Altered contractility, Ca2+ transients, and cell morphology seen in a patient-specific iPSC-CM model of Ebstein's anomaly with left ventricular noncompaction.

Patients with two congenital heart diseases (CHDs), Ebstein's anomaly (EA) and left ventricular noncompaction (LVNC), suffer higher morbidity than either CHD alone. The genetic etiology and pathogenesis of combined EA/LVNC remain largely unknown. We investigated a familial EA/LVNC case associated with a variant (p.R237C) in the gene encoding Kelch-like protein 26 (KLHL26) by differentiating induced pluripotent stem cells (iPSCs) generated from affected and unaffected family members into cardiomyocytes (iPSC-CMs) and assessing iPSC-CM morphology, function, gene expression, and protein abundance. Compared with unaffected iPSC-CMs, CMs containing the KLHL26 (p.R237C) variant exhibited aberrant morphology including distended endo(sarco)plasmic reticulum (ER/SR) and dysmorphic mitochondria and aberrant function that included decreased contractions per minute, altered calcium transients, and increased proliferation. Pathway enrichment analyses based on RNASeq data indicated that the "structural constituent of muscle" pathway was suppressed, whereas the "ER lumen" pathway was activated. Taken together, these findings suggest that iPSC-CMs containing this KLHL26 (p.R237C) variant develop dysregulated ER/SR, calcium signaling, contractility, and proliferation.NEW & NOTEWORTHY We demonstrate here that iPSCs derived from patients with Ebstein's anomaly and left ventricular noncompaction, when differentiated into cardiomyocytes, display significant structural and functional changes that offer insight into disease pathogenesis, including altered ER/SR and mitochondrial morphology, contractility, and calcium signaling.

The Relationship Between Placental Pathology and Neurodevelopmental Outcomes in Complex Congenital Heart Disease.

Complex congenital heart disease (CCHD) is associated with impaired neurodevelopmental outcomes. Peri- and post-operative factors are known contributors while the impact of the prenatal environment is not yet delineated. Variations in fetal circulation, seen in transposition of the great arteries (TGA) and single ventricular physiology (SVP), are associated with placenta abnormalities. These abnormalities may be associated with placental insufficiency, a risk factor for poor neurodevelopmental outcomes. We hypothesized there is a correlation between placental pathology and impaired neurodevelopmental outcomes in patients with CCHD. We performed a single center retrospective cohort study with patients with TGA and SVP from 2010 to 2017 at Children's Wisconsin. Patient variables were obtained from the medical record. Bayley Scales of Infant Development Third Edition standard scores for cognitive, motor, and language performance were collected from neurodevelopmental visits. Placenta pathology reports were reviewed with tabulation of predetermined anatomical and pathological characteristics. We identified 79 patients in our cohort and 61 (77.2%) had abnormal placentas. There was no significant difference between the two groups in any demographic or clinical variables. For cognitive and motor performance, without adjusting for the covariates, infants with placental abnormalities had significantly lower scores compared to infants without (p = 0.026, p = 0.045 respectively). Conversely, there was no significant difference in language scores between the two groups (p = 0.12). Placenta abnormalities are common in patients with CCHD, and placenta abnormalities are associated with impaired neurodevelopmental outcomes. These results underscore the complex causal pathways of neurodevelopmental impairment in infants with CCHD and offer opportunities for targeted postnatal developmental interventions after discharge.

Intranasal dexmedetomidine for transthoracic echocardiography in infants with shunt-dependent single ventricle heart disease.

OBJECTIVES: We investigated the efficacy and complication profile of intranasal dexmedetomidine for transthoracic echocardiography sedation in patients with single ventricle physiology and shunt-dependent pulmonary blood flow during the high-risk interstage period. METHODS: A single-centre, retrospective review identified interstage infants who received dexmedetomidine for echocardiography sedation. Baseline and procedural vitals were reported. Significant adverse events related to sedation were defined as an escalation in care or need for any additional/increased inotropic support to maintain pre-procedural haemodynamics. Minor adverse events were defined as changes from baseline haemodynamics that resolved without intervention. To assess whether sedation was adequate, echocardiogram reports were reviewed for completeness. RESULTS: From September to December 2020, five interstage patients (age 29-69 days) were sedated with 3 mcg/kg intranasal dexmedetomidine. The median sedation onset time and duration time was 24 minutes (range 12-43 minutes) and 60 minutes (range 33-60 minutes), respectively. Sedation was deemed adequate in all patients as complete echocardiograms were accomplished without a rescue dose. When compared to baseline, three (60%) patients had a >10% reduction in heart rate, one (20%) patient had a >10% reduction in oxygen saturations, and one (20%) patient had a >30% decrease in blood pressure. Amongst all patients, no significant complications occurred and haemodynamic changes from baseline did not result in need for intervention or interruption of study. CONCLUSIONS: Intranasal dexmedetomidine may be a reasonable option for echocardiography sedation in infants with shunt-dependent single ventricle heart disease, and further investigation is warranted to ensure efficacy and safety in an outpatient setting.

