Evaluation of Right Ventricular Myocardial Properties Using Systolic Myocardial T1 Mapping.

Introduction Myocardial properties can be quantitatively evaluated using myocardial native T1 values (nT1) obtained using cardiac magnetic resonance imaging (CMR). In terms of myocardial wall thickness, the left ventricular nT1 is easy to measure, but the right ventricular nT1 is difficult. Patients with congenital heart disease often develop right ventricular overload. If right ventricular nT1 can be measured consistently, inflammation and fibrosis of the right ventricular myocardium can be quantitatively evaluated. We aimed to determine whether T1 mapping during systole can be used to evaluate right ventricular myocardial properties. Methods T1 mapping was performed at diastole and systole. Systolic T1 mapping was calculated from diastolic T1 mapping and cine images. The myocardial properties of both ventricles were evaluated in 13 healthy volunteers (21-26 years old) and 12 patients with right ventricular overload (12-41 years old) who underwent CMR examination at our hospital. Results From the analysis of left ventricular nT1, we found that nT1 did not change significantly during the cardiac cycle. However, right ventricular nT1 changed between diastole and systole because the right ventricle is affected by blood. Although there was no difference in right ventricular diastolic nT1 between the patients and volunteers (1,346.8 vs. 1,347.6 ms, p = 0.852), the right ventricular systolic nT1 was significantly higher in patients than in volunteers (1,312.7 vs. 1,233.8 ms, p = 0.002). This indicates that right ventricular myocardial damage occurs in patients with right ventricular overload. Conclusion Systolic right ventricular myocardial T1 mapping allows assessment of right ventricular myocardial properties. The right ventricular myocardial systolic nT1 is useful for evaluating myocardial damage due to right ventricular stress and myocardial injury. Measuring right ventricular nT1 may allow consideration of early therapeutic intervention.

The role of spirituality in the well-being of families with children with congenital heart disease: scoping review.

Background: Congenital heart disease (CHD) is the leading cause of death from malformations in infants and has a significant psychological impact on families. This scoping review explored the role of spirituality in supporting families of children with CHD. It also sought to identify gaps in the existing literature and suggest directions for future research. Methods: A synthesis review was conducted following the framework of Arksey and O'Malley, incorporating the principles of the Joanna Briggs Institute. We systematically searched four databases-Medline, Embase, Lilacs, and Scielo-selecting studies based on inclusion criteria focused on spirituality in families of children with CHD. Articles without full text, book chapters, lectures, conference abstracts, review articles, and editorials were excluded. We analyzed the year of publication, study location, objectives, methodology, participants of the study, and main results. Results: A total of 17 studies were included in the review, most of which were conducted in the past 10 years. The studies were conducted in various regions of the world, including Japan, the USA, China, Iran, Sweden, and Brazil, and they examined different religious traditions, including Christianity, Islam, Buddhism, and non-denominational spiritual practices. Twelve qualitative studies, three descriptive studies, one cross-sectional study, and one case report were included. The articles were categorized based on several themes: the influence of spirituality on mental and emotional well-being, cultural and religious diversity, integration of spirituality into health care, and its assistance in decision-making. Conclusions: Spirituality plays a crucial role in addressing the emotional and psychological challenges of CHD. There is a need for structured models of spiritual counseling and more research in diverse cultural and socioeconomic contexts. Identifying these gaps can help guide future studies to enhance our understanding and improve the support provided to these families, thereby promoting more holistic and patient-centered healthcare.

Genetics of anomalies of the kidney and urinary tract with congenital heart disease: A review.

Congenital anomalies of the kidney and urinary tract (CAKUT) and congenital heart disease (CHD) are the most common congenital defects and constitute a major cause of morbidity in children. Anomalies of both systems may be isolated or associated with congenital anomalies of other organ systems. Various reports support the co-occurrence of CAKUT and CHD, although the prevalence can vary. Cardiovascular anomalies occur in 11.2% to 34% of patients with CAKUT, and CAKUT occur in 5.3% to 35.8% of those with CHD. The co-occurrence of genetic factors in both CAKUT and CHD would raise common etiologies including genetics, genetic-environmental interactions, or shared molecular mechanisms and pathways such as NODAL, NOTCH, BMP, WNT, and VEGF. Studies in animal models and humans have indicated a genetic etiology for CHD and CAKUT with hundreds of genes recognized and thousands of entries, found in a catalog of human genetic disorders. There are over 80 CAKUT genes and over 100 CHD genes available for clinical testing. For example, the HNFIB gene accounts for 5% to 31% of reported cases of CAKUT. In view of the association between CAKUT and CHD, a thorough cardiac examination should be performed in patients with CAKUT, and a similar evaluation for CAKUT in the presence of CHD. This will allow early diagnosis and therapeutic intervention to improve the long- term outcome of patients affected, and test for at-risk family members. We present here evidence for an association of anomalies involving the two organ systems, and discuss possible etiologies of targeted genes, their functions, biological processes and interactions on embryogenesis.

