Insights and perspectives into clinical biomarker discovery in pediatric heart failure and congenital heart disease-a narrative review.

Background and Objective: Heart failure (HF) in the pediatric population is a multi-factorial process with a wide spectrum of etiologies and clinical manifestations, that are distinct from the adult HF population, with congenital heart disease (CHD) as the most common cause. CHD has high morbidity/mortality with nearly 60% developing HF during the first 12 months of life. Hence, early discovery and diagnosis of CHD in neonates is pivotal. Plasma B-type natriuretic peptide (BNP) is an increasingly popular clinical marker in pediatric HF, however, in contrast to adult HF, it is not yet included in pediatric HF guidelines and there is no standardized reference cut-off value. We explore the current trends and prospects of biomarkers in pediatric HF, including CHD that can aid in diagnosis and management. Methods: As a narrative review, we will analyze biomarkers with respect to diagnosis and monitoring in specific anatomical types of CHD in the pediatric population considering all English PubMed publications till June 2022. Key Content and Findings: We present a concise description of our own experience in applying plasma BNP as a clinical biomarker in pediatric HF and CHD (tetralogy of fallot vs. ventricular septal defect) in the context of surgical correction, as well as untargeted metabolomics analyses. In the current age of Information Technology and large data sets we also explored new biomarker discovery using Text Mining of 33M manuscripts currently on PubMed. Conclusions: (Multi) Omics studies from patient samples as well as Data Mining can be considered for the discovery of potential pediatric HF biomarkers useful in clinical care. Future research should focus on validation and defining evidence-based value limits and reference ranges for specific indications using the most up-to-date assays in parallel to commonly used studies.

Long-Term Survival and Causes of Death in Children with Trisomy 21 After Congenital Heart Surgery.

OBJECTIVE: To evaluate long-term transplant-free survival and causes of death in the trisomy 21 (T21) population after surgery for congenital heart disease (CHD) in comparison with patients who are euploidic. STUDY DESIGN: This is a retrospective cohort study from the Pediatric Cardiac Care Consortium, enriched with prospectively collected data from the National Death Index and the Organ Procurement and Transplantation Network for patients with sufficient direct identifiers. Kaplan-Meier survival plots were generated and multivariable Cox proportional hazards models were used to examine risk factors for mortality between patients with T21 and 1:1 matched patients with comparable CHD who are euploidic. RESULTS: A long-term survival analysis was completed for 3376 patients with T21 (75 155 person-years) who met inclusion criteria. The 30-year survival rate for patients with T21 ranged from 92.1% for ventricular septal defect to 65.3% for complex common atrioventricular canal. Of these, 2185 patients with T21 were successfully matched with a patient who was euploidic. After a median follow-up of 22.86 years (IQR, 19.45-27.14 years), 213 deaths occurred in the T21 group (9.7%) compared with 123 (5.6%) in the euploidic comparators. After adjustment for age, sex, era, CHD complexity, and initial palliation, the hazard ratio of CHD-related mortality was 1.34 times higher in patients with T21 (95% CI, 0.92-1.97; P = .127). CONCLUSIONS: CHD-related mortality for patients with T21 after cardiac surgical intervention is comparable with euploidic comparators. Children with T21 require lifelong surveillance for co-occurring conditions associated with their chromosomal abnormality.

Sterility and performance of open and closed extracorporeal circuits after long-term dry-wet setups.

BACKGROUND: The timeframe for safely using previously setup dry, crystalloid, and blood-primed extracorporeal circuits has long been debated. This study was undertaken to determine a safe deviation from standardized recommendations. METHODS: Open (cardiopulmonary bypass) circuits and closed extracorporeal membrane oxygenation circuits were setup dry for up to 60 days and wet primed for up to 6 weeks with one control inoculated with Escherichia coli. Open circuits were cultured daily, closed circuits weekly. Circuits were primed with blood, albumin, heparin, NaHCO3, and CaCl2. Baseline pCO2, pO2, hemoglobin, lactate dehydrogenase, and plasma free hemoglobin were measured. Circuits were recirculated at a blood flow of 6 Liters/minute with a sweep gas of 1 Liter/minute at 100% FiO2 for 1 minute. Post oxygenator blood gases were collected at 8-, 16-, and 24-hour intervals. RESULTS: There was no observed compromise to the sterility of the circuits and no clinically significant gas exchange abnormalities observed over the duration of the study period. Statistical significance (p < 0.01) was seen in free hemoglobin and lactate dehydrogenase levels, most significant in between the 16- and 24-hour time point in the closed systems intentionally inoculated with E. coli. CONCLUSION: Open and closed circuits can be safely setup dry for up to 60 days. Open, wet-primed circuits can be used safely up to 5 days. Closed, wet-primed circuits can be used safely up to 6 weeks. Blood-primed circuits can be safely run up to 16 hours prior to patient use but should be validated in a randomized clinical study.