The pediatric heart network's study on long-term outcomes of children with HLHS and the impact of Norwood Shunt type in the single ventricle reconstruction trial cohort (SVRIII): Design and adaptations.

BACKGROUND: The Single Ventricle Reconstruction (SVR) Trial was the first randomized clinical trial of a surgical approach for treatment of congenital heart disease. Infants with hypoplastic left heart syndrome (HLHS) and other single right ventricle (RV) anomalies were randomized to a modified Blalock Taussig Thomas shunt (mBTTS) or a right-ventricular-to-pulmonary-artery shunt (RVPAS) at the time of the Norwood procedure. The aim of the Long-term Outcomes of Children with HLHS and the Impact of Norwood Shunt Type (SVR III) study is to compare early adolescent outcomes including measures of cardiac function, transplant-free survival, and neurodevelopment, between those who received a mBTTS and those who received an RVPAS. METHODS: Transplant-free survivors of the SVR cohort were enrolled at 10 to 15 years of age for multifaceted in-person evaluation of cardiac function (cardiac magnetic resonance [CMR], echocardiogram and exercise test) and neurodevelopmental evaluation. Right ventricular ejection fraction measured by CMR served as the primary outcome. Development of arrhythmias, protein losing enteropathy, and other comorbidities were assessed through annual medical history interview. Through the course of SVR III, protocol modifications to engage SVR trial participants were designed to enhance recruitment and retention. CONCLUSIONS: Evaluation of long-term outcomes will provide important data to inform decisions about the shunt type placed at the Norwood operation and will improve the understanding of cardiovascular and neurodevelopmental outcomes for early adolescents with HLHS.

Increases in oxygen saturation following discharge from Fontan palliation - an indicator of resolution of pulmonary arteriovenous malformations?

BACKGROUND: Pulmonary arteriovenous malformations in single ventricle congenital heart disease are poorly understood. Previous studies investigating pulmonary arteriovenous malformations predominantly focus on patients with heterotaxy syndrome and interrupted inferior caval vein. It is unknown if development and resolution of pulmonary arteriovenous malformations are similar for patients with and without heterotaxy syndrome. METHODS: In this retrospective single-institution study, we identified patients with a history of single ventricle congenital heart disease and Fontan palliation. We then matched patients with heterotaxy syndrome (intact and interrupted inferior caval vein) and non-heterotaxy hypoplastic left heart syndrome. To compare development of pulmonary arteriovenous malformations, we identified the frequency of positive diagnoses pre-Fontan. To compare resolution of pulmonary arteriovenous malformations, we recorded oxygen saturation changes for 12 months following Fontan. RESULTS: A total of 124 patients were included. Patients with heterotaxy and interrupted inferior caval vein were more likely to have a pre-Fontan contrast echocardiogram performed (p < 0.01) and more likely to be diagnosed with pulmonary arteriovenous malformations pre-Fontan (p < 0.01). There was no difference in oxygen saturation prior to Fontan, yet all patient groups had increased their oxygen saturations in the first year after Fontan discharge. CONCLUSIONS: Pulmonary arteriovenous malformations are variably diagnosed prior to Fontan palliation; however, all study groups had increased oxygen saturations after Fontan discharge, potentially indicating resolution of pulmonary arteriovenous malformations in all groups. The prevalence of pulmonary arteriovenous malformations pre-Fontan is likely underestimated. A quantitative, systematic approach to diagnosis and follow-up of pulmonary arteriovenous malformations is needed to better understand susceptibility and pathophysiology.

Echocardiographic Identification of Pulmonary Artery Flow Reversal: An Indicator of Adverse Outcomes in Single Ventricle Physiology.

Individuals with single ventricle congenital heart disease (CHD) undergo multiple staged surgical palliations. Staged single ventricle palliation with a superior cavopulmonary connection (SCPC) in infancy followed by a Fontan in early childhood relies on passive, unobstructed pulmonary blood flow and normal pulmonary vasculature. We hypothesized that patients with echocardiographic identification of retrograde flow in a branch pulmonary artery (PA) after SCPC or Fontan are at increased risk for adverse outcomes. We conducted a retrospective chart review of patients seen at Children's Wisconsin from 1999 to 2019. Inclusion criteria included a history of single ventricle congenital heart disease and surgical palliation with a superior cavopulmonary connection (SCPC). We created two cohorts based on transthoracic echocardiographic identification of branch PA flow patterns: those with color Doppler-defined pulmonary artery flow reversal (PA reversal cohort) and those with normal anterograde flow (Non-reversal cohort). We identified 21 patients in the PA reversal cohort and 539 patients in the Non-reversal cohort. The PA reversal cohort had increased hospital length of stay after SCPC palliation (p < 0.001) and decreased transplant-free survival (p = 0.032), but there was no difference in overall survival (p = 0.099). There was no difference in hospital length of stay after Fontan (p = 0.17); however, the PA reversal cohort was significantly less likely to progress to Fontan palliation during early childhood (p = 0.005). Echocardiographic color Doppler identification of branch PA flow reversal in patients with single ventricle physiology is a high-risk indicator for adverse short- and long-term outcomes.

