Neurodevelopmental outcomes in congenital heart disease: Usefulness of biomarkers of brain injury.

INTRODUCTION: At present, neurodevelopmental abnormalities are the most frequent type of complication in school-aged children with congenital heart disease (CHD). We analysed the incidence of acute neurologic events (ANEs) in patients with operated CHD and the usefulness of neuromarkers for the prediction of neurodevelopment outcomes. METHODS: Prospective observational study in infants with a prenatal diagnosis of CHD who underwent cardiac surgery in the first year of life. We assessed the following variables: (1) serum biomarkers of brain injury (S100B, neuron-specific enolase) in cord blood and preoperative blood samples; (2) clinical and laboratory data from the immediate postnatal and perioperative periods; (3) treatments and complications; (4) neurodevelopment (Bayley-III scale) at age 2 years. RESULTS: the study included 84 infants with a prenatal diagnosis of CHD who underwent cardiac surgery in the first year of life. Seventeen had univentricular heart, 20 left ventricular outflow obstruction and 10 genetic syndromes. The postoperative mortality was 5.9% (5/84) and 10.7% (9/84) patients experienced ANEs. The mean overall Bayley-III scores were within the normal range, but 31% of patients had abnormal scores in the cognitive, motor or language domains. Patients with genetic syndromes, ANEs and univentricular heart had poorer neurodevelopmental outcomes. Elevation of S100B in the immediate postoperative period was associated with poorer scores. CONCLUSIONS: children with a history of cardiac surgery for CHD in the first year of life are at risk of adverse neurodevelopmental outcomes. Patients with genetic syndromes, ANEs or univentricular heart had poorer outcomes. Postoperative ANEs may contribute to poorer outcomes. Elevation of S100B levels in the postoperative period was associated with poorer neurodevelopmental outcomes at 2 years. Studies with larger samples and longer follow-ups are needed to define the role of these biomarkers of brain injury in the prediction of neurodevelopmental outcomes in patients who undergo surgery for management of CHD.

Pediatric Animal Model of Extracorporeal Cardiopulmonary Resuscitation after Prolonged Circulatory Arrest.

Congenital heart disease (CHD) is the most prevalent congenital malformation, with about one million births impacted worldwide per year. Comprehensive investigation of this disease requires appropriate and validated animal models. Piglets are commonly used for translational research due to their analogous anatomy and physiology. This work aimed to describe and validate a neonatal piglet model of cardiopulmonary bypass (CPB) with circulatory and cardiac arrest (CA) as a tool for studying severe brain damage and other complications of cardiac surgery. In addition to including a list of materials, this work provides a roadmap for other investigators to plan and execute this protocol. After experienced practitioners performed several trials, the representative results of the model demonstrated a 92% success rate, with failures attributed to small piglet size and variant vessel anatomy. Furthermore, the model allowed practitioners to select from a wide variety of experimental conditions, including varying times in CA, temperature alterations, and pharmacologic interventions. In summary, this method uses materials readily available in most hospital settings, is reliable and reproducible, and can be widely employed to enhance translational research in children undergoing heart surgery.

Cord blood cardiovascular biomarkers in tetralogy of fallot and D-transposition of great arteries.