Missense mutations in the CITED2 gene may contribute to congenital heart disease.

BACKGROUND: Congenital heart disease (CHD) is a lifelong abnormality present from birth. Multiple studies have shown that mutations in genes involved in heart development could cause congenital heart disease. The CITED2 gene works as a transcription factor in the hypoxic pathway for the development of the heart. Therefore, five CHD types, ventricular septal defect, atrial septal defect, atrioventricular septal defect, tetralogy of fallot, and patent ductus arteriosus, were evaluated by conducting a targeted single nucleotide polymorphism (SNP) analysis of the CITED2 gene variant rs375393125 (T > C). This study aimed to identify the association of CITED2 gene mutations in CHD patients. METHODS: Three hundred fifty samples, 250 from patients and 100 from controls, were collected for this genetic analysis. Allele-specific PCR and gel electrophoresis were used to identify the target missense mutations. The genotypic results of the CHDs were further validated through Sanger sequencing. RESULTS: The frequency of the homozygous mutant (CC) in CHD patients was 48.4%, and of the heterozygous mutant (TC) genotype was 11.4%; these percentages are higher than controls (1%). The control samples had only one heterozygous TC and no homozygous CC genotype. The chi-square value was obtained at 103.9 with a probability of 0.05, more significant than the significance value of 21.03. The odds ratio was 43.7, which is > 1. The calculated value of ANOVA was 11.6, which was more significant than the F critical value of 3.7. As a result of sequencing, the mutant sample of each selected CHD type was found heterozygous or homozygous, and the results were like those obtained through conventional PCR. CONCLUSION: The samples of CHD patients showed mutations. Therefore, the CITED2 gene SNP might be associated with CHD.

Cardiac Phenotype and Gene Mutations in RASopathies.

Cardiac involvement is a major feature of RASopathies, a group of phenotypically overlapping syndromes caused by germline mutations in genes encoding components of the RAS/MAPK (mitogen-activated protein kinase) signaling pathway. In particular, Noonan syndrome (NS) is associated with a wide spectrum of cardiac pathologies ranging from congenital heart disease (CHD), present in approximately 80% of patients, to hypertrophic cardiomyopathy (HCM), observed in approximately 20% of patients. Genotype-cardiac phenotype correlations are frequently described, and they are useful indicators in predicting the prognosis concerning cardiac disease over the lifetime. The aim of this review is to clarify the molecular mechanisms underlying the development of cardiac diseases associated particularly with NS, and to discuss the main morphological and clinical characteristics of the two most frequent cardiac disorders, namely pulmonary valve stenosis (PVS) and HCM. We will also report the genotype-phenotype correlation and its implications for prognosis and treatment. Knowing the molecular mechanisms responsible for the genotype-phenotype correlation is key to developing possible targeted therapies. We will briefly address the first experiences of targeted HCM treatment using RAS/MAPK pathway inhibitors.

Assessment of 4D flow MRI for quantification of left-to-right shunt in pediatric patients with ventricular septal defect: comparison with right heart catheterization.