Challenges and lessons learned from the Pediatric Heart Network Normal Echocardiogram Database study.

BACKGROUND: The Pediatric Heart Network Normal Echocardiogram Database Study had unanticipated challenges. We sought to describe these challenges and lessons learned to improve the design of future studies. METHODS: Challenges were divided into three categories: enrolment, echocardiographic imaging, and protocol violations. Memoranda, Core Lab reports, and adjudication logs were reviewed. A centre-level questionnaire provided information regarding local processes for data collection. Descriptive statistics were used, and chi-square tests determined differences in imaging quality. RESULTS: For the 19 participating centres, challenges with enrolment included variations in Institutional Review Board definitions of "retrospective" eligibility, overestimation of non-White participants, centre categorisation of Hispanic participants that differed from National Institutes of Health definitions, and exclusion of potential participants due to missing demographic data. Institutional Review Board amendments resolved many of these challenges. There was an unanticipated burden imposed on centres due to high numbers of echocardiograms that were reviewed but failed to meet submission criteria. Additionally, image transfer software malfunctions delayed Core Lab image review and feedback. Between the early and late study periods, the proportion of unacceptable echocardiograms submitted to the Core Lab decreased (14 versus 7%, p < 0.01). Most protocol violations were from eligibility violations and inadvertent protected health information disclosure (overall 2.5%). Adjudication committee reviews led to protocol changes. CONCLUSIONS: Numerous challenges encountered during the Normal Echocardiogram Database Study prolonged study enrolment. The retrospective design and flaws in image transfer software were key impediments to study completion and should be considered when designing future studies collecting echocardiographic images as a primary outcome.

Fetal Cardiac Intervention for Pulmonary Atresia with Intact Ventricular Septum: International Fetal Cardiac Intervention Registry.

INTRODUCTION: Invasive fetal cardiac intervention (FCI) for pulmonary atresia with intact ventricular septum (PAIVS) and critical pulmonary stenosis (PS) has been performed with small single-institution series reporting technical and physiological success. We present the first multicenter experience. OBJECTIVES: Describe fetal and maternal characteristics of those being evaluated for FCI, including pregnancy/neonatal outcome data using the International Fetal Cardiac Intervention Registry (IFCIR). METHODS: We queried the IFCIR for PAIVS/PS cases evaluated from January 2001 to April 2018 and reviewed maternal/fetal characteristics, procedural details, pregnancy and neonatal outcomes. Data were analyzed using standard descriptive statistics. RESULTS: Of the 84 maternal/fetal dyads in the registry, 58 underwent pulmonary valvuloplasty at a median gestational age of 26.1 (21.9-31.0) weeks. Characteristics of fetuses undergoing FCI varied in terms of tricuspid valve (TV) size, TV regurgitation, and pulmonary valve patency. There were fetal complications in 55% of cases, including 7 deaths and 2 delayed fetal losses. Among those who underwent successful FCI, the absolute measurement of the TV increased by 0.32 (±0.17) mm/week from intervention to birth. Among 60 liveborn with known outcome, there was a higher percentage having a biventricular circulation following successful FCI (87 vs. 43%). CONCLUSIONS: Our data suggest a possible benefit to fetal therapy for PAIVS/PS, though rates of technically unsuccessful procedures and procedure-related complications, including fetal loss were substantial. FCI criteria are extremely variable, making direct comparison to nonintervention patients challenging and potentially biased. More uniform FCI criteria for fetuses with PAIVS/PS are needed to avoid unnecessary procedures, expose only fetuses most likely to sustain a benefit, and to enable comparisons to be made with nonintervention patients.

Comparison of echocardiographic measurements to invasive measurements of diastolic function in infants with single ventricle physiology: a report from the Pediatric Heart Network Infant Single Ventricle Trial.