Postoperative and long-term outcomes in children with Trisomy 21 and single ventricle palliation.

OBJECTIVE: Patients with Trisomy 21 (T21) and single ventricle (SV) physiology present unique challenges compared to euploidic counterparts. This study reports postoperative and long-term outcomes in patients with T21 and SV palliation. DESIGN: This retrospective cohort study from the Pediatric Cardiac Care Consortium (PCCC) included patients with T21 (<21 years old) that underwent surgical palliation for SV between 1982 and 2008 and control patients without known genetic anomaly following Fontan palliation for similar diagnoses. Kaplan-Meier survival plots were created based on death events obtained from the PCCC and by linkage with the National Death Index (NDI) and the Organ Procurement and Transplantation Network (OPTN) through 2014 for patients with adequate identifiers. RESULTS: We identified 118 children with T21 who underwent initial surgical SV palliation. Among 90 (75.6%) patients surviving their first surgery, 66 (73.3%) underwent Glenn anastomosis and 25 (27.8%) completed Fontan palliation with in-hospital survival of 80.3% and 76.0%, respectively. Fifty-three patients had sufficient identifiers for PCCC-NDI-OPTN linkage. Ten-year survival, conditioned on discharge alive after the Fontan procedure, was 66.7% compared to 92.2% for 51 controls without genetic anomaly (P = .001). Median age at death for T21 patients following initial surgical SV palliation was 2.69 years (IQR 1.34-7.12) with most deaths (89.2%) attributed to the underlying congenital heart disease (CHD). CONCLUSIONS: Children with T21 and SV are at high risk for procedural and long-term mortality related to their genetic condition and underlying CHD. Nevertheless, a select group of patients can successfully complete Glenn or Fontan palliation, reaching satisfactory long-term survival.

An Unusual Cardiac Cause of Unilateral Neonatal Wheezing.

A neonate presented three days after birth with left-sided unilateral inspiratory wheezing, intermittent respiratory distress, and desaturations. She was found to have a large ductus arteriosus aneurysm that caused compression of her left mainstem bronchus and left pulmonary artery. This lesion was not identified prior to birth on routine prenatal screening, which included fetal ultrasonography. Diagnosis was made on day of life (DOL) 5 by a computed tomography with angiography scan. On DOL 7, she underwent cardiac surgery which included resection of the ductal aneurysm, patch reconstruction of the transverse aortic arch and descending aorta, patent ductus arteriosus excision, and atrial secundum septal defect repair. There were no postoperative complications, and she has been asymptomatic since.

Cloud-Based Phrase Mining and Analysis of User-Defined Phrase-Category Association in Biomedical Publications.

The rapid accumulation of biomedical textual data has far exceeded the human capacity of manual curation and analysis, necessitating novel text-mining tools to extract biological insights from large volumes of scientific reports. The Context-aware Semantic Online Analytical Processing (CaseOLAP) pipeline, developed in 2016, successfully quantifies user-defined phrase-category relationships through the analysis of textual data. CaseOLAP has many biomedical applications. We have developed a protocol for a cloud-based environment supporting the end-to-end phrase-mining and analyses platform. Our protocol includes data preprocessing (e.g., downloading, extraction, and parsing text documents), indexing and searching with Elasticsearch, creating a functional document structure called Text-Cube, and quantifying phrase-category relationships using the core CaseOLAP algorithm. Our data preprocessing generates key-value mappings for all documents involved. The preprocessed data is indexed to carry out a search of documents including entities, which further facilitates the Text-Cube creation and CaseOLAP score calculation. The obtained raw CaseOLAP scores are interpreted using a series of integrative analyses, including dimensionality reduction, clustering, temporal, and geographical analyses. Additionally, the CaseOLAP scores are used to create a graphical database, which enables semantic mapping of the documents. CaseOLAP defines phrase-category relationships in an accurate (identifies relationships), consistent (highly reproducible), and efficient manner (processes 100,000 words/sec). Following this protocol, users can access a cloud-computing environment to support their own configurations and applications of CaseOLAP. This platform offers enhanced accessibility and empowers the biomedical community with phrase-mining tools for widespread biomedical research applications.

A reference set of curated biomedical data and metadata from clinical case reports.