Previous reports suggest that cord blood biomarkers could serve as a prognostic tool for conotruncal congenital heart defects (CHD). We aimed to describe the cord blood profile of different cardiovascular biomarkers in a prospective series of fetuses with tetralogy of Fallot (ToF) and D-transposition of great arteries (D-TGA) and to explore their correlation with fetal echocardiography and perinatal outcome. Methods: A prospective cohort study (2014-2019), including fetuses with isolated ToF and D-TGA and healthy controls, was conducted at two tertiary referral centers for CHD in Barcelona. Obstetric ultrasound and fetal echocardiography were performed in the third trimester and cord blood was obtained at delivery. Cord blood concentrations of N-terminal precursor of B-type natriuretic peptide, Troponin I, transforming growth factorß (TGFß), placental growth factor, and soluble fms-like tyrosine kinase-1 were determined. Results: Thirty-four fetuses with conotruncal-CHD (22 ToF and 12 D-TGA) and 36 controls were included. ToF-fetuses showed markedly increased cord blood TGFß (24.9 ng/ml (15.6-45.3) vs. normal heart 15.7 ng/ml (7.2-24.3) vs. D-TGA 12.6 ng/ml (8.7-37.9); P = 0.012). These results remained statistically significant even after adjusting for maternal body mass index, birth weight and mode of delivery. TGFß levels showed a negative correlation with the pulmonary valve diameter z-score at fetal echocardiography (r = -0.576, P = 0.039). No other differences were found in the rest of cord blood biomarkers among the study populations. Likewise, no other significant correlations were identified between cardiovascular biomarkers, fetal echocardiography and perinatal outcome. Conclusions: This study newly describes increased cord blood TGFß concentrations in ToF compared to D-TGA and normal fetuses. We also demonstrate that TGFß levels correlate with the severity of right ventricle outflow obstruction. These novel findings open a window of research opportunities on new prognostic and potential preventive strategies.

Acute myocarditis with transient myocardial thickening in two oncologic patients treated with anti-GD2 immunotherapy.

Immunotherapy has considerably improved clinical outcomes in different types of cancers but has also been associated with the development of myocarditis, especially with that mediated by immune checkpoint inhibitors. To the best of our knowledge, these are the first cases of myocarditis after anti-GD2 immunotherapy reported to date. We present two cases of paediatric patients who, after anti-GD2 infusion, presented severe myocarditis with myocardial hypertrophy detected on echocardiography and confirmed with cardiac magnetic resonance imaging. An increase in myocardial T1 and extracellular volume of up to 30% was observed with heterogeneous intramyocardial late enhancement. Myocarditis after anti-GD2 immunotherapy may be more common than appreciated, occurs early after starting treatment, has a malignant course, and responds to higher steroid doses.

Mid-aortic Syndrome in a Pediatric Cohort.

Mid-aortic syndrome (MAS) is an uncommon condition characterized by severe narrowing of the abdominal aorta, usually involving visceral and renal arteries. Most patients are asymptomatic and typically present with incidental hypertension which might evolve into end-organ damage if untreated. Our aim was to review 8 new pediatric MAS cases. A retrospective observational study of all pediatric patients with MAS diagnosis (April 1992-November 2021) was conducted. Patients underwent systematic evaluation (medical and family history; 12-lead electrocardiogram; echocardiogram; angiography and/or computed tomography or magnetic resonance angiography). 8 pediatric patients with MAS were included. Median age at diagnosis was 2.6 [0.2-4.7] years; median follow-up time was 8.6 [6.6-10.0] years. 6/8 patients presented with incidental hypertension, 1/8 with heart murmur, and 1/8 with heart failure symptoms. All patients were on antihypertensive treatment. 1/8 patients underwent surgery and 7/8 an endovascular treatment. At the end of the study period, among the 6 patients that underwent a successful endovascular procedure, 2 achieved good blood pressure (BP) control, 2 acceptable BP control, 1 stage 1 hypertension and, another, stage 2 hypertension. There was 1 death during follow-up. BP monitoring in pediatric patients is crucial for early recognition of MAS. Treatment should be based on the individual clinical characteristics of patients with careful planning of surgical revascularisation, if possible, after adult growth is completed. Our study demonstrates that endovascular treatment might be a good alternative to surgery. Nevertheless, further trials with larger sample size and longer-term follow-up are required to determine the best treatment approach.

Massive Dilatation of the Ascending Aorta in a Patient With Generalized Arterial Calcification of Infancy.

We report a case of massive ascending aortic dilatation in a patient with generalized arterial calcification of infancy (GACI). He was found to carry compound heterozygous mutations in ABCC6 gene, previously associated with pseudoxanthoma elasticum, although recently linked to GACI. Our case confirms previous reports of a genotypic overlap between both entities.