Objectives: The percentage of shunt fraction significantly impacts the management of patients with congenital shunts, influencing strategic choices such as surgical or interventional procedures. This study compared the estimated shunt fraction (the ratio of pulmonary-to-systemic flow, Qp/Qs) for quantifying the left-to-right shunt in children with ventricular septal defect (VSD) using heart catheterization, four-dimensional (4D) flow, and two-dimensional (2D) flow magnetic resonance imaging (MRI). The goal was to establish a non-invasive and reliable measurement ratio between pulmonary and systemic blood flow in these patients. Methods: Between July 2022 and June 2023, patients scheduled to undergo invasive right heart catheterization were included in this study. MRI was performed one hour before the catheterization procedure. The correlation of shunt fraction was assessed between all methods after calculating the Qp/Qs ratio from 2D and 4D flow MRI and catheterization. Results: A total of 24 patients (aged 3-15 years, eight females) were ultimately included in the study. The Qp/Qs ratios obtained from 4D flow had a robust correlation (correlation coefficient r = 0.962) compared to those obtained during catheterization. Cardiac catheterization recorded the mean shunt fraction at 1.499 ± 0.396, while 4D flow measured it at 1.403 ± 0.344, with no significant difference between the two techniques. Moreover, there was a reasonable correlation (r = 0.894) between 2D flow measurements of Qp/Qs and the results obtained from catheterization, with a mean shunt fraction of 1.326 ± 0.283. Conclusion: 4D flow MRI has the potential to be a non-invasive method for accurately measuring the left-to-right shunt in children with VSD.

Gut Microbiome in Children with Congenital Heart Disease After Cardiopulmonary Bypass Surgery (GuMiBear Study).

The gut microbiome of infants with congenital heart disease (CHD) undergoing cardiopulmonary bypass surgery (CPB) is at risk of profound alteration. The aim of this study was to examine the gut microbiome pre- and post-bypass surgery to explore potential implications of altered gut biodiversity. A prospective cohort study involving infants with CHD who underwent CPB was performed. Faecal samples were collected from infants alongside the collection of demographic and clinical data in order to examine gut microbiome changes before and after surgery. 16S rRNA sequencing analysis was performed on DNA isolated from stool samples to determine changes in gut microbiome composition. Thirty-three patients were recruited, with samples from thirteen of these available for final analysis. Compared with healthy, matched controls, at a genus level, pre-operative samples for infants with CHD demonstrated a higher relative abundance of Escherichia-Shigella (31% vs 2-6%) and a lower relative abundance of Bifidobacterium (13% vs 40-60%). In post-operative samples, the relative abundance of Escherichia-Shigella (35%), Enterococcus (11%), Akkermansia (6%), and Staphylococcus (5%) were higher than pre-op samples. One infant developed post-operative necrotising-enterocolitis (NEC). They displayed a marked abundance of the Enterococcus (93%) genus pre-operatively. This study demonstrates that infants with CHD have an altered gut microbiome when compared with healthy controls and there might be a possible link between an abundance of virulent species and NEC.

Beyond borders: an appraisal of the global congenital cardiac surgery workforce.

Background: Congenital heart disease (CHD) is the most common congenital abnormality worldwide. Patients in resource-constrained environments experience higher levels of mortality and morbidity from CHD. Many studies have quantified the incidence of CHD in resource-constrained environments and compared these to availability of surgeons per population. However, no study to date has compiled and created a repository of the global paediatric cardiac surgical workforce. We aimed to quantify the number and details of the congenital cardiac surgeons globally, compare the population of under 15's in each respective countries, and address the workforce gaps that currently exist within paediatric cardiac surgery. Methods: Cardiothoracic Surgery Network (CTSNet) was searched in 2021 to extrapolate the current paediatric cardiac surgical workforce. The data was evaluated with the current literature to address current gaps in workforce planning and sustainability to produce this appraisal. Results: A total of 4,027 congenital cardiac surgeons were identified from CTSNet with 75% residing in high-income countries (HICs) or upper-middle-income countries (UMICs) despite these income groups only accounting for 16% of the world population. Despite similar incidence and prevalence of CHD globally, we found an unequal distribution in the availability of congenital cardiac surgeons worldwide. Conclusions: The disparity in the availability of surgeons between HICs and low-middle-income countries (LMICs) is a global health issue that will require serous thought and planning to resolve. The high proportion of preventable deaths from CHD cases is a regrettable figure that governments and medical organisations should further strive to decrease. Education and proactive investments in training up local teams in LMICs will allow for sustainability in global congenital cardiac surgery.

Pediatric Quadricuspid Aortic Valve: Morphology, Characteristics, Clinical Outcomes, and Literature Review.