Clinical case reports (CCRs) provide an important means of sharing clinical experiences about atypical disease phenotypes and new therapies. However, published case reports contain largely unstructured and heterogeneous clinical data, posing a challenge to mining relevant information. Current indexing approaches generally concern document-level features and have not been specifically designed for CCRs. To address this disparity, we developed a standardized metadata template and identified text corresponding to medical concepts within 3,100 curated CCRs spanning 15 disease groups and more than 750 reports of rare diseases. We also prepared a subset of metadata on reports on selected mitochondrial diseases and assigned ICD-10 diagnostic codes to each. The resulting resource, Metadata Acquired from Clinical Case Reports (MACCRs), contains text associated with high-level clinical concepts, including demographics, disease presentation, treatments, and outcomes for each report. Our template and MACCR set render CCRs more findable, accessible, interoperable, and reusable (FAIR) while serving as valuable resources for key user groups, including researchers, physician investigators, clinicians, data scientists, and those shaping government policies for clinical trials.

Anomalous left subclavian artery from the pulmonary artery in a neonate.

The presence of an isolated left subclavian artery arising from the pulmonary artery in a patient with d-transposition of the great arteries is exceedingly rare. Prior to undertaking repair of this congenital cardiac anomaly, identification of an isolated left subclavian artery originating from the pulmonary artery is imperative in order to plan the appropriate intervention to prevent the development of subclavian artery steal or vertebrobasilar insufficiency. We describe the case of a 5 day-old girl in whom an isolated left subclavian artery arising from the pulmonary artery was detected after surgical entry for repair of transposition of the great arteries.

Healthcare Disparities in Outcomes of a Metropolitan Congenital Heart Surgery Center: The Effect of Clinical and Socioeconomic Factors.

OBJECTIVE: The purpose of this study is to identify the impact of demographic, socioeconomic, and clinical factors on congenital heart surgery outcomes. STUDY DESIGN: This retrospective cohort study included 234 congenital heart surgery patients from 2011 through 2015, in a racially/ethnically diverse metropolitan children's hospital. Outcomes included length of stay (LOS), age at first echocardiogram, length of mechanical ventilation, and incidence of complications. RESULTS: Compared to others, black children underwent their first echocardiogram at a later age (median 23 versus 2 days, p = 0.014) and were more likely to be diagnosed with congenital heart disease in the emergency room (p = 0.026). Hispanic children were more likely to have major non-cardiac congenital anomalies (p = 0.045). Increased LOS during elective admissions was associated with higher surgical complexity (STAT category 4 and 5 Estimate 3.905 days, p = 0.001), compared to STAT category 1, and number of complications (Estimate = 2.306 days per complication, p < 0.001). Increased LOS in non-elective admissions was associated with the number of complex chronic conditions (Estimate = 15.446 days, p = 0.045) and the number of complications (Estimate = 11.591 days per complication, p < 0.001). However, in multivariate analysis, race and ethnicity was not associated with increased LOS or age at first echocardiogram. CONCLUSION: In this diverse setting, race/ethnicity was not associated with increased LOS, age at first echocardiogram, length of ventilation, or complications. Surgical complexity, chronic conditions, and complications were associated with increased LOS. We discuss some interventions to reduce disparities in congenital heart surgery outcomes.

Long-Term Outcomes of Children With Trisomy 13 and 18 After Congenital Heart Disease Interventions.

BACKGROUND: The purpose of this study is to report short- and long-term outcomes after congenital heart defect (CHD) interventions in patients with trisomy 13 or 18. METHODS: A retrospective review of the Pediatric Cardiac Care Consortium (PCCC) identified children with trisomy 13 or 18 with interventions for CHD between 1982 and 2008. Long-term survival and cause of death were obtained through linkage with the National Death Index. RESULTS: A total of 50 patients with trisomy 13 and 121 patients with trisomy 18 were enrolled in PCCC between 1982 and 2008; among them 29 patients with trisomy 13 and 69 patients with trisomy 18 underwent intervention for CHD. In-hospital mortality rates for patients with trisomy 13 or trisomy 18 were 27.6% and 13%, respectively. Causes of in-hospital death were primarily cardiac (64.7%) or multiple organ system failure (17.6%). National Death Index linkage confirmed 23 deaths after discharge. Median survival (conditioned to hospital discharge) was 14.8 years (95% confidence interval [CI]: 12.3 to 25.6 years) for patients with trisomy 13 and 16.2 years (95% CI: 12 to 20.4 years) for patients with trisomy 18. Causes of late death included cardiac (43.5%), respiratory (26.1%), and pulmonary hypertension (13%). CONCLUSIONS: In-hospital mortality rate for all surgical risk categories was higher in patients with trisomy 13 or 18 than that reported for the general population. However, patients with trisomy 13 or 18, who were selected as acceptable candidates for cardiac intervention and who survived CHD intervention, demonstrated longer survival than previously reported. These findings can be used to counsel families and make program-level decisions on offering intervention to carefully selected patients.

Current trends in racial, ethnic, and healthcare disparities associated with pediatric cardiac surgery outcomes.