Cardiac function in bronchiolitis: Not only a right ventricle matter.

OBJECTIVES: Extrapulmonary manifestations of bronchiolitis have been previously studied, with some identifying right ventricle (RV) diastolic/systolic dysfunction. We hypothesized that severe cases of bronchiolitis would have cardiac dysfunction resulting an increase in N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP) values and worse outcomes. Therefore, the objective was to evaluate the existence of cardiac dysfunction and to determine its association with severe bronchiolitis. METHODS: This prospective cohort study included children hospitalized for bronchiolitis under 1-year old between January 2019 and March 2020. At admission, an echocardiography was performed and plasma levels of NT-proBNP were measured. To analyze outcomes, the cohort was divided into two groups based on the need for positive pressure respiratory support (PPRS), and both were compared to healthy infants. STATISTICS: bivariant analysis, significant differences p < 0.05. RESULTS: One hundred eighty-one patients were included; median age was 2 months. Seventy-three patients required PPRS. Compared to controls, patients requiring PPRS showed worse RV systolic function, with lower tricuspid annular-plane systolic excursion (p = 0.002) and parameters of worse right and left diastolic function (trans-tricuspid E and A wave [p = 0.004 and p = 0.04, respectively] and tricuspid tissue doppler imaging [TDI] e' [p = 0.003], trans-mitral E and mitral TDI a' [p = 0.02 and p = 0.005, respectively]). An NT-ProBNP greater than 3582 pg/dl predicts the need for longer necessity of PPRS in patients younger than 2 months. CONCLUSIONS: In addition to the expected RV systolic dysfunction, patients with severe bronchiolitis have parameters of global diastolic worse function possibly secondary to intrinsic myocardial involvement. NT-ProBNP values at admission had strong discriminatory power to predict worse outcomes.

Echocardiographic Markers of Mild Pulmonary Hypertension are not Correlated with Worse Respiratory Outcomes in Infants with Bronchiolitis.

Pulmonary hypertension has been reported as a crucial factor in the pathophysiology of severe bronchiolitis. The aim of this study was to evaluate pulmonary artery pressure (PAP) in patients with bronchiolitis and to analyze their correlation with clinical outcomes. This prospective cohort study examined children admitted for bronchiolitis. PAP was assessed by right ventricle (RV) acceleration/ejection time ratio (AT/ET), isovolumic relaxation time, eccentricity index, and the presence of a pulmonary systolic notch. Pulmonary hypertension (PH) was considered if at least two altered parameters were present. Severity of clinical course was established by higher N-terminal (NT)-prohormone BNP (NT-proBNP) values, the need for positive pressure respiratory support (PPRS), and the duration of hospital admission. One hundred sixty-nine children were included in analysis. Sixty-eight patients (40%) required PPRS, and those patients had increased NT-proBNP values and worse tricuspid annular systolic excursion (TAPSE) compared to mild cases (p < 0.001and p < 0.001, respectively). Twenty-two (13%) cases had at least two altered parameters of PAP and met criteria for presumed PH, with no differences in NT-proBNP values, TAPSE, need for PPRS or hospital length of stay compared to normal PAP group (p = 0.98, p = 0.07, p = 0.94 and p = 0.64, respectively). We found no correlation between altered RV AT/ET and worse cardiac function, NT-proBNP values or hospital length of stay. In our cohort, the presence of echocardiographic findings of PH were not associated with worse clinical outcomes. Patients with severe bronchiolitis had higher values ​​of NT-proBNP but, interestingly, no clear association with PH.

Machine Learning-Based Systems for the Anticipation of Adverse Events After Pediatric Cardiac Surgery.