BACKGROUND: Quadricuspid aortic valve (QAV) is an exceedingly rare congenital heart defect (CHD) which has not been well-defined in a pediatric population. METHODS: The Mayo Clinic echocardiography database was retrospectively analyzed to identify patients ≤18 years diagnosed with QAV from January 1990 to December 2023. Patients with truncus arteriosus were excluded. All images were independently reviewed to define morphology of the QAV by using the Hurwitz and Roberts classification. RESULTS: Fourteen patients with QAV were identified with a median age at time of diagnosis being 10.5 years (interquartile range [IQR] 6-14 years). Male-to-female ratio was 3:1. Associated CHDs were present in 50% (n = 7) patients. The most common morphological subtypes of QAV were Type D in 43% (n = 6) and Type B in 29% (n = 4). Aortic regurgitation was the most frequently associated valvular abnormality affecting 86% (n = 12) cases, with greater than moderate regurgitation in only two patients. Aortic valve stenosis was observed in 14% (n = 2) patients. Ascending aortic dilatation was present in 21% (3/14) of the cohort, but only 14% (1/7) of isolated QAV patients. At a mean follow up of 11 ± 6.6 years and a median follow-up age of 22 years (IQR 14-27 years), survival was 100% with no primary interventions on the aortic valve or aorta. However, four patients required surgical interventions for associated CHDs. CONCLUSION: Among children with QAV, almost half of the patients had additional CHD. Aortic regurgitation was the predominant hemodynamic abnormality. Long-term survival was excellent with minimal progression during childhood and adolescence.

Contemporary survival outcomes of congenital systemic-to-pulmonary shunt in children with borderline pulmonary vascular resistant index compared to Eisenmenger syndrome.

Pulmonary arterial hypertension (PAH) associated with congenital heart disease (PAH-CHD) is a complication that occurs after unrepaired significant systemic-to-pulmonary shunt. Treatment options for PAH-CHD-predominantly left-to-right (L-R) shunt in children with borderline-high pulmonary vascular resistant index (PVRi) have been debated. We aimed to assess the treatment and survival of children with PAH-CHD-predominantly L-R shunt with borderline to high PVRi, using Eisenmenger syndrome (ES) for comparison. In 1995-2021, a total of 142 patients with ES and 192 children with PAH-CHD-predominantly L-R shunt were eligible for our analysis. The PVRi in ES patients was 26.7 ± 16.8 WU m2. Most patients (91%) received PAH-targeted therapy. Of the 192 children with PAH-CHD-predominantly L-R shunt, the baseline PVRi was 9.2 ± 5.8 WU m2. A total of 64 patients (33.3%) had borderline PVRi (4-8 WU m2) and 98 patients (51%) had high PVRi (> 8 WU m2). Most patients (88.5%) responded to acute pulmonary vasodilatory testing and underwent repair, with 158 undergoing defect closure and 12 having fenestrated closure. A treat-and-repair strategy was used in 33 children (17.1%). The 10- and 15-year survival rates for patients with ES were 79.3% and 72.4%, respectively, which was significantly inferior to children with borderline PVRi [97.3% and 87.8% (p = 0.02)]; and high PVRi [91.6% and 89.5% (p = 0.06)], respectively. The survival rate of children receiving treat-and-repair was slightly higher than that of ES (p = 0.16). The independent mortality risk in children with PAH-CHD-predominantly L-R shunt was persistent PAH following the defect correction (adjusted hazard ratio 5.8, 95% CI 1.7-19.9, p = 0.005).Trial registration: TCTR20200420004.

Importance of Cardiovascular Magnetic Resonance Applied to Congenital Heart Diseases in Pediatric Age: A Narrative Review.

Congenital heart diseases (CHDs) represent a heterogeneous group of congenital defects, with high prevalence worldwide. Non-invasive imaging is essential to guide medical and surgical planning, to follow the patient over time in the evolution of the disease, and to reveal potential complications of the chosen treatment. The application of cardiac magnetic resonance imaging (CMRI) in this population allows for obtaining detailed information on the defects without the necessity of ionizing radiations. This review emphasizes the central role of CMR in the overall assessment of CHDs, considering also the limitations and challenges of this imaging technique. CMR, with the application of two-dimensional (2D) and tri-dimensional (3D) steady-state free precession (SSFP), permits the obtaining of very detailed and accurate images about the cardiac anatomy, global function, and volumes' chambers, giving essential information in the intervention planning and optimal awareness of the postoperative anatomy. Nevertheless, CMR supplies tissue characterization, identifying the presence of fat, fibrosis, or oedema in the myocardial tissue. Using a contrast agent for angiography sequences or 2D/four-dimensional (4D) flows offers information about the vascular, valvular blood flow, and, in general, the cardiovascular system hemodynamics. Furthermore, 3D SSFP CMR acquisitions allow the identification of coronary artery abnormalities as an alternative to invasive angiography and cardiovascular computed tomography (CCT). However, CMR requires expertise in CHDs, and it can be contraindicated in patients with non-conditional devices. Furthermore, its relatively longer acquisition time and the necessity of breath-holding may limit its use, particularly in children under eight years old, sometimes requiring anesthesia. The purpose of this review is to elucidate the application of CMR during the pediatric age.