OBJECTIVE: Despite overall improvements in congenital heart disease outcomes, racial and ethnic disparities have continued. The purpose of this study is to examine the effect of race and ethnicity, as well as other risk factors on congenital heart surgery length of stay and in-hospital mortality. DESIGN: From the 2012 Healthcare Cost and Utilization Project Kids Inpatient Database (KID), we identified 13 130 records with Risk Adjustment in Congenital Heart Surgery complexity score-eligible procedures. Multivariate logistic and linear regression modeling with survey weights, stratification and clustering was used to examine the relationships between predictor variables and length of stay as well as in-hospital mortality. RESULTS: No significant mortality differences were found among all race and ethnicity groups across each age group. Black neonates and black infants had a longer length of stay (neonatal estimate = 8.73 days, P = .0034; infant estimate 1.10 days, P = .0253), relative to whites. Government-sponsored insurance was associated with increased odds of neonatal mortality (odds ratio = 1.51, P = .0055), increased length of stay in neonates (estimate = 4.26 days, P = .0009) and infants (estimate = 1.52 days, P = .0181), relative to private insurance. Government-sponsored insurance was associated with increased number of chronic conditions, which were also associated with increased LOS (estimate 8.39 days, P < .001 in neonates; estimate 3.60 days, P < .001 in infants; estimate 1.87 days, P < .001 children). CONCLUSIONS: Racial/ethnic disparities in congenital heart surgical outcomes may be changing compared with previous studies using the KID database. Increased length of stay in children with government-sponsored insurance may reflect expansion of individual states government-sponsored insurance eligibility criteria for children with complex chronic medical conditions. These findings warrant cautious optimism regarding racial and ethnic disparities in congenital heart surgery outcomes.

Double-chambered right ventricle with cough, endocarditis, and lung mass.

Pulmonary valve endocarditis is an uncommon complication of a double-chambered right ventricle. A persistent cough is an atypical presentation for a double-chambered right ventricle, and in this patient it was the result of pulmonary valve bacterial endocarditis with eventual bacterial vegetation embolization to the lung. Our patient underwent surgical repair of all cardiac defects, which resulted in the resolution of all of her symptoms.

Treatment of right ventricle to coronary artery connections in infants with pulmonary atresia and intact ventricular septum.

OBJECTIVE: At the severe end of the spectrum of infants with pulmonary atresia and intact ventricular septum, the likelihood of significant right ventricle to coronary artery connections increases. Our purpose is to present the first series of right ventricle to coronary artery connections ligated off bypass before right ventricular decompression and to evaluate the consequences of this approach. METHODS: From 1988 to 2007, 19 patients with pulmonary atresia and intact ventricular septum had a total of 69 right ventricle to coronary artery connections identified preoperatively, and 10 more were located intraoperatively. Of these, 71 were judged large enough to warrant off-pump direct ligation. Preoperative diagnosis was by transthoracic echocardiography and angiography. Transesophageal and surface echocardiography were used for intraoperative location. Direct visualization and echocardiographic assessment for regional wall motion abnormalities determined the effects of ligation. Right ventricular decompression was done in all patients. RESULTS: After ligation, coronary flow converted from moderately or largely retrograde to antegrade perfusion. Ligation produced no visual myocardial consequences or immediate local wall motion abnormalities. For 3 patients, however, apical-septal wall motion abnormalities appeared from 2 hours to 3 days postoperatively. Serial studies were done to assess the later effects in the 16 of 19 30-day survivors. No evidence for myocardial injury was found, and all continued on a 2-ventricle repair course. CONCLUSION: The location and ligation of right ventricle to coronary artery connections can be reliably accomplished off bypass. Coronary flow became antegrade, improving myocardial oxygenation. No myocardial damage was observed. Inapparent right ventricle to coronary artery connections occasionally enlarge secondarily after right ventricular decompression, making early follow-up evaluation necessary after ligation. Despite the initial presence of significant right ventricle to coronary artery connections, 2-ventricle repairs are possible with long-term benefits.

Transesophageal echocardiography guidance for repair of complex cardiac injuries.

Our patient suffered a single stab wound to the heart that resulted in a coronary artery to ventricle fistula, a ventricular septal defect, mitral regurgitation from chordal transection, and a delayed left ventricular aneurysm. We used transesophageal echocardiography to characterize these multiple defects to help guide successful surgical repair. The patient recovered uneventfully.

Fontan procedure: old lessons and new frontiers.

The Fontan procedure is an operation created for patients with single ventricular physiology. These patients have the potential to survive well into adulthood, however new problems can arise. Various topics, including physiological constraints, patient care, morbidity and clinical outcomes are discussed. The aim of this review is to identify current topics within the care of the Fontan patient population for the physician not comfortable with their unique physiology and complications.