs were the most common, accounting for 79.21% of all cases, while cyanotic CHDs accounted for only 20.79%. Ventricular septal defect (VSD), atrial septal defect (ASD), and patent ductus arteriosus (PDA) were the most common acyanotic CHDs, accounting for 35.69%, 24.31%, and 8% of total cases, respectively. The most common cyanotic CHDs were Tetralogy of Fallot (7.14%) and Total Anomalies of Pulmonary Venous Connection (TAPVC) (1.57%). The most common Cath intervention was patent ductus arteriosus (PDA). Conclusions: This study’s results are similar to those described in previous studies from around the world, except for the unreported Transposition of the Great Arteries (TGA) cases. This kind of information is very important for setting priorities in the Saudi Arabian health sector in light of the National Transformation Program.

Abstract EC.08: Novel Candidate Variant In The Gene Coding For Receptor Tyrosine-protein Kinase ErbB-2 Is Associated With Left Ventricular Outflow Tract Obstruction Defects In Human

Congenital heart defects (CHD) are the most common congenital malformations. Both genetic and environmental factors, such as blood flow during development, are known to contribute to disease development. The genetic predisposition is likely in most cases oligogenic, and currently, robust evidence for few predisposing genes for monogenic forms exist. Here we show evidence for a rare variant in the ERBB2 gene as potentially causal for CHD. ERBB2 is known to be essential for cardiac development in animal models, but so far human data are lacking. We studied a Finnish cohort of left ventricular outflow tract obstruction (LVOTO) patients and their families and identified a variant in ERBB2 (R569C) that segregated with disease in three unrelated families with multiple affected members. We performed functional studies, and show that the mutated receptor is functional, as NRG1 stimulation phosphorylates the receptor. However, a protein-protein interaction assay showed that the mutated receptor is mainly located in ER/mitochondria, whereas the wild type ERBB2 is located at the plasma membrane. This was confirmed by a flow cytometry analysis showing decreased receptor presence in the plasma membrane of patient derived cells. Zebrafish embryos expressing the R599C mutant allele demonstrated altered myocardium structure and reduced contractility compared to the wild-type allele or a mock control. Finally, we differentiated induced pluripotent stem cells (iPSCs) from a patient with the variant into cardiomyocytes. Single-cell RNA sequencing demonstrated reduced expression of genes related to heart development, muscle contraction and response to oxidative stress in patient cells compared to healthy controls. As endothelial cells (EC) are important during cardiac development, we also differentiated patient and healthy control iPSCs into ECs. Transcriptomic analysis showed significant differences in the expression of angiogenesis and vasculature development related genes in the patient cells. In summary, ERBB2 R599C variant segregates with CHD patients in three unrelated families with LVOTO defects. The variant influences location of the protein and causes compromised heart function in zebrafish embryos. We propose ERBB2 as a new candidate gene for CHD.

Long-term neurodevelopmental outcome and serial cerebral magnetic resonance imaging assessment in Fontan patients at school age.

Children with univentricular congenital heart disease undergoing staged surgical palliation are at risk for impaired neurodevelopmental (ND) outcome. Little is known about the long-term effects on brain growth until school age. In a prospective two-centre study, consecutive patients undergoing stage I (Hybrid or Norwood) to stage III (Fontan procedure) were evaluated by 2 serial cerebral magnetic resonance imaging examinations, somatic growth and ND testing before Fontan procedure at 2 years of age (Bayley-III) and after Fontan at 6-8 years of age (Wechsler Intelligence Scale for Children-third edition). Magnetic resonance imaging findings were compared with 8 healthy controls. Medical and sociodemographic characteristics were documented and related to cerebral and ND findings. We examined 33 children (16 female) at a mean age of 2.3 (0.35) and 6.8 (± 0.7) years. The mean Bayley-III cognitive scales were 99.1 (9.9), language scales 98.4 (11.9) and motor scales 98.5 (13.8) at the first examination. Follow-up at school age showed a mean total IQ of 86.7 (13.6). The rate of structural brain lesions increased from 39% at 2 years to 58% at school age. Bayley-III language scale (P = 0.021) and mean Wechsler Intelligence Scale for Children-third edition (P = 0.019) were lower in children with pathological MR findings. Total brain volume (P < 0.001), total grey matter volume (P = 0.002), deep grey matter volume (P = 0.001) and white matter volume (P < 0.001) were smaller in patients compared to age- and gender-matched healthy controls. Smaller brain volumes and structural brain lesions in complex congenital heart defect patients at school age are associated with impaired ND outcome. For the evaluation of predictive surgical or clinical factors, larger multicentre studies are needed.