Vectorcardiography signs of a failing Fontan: Heart rate, PR interval, RtQRSvm, QRSvm and SPQRS-T angle as noninvasive markers of late Fontan complications and mortality.

BACKGROUND: Limited data exists on interpreting vectorcardiography (VCG) parameters in the Fontan population. OBJECTIVE: The purpose of this study was to demonstrate the associations between ECG/VCG parameters and Fontan failure (FF). METHODS/RESULTS: 107 patients with a Fontan operation after 1990 and without significant ventricular pacing were included. FF and Fontan survival (FS) groups were compared. The average follow-up after Fontan operation was 11.8 years ±7.1 years. 14 patients had FF (13.1%) which was defined as having protein-losing-enteropathy (1.9%), plastic bronchitis (2.8%), Fontan takedown (1.9%), heart transplant (5.6%), NYHA class III-IV (2.8%) or death (0.9%). A 12­lead ECG at last follow up or prior to FF was assessed for heart rate, PR interval, QRS duration, Qtc and left/right sided precordial measures (P-wave, QRS and T-wave vector magnitudes, spatial P-R and QRS-T angles). Transthoracic echocardiogram evaluated atrioventricular valve regurgitation and ventricular dysfunction at FF or last follow up. A cox multivariate regression analysis adjusted for LV dominance, ventricular dysfunction, HR, PR, QTc, Pvm, QRSvm, SPQRST-angle, RtPvm, RtQRSvm and RtTvm. Ventricular dysfunction, increased heart rate and prolonged PR interval were significantly associated to FF at the multivariate analysis. ROC analysis and Kaplan-meier analysis revealed an increased total mortality associated with a heart rate > 93 bpm, PR interval > 155 mv, QRSvm >1.91 mV, RtQRSvm >1.8 mV and SPQRST angle >92.3 mV with p values <0.001 to 0.018. CONCLUSION: We demonstrate the importance of ECG/VCG monitoring in the Fontan population and suggest specific indicators of late complications and mortality.

From genes to therapy: A comprehensive exploration of congenital heart disease through the lens of genetics and emerging technologies.

Congenital heart disease (CHD) affects approximately 1 % of live births worldwide, making it the most common congenital anomaly in newborns. Recent advancements in genetics and genomics have significantly deepened our understanding of the genetics of CHDs. While the majority of CHD etiology remains unclear, evidence consistently indicates that genetics play a significant role in its development. CHD etiology holds promise for enhancing diagnosis and developing novel therapies to improve patient outcomes. In this review, we explore the contributions of both monogenic and polygenic factors of CHDs and highlight the transformative impact of emerging technologies on these fields. We also summarized the state-of-the-art techniques, including targeted next-generation sequencing (NGS), whole genome and whole exome sequencing (WGS, WES), single-cell RNA sequencing (scRNA-seq), human induced pluripotent stem cells (hiPSCs) and others, that have revolutionized our understanding of cardiovascular disease genetics both from diagnosis perspective and from disease mechanism perspective in children and young adults. These molecular diagnostic techniques have identified new genes and chromosomal regions involved in syndromic and non-syndromic CHD, enabling a more defined explanation of the underlying pathogenetic mechanisms. As our knowledge and technologies continue to evolve, they promise to enhance clinical outcomes and reduce the CHD burden worldwide.

Deciphering Congenital Heart Disease Using Human Induced Pluripotent Stem Cells.