Pediatric congenital heart disease (CHD) patients are at higher risk of postoperative complications and clinical deterioration either due to their underlying pathology or due to the cardiac surgery, contributing significantly to mortality, morbidity, hospital and family costs, and poor quality of life. In current clinical practice, clinical deterioration is detected, in most of the cases, when it has already occurred. Several early warning scores (EWS) have been proposed to assess children at risk of clinical deterioration using vital signs and risk indicators, in order to intervene in a timely manner to reduce the impact of deterioration and risk of death among children. However, EWS are based on measurements performed at a single time point without incorporating trends nor providing information about patient's risk trajectory. Moreover, some of these measurements rely on subjective assessment making them susceptible to different interpretations. All these limitations could explain why the implementation of EWS in high-resource settings failed to show a significant decrease in hospital mortality. By means of machine learning (ML) based algorithms we could integrate heterogeneous and complex data to predict patient's risk of deterioration. In this perspective article, we provide a brief overview of the potential of ML technologies to improve the identification of pediatric CHD patients at high-risk for clinical deterioration after cardiac surgery, and present the CORTEX traffic light, a ML-based predictive system that Sant Joan de Déu Barcelona Children's Hospital is implementing, as an illustration of the application of an ML-based risk stratification system in a relevant hospital setting.

Ausencia parcial de pericardio: ¿únicamente un hallazgo incidental? / Partial absence of the pericardium: Only an incidental finding?

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Oxidative Stress and Indicators of Brain Damage Following Pediatric Heart Surgery.

Pediatric cardiac surgery induces an increased oxidative stress (OS) response. Increased OS is associated with poor neurologic outcomes in neonatal populations with similar patterns of brain injury. We investigated OS and brain injury in infants undergoing heart surgery. Patients 6 months or younger, undergoing cardiac surgery with or without cardiopulmonary bypass (CPB), were included in this prospective, observational study. Patients were divided into infant (30 days−6 months) and neonatal (<30 days) groups for analysis. Urine OS biomarker 8-iso-prostaglandin F2α (8-iso-PGF2α) was quantified pre-surgery and at 0 and 24 h post-surgery. A serum brain damage biomarker S100B protein was also measured pre-surgery and at 0 and 72 h post-surgery. Amplitude-integrated electroencephalography during surgery was analyzed. Neuropsychological evaluation using the Bayley III or Vineland test was performed in all patients at 24 months of age. Sixty-two patients were included, 44 of whom underwent follow-up neurologic evaluation. 8-iso-PGF2α and S100B levels were increased after surgery. Postoperative levels of S100B were positively correlated with 8-iso-PGF2α levels 24 h after surgery (rho = 0.5224; p = 0.0261). There was also a correlation between immediate post-surgery levels of 8-iso-PGF2α and intra-surgery seizure burden (rho = 0.4285, p = 0.0205). Patients with an abnormal neurological evaluation had increased levels of S100B 72 h after surgery (p = 0.048). 8-iso-PGF2α levels 24 h after surgery were also related to abnormal neurologic outcomes. Levels of 8-iso-PGF2α following pediatric cardiac surgery are associated with several indicators of brain injury including brain damage biomarkers, intra-operative seizures, and abnormal neurological evaluation at follow-up, suggesting the importance of oxidative stress response in the origin of brain damage in this population.

S100B Maternal Blood Levels in Gestational Diabetes Mellitus Are Birthweight, Gender and Delivery Mode Dependent.

Gestational Diabetes Mellitus (GDM) is one of the main causes of perinatal mortality/morbidity. Today, a parameter offering useful information on fetal central nervous system (CNS) development/damage is eagerly awaited. We investigated the role of brain-protein S100B in the maternal blood of GDM pregnancies by means of a prospective case-control study in 646 pregnancies (GDM: n = 106; controls: n = 530). Maternal blood samples for S100B measurement were collected at four monitoring time-points from 24 weeks of gestation to term. Data was corrected for gender and delivery mode and correlated with gestational age and weight at birth. Results showed higher (p < 0.05) S100B from 24 to 32 weeks and at term in GDM fetuses than controls. Higher (p < 0.05) S100B was observed in GDM male new-borns than in females from 24 to 32 weeks and at term, in GDM cases delivering vaginally than by caesarean section. Finally, S100B positively correlated with gestational age and weight at birth (R = 0.27; R = 0.37, respectively; p < 0.01). The present findings show the usefulness of S100B in CNS to monitor high-risk pregnancies during perinatal standard-of-care procedures. The results suggest that further investigations into its potential role as an early marker of CNS growth/damage in GDM population are needed.