P49: Are We Timely Detecting Congenital Heart Defects in Bogotá and Cali (Colombia)?

Background: Congenital heart defects (CHD) are the main cause of infant mortality. Properly attending CHD demands strategies to improve prenatal diagnosis, planning birth on adequate hospitals, assure timely clinical care for complex cases, and guarantee follow-up and health care access for patients lifelong. Accordingly, Colombian normativity dictates that all pregnant women must have at least a first and second trimester screening with fetal heart examination, 7 to 10 prenatal control visits, and psychological support and information on voluntary termination. The aim of this study was to characterize demographics and prenatal care of expectant mothers of pediatric patients with a confirmed CHD diagnosis. Methods: This study was prospective and observational with an incidental sampling of 134 CHD patients treated at Fundación Cardioinfantil (Bogotá), Hospital Universitario San Ignacio (Bogotá), and Clinica Imbanaco (Cali) in Colombia. Women, after consent, were interviewed about demographics, prenatal care, pre and postnatal diagnosis, and children clinical evolution. We analyzed CHD according to their complexity (simple, moderate or complex) and clinical presentation (isolated, multiple anomalies or syndromes). Data were collected using the REDCap tool, descriptive statistics were calculated using Excel. Variables were expressed as mean (range). Results: 43% of all CDH were prenatally detected (66% of complex CHD were only detected postnatally). Mothers were young (mean age 28.1 years, DE 6.2), 82.1% had completed high school, 71.6% had low-income and 82.1% lived in urban areas with the father. Only 3% had twin pregnancies and 19% had chronic comorbidities (hypertensive disorders, diabetes, or hypothyroidism). On average, mothers had 6.8 prenatal control visits (DE 2.6) and 4.6 ultrasound scans (DE 2.5). As for the proper moment for ultrasound scans, only 61.1% of first-trimester scans and 58.9% of second-trimester scans were on time according to normative. 41% of women did not have psychological support, and 49% did not receive information on voluntary termination. About labor, 45% were spontaneous and 55% cesarian deliveries. Regarding babies (50.7% females), 24.0% were small for gestational age and 25.4% were born before 37 weeks. Most babies had an isolated CHD (15% simple, 76% complex), 5% had multiple anomalies, and 5% syndromes. Comparing prenatal diagnosis (ultrasound scans) and postnatal diagnosis, only in 22% of cases we found a complete agreement, and in 56% CDH was not reported on the ultrasound exams. Conclusion: Ultrasonography is a useful tool to detect CHD, but improving early detection requires better and timely access, especially for complex cases. Colombian normative for prenatal care is not working as expected. Delfos program is funded by Minciencias (Contract No.120484267276).

Nationwide Survey Reveals High Prevalence of Non-Swimmers among Children with Congenital Heart Defects.

Physical activity is important for children with congenital heart defects (CHD), not only for somatic health, but also for neurologic, emotional, and psychosocial development. Swimming is a popular endurance sport which is in general suitable for most children with CHD. Since we have previously shown that children with CHD are less frequently physically active than their healthy peers, we hypothesized that the prevalence of non-swimmers is higher in CHD patients than in healthy children. To obtain representative data, we performed a nationwide survey in collaboration with the German National Register of Congenital Heart Defects (NRCHD) and the Institute for Sport Sciences of the Karlsruhe Institute for Technology (KIT). The questionnaire included questions capturing the prevalence of swimming skills and the timing of swim learning and was part of the "Motorik-Modul" (MoMo) from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS). A representative age-matched subset of 4569 participants of the MoMo wave two study served as a healthy control group. From 894 CHD-patients (mean age of 12.5 ± 3.1 years), the proportion of non-swimmers in children with CHD was significantly higher (16% versus 4.3%; p < 0.001) compared to healthy children and was dependent on CHD severity: Children with complex CHD had an almost five-fold increased risk (20.4%) of being unable to swim, whereas in children with simple CHD, the ability to swim did not differ significantly from their healthy reference group (5.6% vs. 4.3% non-swimmers (p = not significant). According to our results, one in five patients with complex CHD are non-swimmers, a situation that is concerning in regard of motoric development, inclusion and integration, as well as prevention of drowning accidents. Implementation of swim learning interventions for children with CHD would be a reasonable approach.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome and tetralogy of fallot; Case report and literature review

WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome is a rare primary immunodeficiency disorder characterized by susceptibility to human papillomavirus (HPV) infections, neutropenia, and hypogammaglobulinemia. WHIM syndrome is caused by a gain-of-function mutation CXCR4, leading to increased responsiveness of neutrophils and lymphocytes to CXCL12. This results in an accumulation of atypical hypersegmented mature neutrophils in the bone marrow and peripheral blood neutropenia. This case report discusses a 10-year-old girl who was diagnosed with WHIM syndrome at the age of four years following Haemophilus influenzae meningitis. She was found to have Tetralogy of Fallot at birth, which was surgically repaired when she was one year old. She was also found to have significant neutropenia during surgery and received multiple doses of G-CSF with a good response. She presented to the hospital at the age of four years with fever, neck stiffness, lethargy, and headache and was diagnosed with H. influenzae meningitis. Her immunology workup revealed significant neutropenia and hypogammaglobulinemia, as well as low antibody levels to H. influenza type B, tetanus toxoid, and Streptococcus pneumonia, despite up-to-date vaccination. Furthermore, decreased levels of T cells and B cells were detected. The patient was started on IgG replacement therapy and Bactrim prophylaxis. Bone marrow biopsy revealed granulocytic hyperplasia and occasional hypersegmented neutrophils, suggesting myelokathexis. Genetic testing revealed a heterozygous CXCR4 mutation with a premature stop codon (p.Ser338Ter), confirming the diagnosis of WHIM syndrome. This case report highlights the association of WHIM syndrome with congenital heart defects, such as Tetralogy of Fallot. A literature review revealed three other cases of congenital heart defects in patients with WHIM syndrome, indicating a potential role for CXCR4 and CXCL12 in septum formation. The rarity of the disorder and the lack of a universal screening tool makes the diagnosis of WHIM syndrome difficult. Therefore, physicians should consider WHIM syndrome in patients with congenital heart defects, particularly if they have recurrent HPV infections, neutropenia, and hypogammaglobulinemia.

Association of maternal hypertension and diabetes with variants of the NKX2-5, LEFTY1 and LEFTY2 genes in children with congenital heart defects: a case-control study from Pakistani Population.

Globally, congenital heart defect (CHD) is the most common congenital malformation, responsible for higher morbidity and mortality in the pediatric population. It is a complex multifactorial disease influenced by gene-environment and gene-gene interactions. The current study was the first attempt to study these polymorphisms in common clinical phenotypes of CHD in Pakistan and the association between maternal hypertension and diabetes with single nucleotide polymorphisms (SNPs) in children. A total of 376 subjects were recruited in this current case-control study. Six variants from three genes were analyzed by cost-effective multiplex PCR and genotyped by minisequencing. Statistical analysis was done by GraphPad prism and Haploview. The association of SNPs and CHD was determined using logistic regression. The risk allele frequency was higher in cases as compared to healthy subjects, but the results were not significant for rs703752. However, stratification analysis suggested that rs703752 was significantly associated with the tetralogy of Fallot. The rs2295418 was significantly associated with maternal hypertension (OR = 16.41, p = 0.003), while a weak association was present between maternal diabetes and rs360057 (p = 0.08). In conclusion, variants in transcriptional and signaling genes were associated with Pakistani pediatric CHD patients that showed varied susceptibility between different clinical phenotypes of CHD. In addition, this study was the first report regarding the significant association between maternal hypertension and the LEFTY2 gene variant.