Congenital heart disease (CHD) is a leading cause of birth defect-related death. Despite significant advances, the mechanisms underlying the development of CHD are complex and remain elusive due to a lack of efficient, reproducible, and translational model systems. Investigations relied on animal models have inherent limitations due to interspecies differences. Human induced pluripotent stem cells (iPSCs) have emerged as an effective platform for disease modeling. iPSCs allow for the production of a limitless supply of patient-specific somatic cells that enable advancement in cardiovascular precision medicine. Over the past decade, researchers have developed protocols to differentiate iPSCs to multiple cardiovascular lineages, as well as to enhance the maturity and functionality of these cells. With the development of physiologic three-dimensional cardiac organoids, iPSCs represent a powerful platform to mechanistically dissect CHD and serve as a foundation for future translational research.

Pediatric vascular ring outcomes for surgically repaired vs. unoperated children: a single-center experience.

Background: Vascular rings represent 1% of congenital cardiovascular abnormalities. Phenotypic expression varies from asymptomatic to severe forms related to either oesophageal or tracheal compression. While refinement in prenatal screening led to an increase in fetal diagnosis, optimal management in asymptomatic neonates and infants is currently a matter of debate. We report our center experience of vascular ring management over three decades. Methods: In this single-center retrospective study, data were extracted from patient medical records. To obtain information on symptoms/medication at follow-up, clinical records from pediatric clinics were reviewed. For patients followed in other institutions, a web-based questionnaire was sent to referring pediatricians. Results: Out of 82 patients, 69 were symptomatic (84%). Common symptoms included recurrent respiratory tract infections (43%), stridor (32%), gastro-esophageal reflux (33%), and dysphagia (26%). Diagnosis relied on cardiac ultrasound, barium swallow studies, and chest computerized tomography scan. Surgical repair (thoracotomy 91%) was performed in 79 patients (96%). Median age at repair was 13 [interquartile range (IQR), 4.4-48] months. There was no mortality. Minor complications occurred in 14 patients (18%). Median hospital length of stay was 7 (IQR, 6-9) days. In total, 24% of patients remained symptomatic (median follow-up 54 months). Half of those were asthma-related, with nearly 90% freedom from ring-related symptoms. Conclusions: Most patients were symptomatic at the time of diagnosis. Vascular rings such as pulmonary slings or tracheal compression syndromes require prompt management. Despite surgery, 24% of patients were not symptom-free at follow-up. Finally, surgery in asymptomatic patients resulted in low morbidity supporting the current recommendation of early surgical repair. Level of Evidence: III.

Incidence, Risk Factors and Outcomes of Acute Kidney Injury in Neonates Undergoing Open-heart Surgeries: Single Center Experience.

Background: Incidence and outcomes of acute kidney injury (AKI) among neonates who underwent open-heart surgery are not well highlighted in the literature. We aim to assess the incidence, risk factors, and outcome of AKI among neonates undergoing open-heart surgery. Methods: This is a retrospective cohort study between 2016 and 2021 for all neonates requiring open heart surgery. The cases were divided into 2 groups: the AKI (index) group and the non-AKI (control) group. The two groups were statistically compared for risk factors, needs for dialysis, and outcomes. Results: 100 patients fulfilled the inclusion criteria. Among them, 74 (74%) developed AKI, including 41 (55%), 15 (21%), and 18 (24%) patients in KDIGO stages 1, 2, and 3, respectively. Multivariate analysis comparing both groups demonstrated that low pre-operative creatinine (p = 0.01), prolonged bypass time (p = 0.0004) and high vasoactive inotropic score (VIS), (p = 0.0008) were risk factors for developing AKI post-operatively. Furthermore, in the AKI group, 17 (23%) neonates required renal replacement therapy in the form of peritoneal dialysis. The length of stay was higher in the AKI index group (p = 0.015). Patients who had AKI recovered their kidney function at discharge. There was no difference in mortality between both groups. Conclusion: The AKI occurred in 74% of neonates undergoing open-heart surgery, with 23% of them needing peritoneal dialysis. Low pre-operative creatinine, high VIS score, and prolonged bypass time are potential risk factors for AKI development after neonatal open-heart surgery. AKI may lead to prolonged hospitalization, though most affected patients recovered their normal kidney function at discharge.

Molecular Pathways and Animal Models of Hypoplastic Left Heart Syndrome.