Brain Oxygen Perfusion and Oxidative Stress Biomarkers in Fetuses with Congenital Heart Disease-A Retrospective, Case-Control Pilot Study.

Fetuses with congenital heart disease (CHD) have circulatory changes that may lead to predictable blood flow disturbances that may affect normal brain development. Hypoxemia and hypoperfusion may alter the redox balance leading to oxidative stress (OS), that can be assessed measuring stable end-products. OS biomarkers (OSB) were measured in amniotic fluid in fetuses with (n = 41) and without CHD (n = 44) and analyzed according to aortic flow, expected cyanosis after birth, and a CHD classification derived from this. Birth head circumference (HC) was used as a neurodevelopment biomarker. CHD fetuses had higher levels of ortho-Tyrosine (o-Tyr) than controls (p = 0.0003). There were no differences in o-Tyr levels considering aortic flow obstruction (p = 0.617). Fetuses with expected extreme cyanosis presented the highest levels of o-Tyr (p = 0.003). Among groups of CHD, fetuses without aortic obstruction and extreme cyanosis had the highest levels of o-Tyr (p = 0.005). CHD patients had lower HC than controls (p = 0.023), without correlation with OSB. Patients with HC < 10th percentile, presented high levels of o-Tyr (p = 0.024). Fetuses with CHD showed increased OSB and lower HC when compared to controls, especially those with expected extreme cyanosis. Our results suggest that increased levels of OSB are more influenced by the effect of low oxygenation than by aortic flow obstruction. Future studies with larger sample size are needed to further investigate the role of OSB as an early predictor of neurodevelopmental problems in CHD survivors.

Functional and morphometric changes in children after neonatal arterial switch operation for transposition of the great arteries.

Background: The increase in the survival of patients with D-Transposition of the great arteries (TGA) after arterial switch operation (ASO) has now turned our focus to the evaluation of mid and long-term outcomes. Although most patients are followed by conventional echocardiography, the study of cardiac functionality and morphometric parameters in children with TGA after ASO is scarce. The present study aims to describe the functional and morphometric echocardiographic changes in children after ASO. Methods: We performed an observational study in patients aged 1-5 years with TGA who underwent neonatal ASO. Morphometric and functional echocardiographic parameters were analyzed in 21 patients and compared with 52 age-matched healthy controls. Results: We found morphological and functional changes, especially in the right ventricle, which is more globular (right ventricle [RV] basal sphericity index 1.5 vs. 1.8, P = 0.016), and with a decreased systolic function compared to healthy controls (fractional area change 51 vs. 58%, P = 0.006; tricuspid annular plane systolic excursion 13 vs. 20 mm, P = 0.001; s' 7 vs. 12 cm/s, P = 0.001). In the speckle-tracking strain imaging, there was a decrease in the longitudinal deformation of the apical septal myocardium (-23% vs. -27%; P = 0.005). Preoperative systemic overload to the right ventricle could be an important factor in the origin of these changes. Conclusions: In patients with TGA after ASO, there are morphometric and functional echocardiographic changes, such as globular form and decreased function, especially in the RV; the effect of these changes on long-term outcomes would require prospective follow-up studies.

Neonatal Rupture of the Tricuspid Valve and Maternal Lupus: Is There a Correlation?

Valve dysfunction is not widely recognized as a feature in newborns born to mothers with positive anti-Ro/SSA antibodies, and only scarce reports have suggested an association between rupture of the atrioventricular valve tensor apparatus and these maternal antibodies. We report the follow-up from fetal life to the time of postnatal surgery of a patient with severe tricuspid regurgitation due to a flail of the anterior tricuspid valve leaflet who was born to an anti-Ro/SSA antibodies positive mother.