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) with underdevelopment of left-sided heart structures. While previously uniformly fatal, surgical advances now provide highly effective palliation that allows most HLHS patients to survive their critical CHD. Nevertheless, there remains high morbidity and mortality with high risk of heart failure. As hemodynamic compromise from restricted aortic blood flow has been suggested to underlie the poor LV growth, this suggests the possibility of prenatal fetal intervention to recover LV growth. As such interventions have yielded ambiguous results, the optimization of therapy will require more mechanistic insights into the developmental etiology for HLHS. Clinical studies have shown high heritability for HLHS, with an oligogenic etiology indicated in conjunction with genetic heterogeneity. This is corroborated with the recent recovery of mutant mice with HLHS. With availability-induced pluripotent stem cell (iPSC)-derived cardiomyocytes from HLHS mice and patients, new insights have emerged into the cellular and molecular etiology for the LV hypoplasia in HLHS. Cell proliferation defects were observed in conjunction with metaphase arrest and the disturbance of Hippo-YAP signaling. The left-sided restriction of the ventricular hypoplasia may result from epigenetic perturbation of pathways regulating left-right patterning. These findings suggest new avenues for fetal interventions with therapies using existing drugs that target the Hippo-YAP pathway and/or modulate epigenetic regulation.

Postnatal Brain Trajectories and Maternal Intelligence Predict Childhood Outcomes in Complex CHD.

Objective: To determine whether early structural brain trajectories predict early childhood neurodevelopmental deficits in complex CHD patients and to assess relative cumulative risk profiles of clinical, genetic, and demographic risk factors across early development. Study Design: Term neonates with complex CHDs were recruited at Texas Children's Hospital from 2005-2011. Ninety-five participants underwent three structural MRI scans and three neurodevelopmental assessments. Brain region volumes and white matter tract fractional anisotropy and radial diffusivity were used to calculate trajectories: perioperative, postsurgical, and overall. Gross cognitive, language, and visuo-motor outcomes were assessed with the Bayley Scales of Infant and Toddler Development and with the Wechsler Preschool and Primary Scale of Intelligence and Beery-Buktenica Developmental Test of Visual-Motor Integration. Multi-variable models incorporated risk factors. Results: Reduced overall period volumetric trajectories predicted poor language outcomes: brainstem ((ß, 95% CI) 0.0977, 0.0382-0.1571; p = 0.0022) and white matter (0.0023, 0.0001-0.0046; p = 0.0397) at 5 years; brainstem (0.0711, 0.0157-0.1265; p = 0.0134) and deep grey matter (0.0085, 0.0011-0.0160; p = 0.0258) at 3 years. Maternal IQ was the strongest contributor to language variance, increasing from 37% at 1 year, 62% at 3 years, and 81% at 5 years. Genetic abnormality's contribution to variance decreased from 41% at 1 year to 25% at 3 years and was insignificant at 5 years. Conclusion: Reduced postnatal subcortical-cerebral white matter trajectories predicted poor early childhood neurodevelopmental outcomes, despite high contribution of maternal IQ. Maternal IQ was cumulative over time, exceeding the influence of known cardiac and genetic factors in complex CHD, underscoring the importance of heritable and parent-based environmental factors.

Continuous Electroencephalogram (cEEG) Findings and Neurodevelopmental Outcomes in Neonates with Congenital Heart Disease (CHD) at 12-24 Months of Age.

OBJECTIVE: This study aims to assess the role of continuous EEG (cEEG) background patterns and duration of cross-clamp time and cardiopulmonary bypass (CPB) in children with congenital heart disease (CHD) undergoing cardiac surgery and its correlation with abnormal neurodevelopmental outcomes at 12-24 months on Bayley Scales of Infant and Toddler Development (BSID-III). METHODS: This retrospective cohort study included infants with CHD and cEEG monitoring, who underwent surgery by 44 weeks gestational age. RESULTS: 34 patients were included, who were operated at median age - 7 days. Longer duration of cross- camp time was associated with poor language composite scores (LCS) (p value = 0.036). A significant association existed between severity of encephalopathy in 24-hour post-operative period and poor LCS (p value = 0.026). CONCLUSION: Majority of neonates with CHD have below average cognitive, language and motor composite scores on BSID-III. Longer duration of cross-clamp time and severity of encephalopathy during 24-hour post-operative EEG monitoring are associated with poor LCS.