BACKGROUND: While echocardiographic parameters are used to quantify ventricular function in infants with single ventricle physiology, there are few data comparing these to invasive measurements. This study correlates echocardiographic measures of diastolic function with ventricular end-diastolic pressure in infants with single ventricle physiology prior to superior cavopulmonary anastomosis. METHODS: Data from 173 patients enrolled in the Pediatric Heart Network Infant Single Ventricle enalapril trial were analysed. Those with mixed ventricular types (n = 17) and one outlier (end-diastolic pressure = 32 mmHg) were excluded from the analysis, leaving a total sample size of 155 patients. Echocardiographic measurements were correlated to end-diastolic pressure using Spearman's test. RESULTS: Median age at echocardiogram was 4.6 (range 2.5-7.4) months. Median ventricular end-diastolic pressure was 7 (range 3-19) mmHg. Median time difference between the echocardiogram and catheterisation was 0 days (range -35 to 59 days). Examining the entire cohort of 155 patients, no echocardiographic diastolic function variable correlated with ventricular end-diastolic pressure. When the analysis was limited to the 86 patients who had similar sedation for both studies, the systolic:diastolic duration ratio had a significant but weak negative correlation with end-diastolic pressure (r = -0.3, p = 0.004). The remaining echocardiographic variables did not correlate with ventricular end-diastolic pressure. CONCLUSION: In this cohort of infants with single ventricle physiology prior to superior cavopulmonary anastomosis, most conventional echocardiographic measures of diastolic function did not correlate with ventricular end-diastolic pressure at cardiac catheterisation. These limitations should be factored into the interpretation of quantitative echo data in this patient population.

Preschool Neurodevelopmental Outcomes in Children with Congenital Heart Disease.

OBJECTIVE: To describe preschool neurodevelopmental outcomes of children with complex congenital heart disease (CHD), who were evaluated as part of a longitudinal cardiac neurodevelopmental follow-up program, as recommended by the American Heart Association and the American Academy of Pediatrics, and identify predictors of neurodevelopmental outcomes in these children. STUDY DESIGN: Children with CHD meeting the American Heart Association/American Academy of Pediatrics high-risk criteria for neurodevelopmental delay were evaluated at 4-5 years of age. Testing included standardized neuropsychological measures. Parents completed measures of child functioning. Scores were compared by group (single ventricle [1V]; 2 ventricles [2V]; CHD plus known genetic condition) to test norms and classified as: normal (within 1 SD of mean); at risk (1-2 SD from mean); and impaired (>2 SD from mean). RESULTS: Data on 102 patients were analyzed. Neurodevelopmental scores did not differ based on cardiac anatomy (1V vs 2V); both groups scored lower than norms on fine motor and adaptive behavior skills, but were within 1 SD of norms. Patients with genetic conditions scored significantly worse than 1V and 2V groups and test norms on most measures. CONCLUSIONS: Children with CHD and genetic conditions are at greatest neurodevelopmental risk. Deficits in children with CHD without genetic conditions were mild and may not be detected without formal longitudinal testing. Parents and providers need additional education regarding the importance of developmental follow-up for children with CHD.

Transplacental treatment of fetal tachycardia: A systematic review and meta-analysis.

OBJECTIVE: Multiple transplacental medications can be used to treat fetal tachycardia. We sought to perform a systematic review and meta-analysis to determine whether digoxin, flecainide, or sotalol was the most efficacious therapy for converting fetal tachycardia to sinus rhythm. METHOD: We performed a systematic review and meta-analysis to compare digoxin, flecainide, or sotalol as first-line therapy for fetal tachycardia. Studies were identified by a search of PubMed (Medline), Web of Science, and Scopus. RESULTS: There were 21 studies included. Flecainide (OR: 1.4, 95% CI: 1.1-2.0, I2  = 60%, P = 0.03) and sotalol (OR:1.4, 95% CI:1.1-2.0, I2  = 30%, P = 0.02) were superior to digoxin for conversion of fetal tachycardia to sinus rhythm. In those with hydrops, the benefit over digoxin was more notable for both flecainide (OR: 5.0, 95% CI: 2.5-10.0, I2  = 0%, P < 0.001) and sotalol (OR: 2.5, 95% CI: 1.7-5.0, I2  = 0%, P < 0.001). When limited to atrioventricular reentrant tachycardia, flecainide was superior to digoxin (OR:1.7, 95% CI:1.1-3.3, I2  = 62%, P = 0.03) and sotalol (OR:1.3, 95% CI:1.1-1.7, I2  = 0%, P = 0.01). CONCLUSION: Digoxin should not be first-line therapy for fetal tachycardia, particularly in the presence of hydrops fetalis. Flecainide should be the first-line therapy of choice in atrioventricular reentrant tachycardia. Further study may identify further sub-populations responding differently.

Translating clinical trials into clinical practice: a survey assessing the potential impact of the Pediatric Heart Network Infant Single Ventricle Trial.

BACKGROUND: A few studies have evaluated the impact of clinical trial results on practice in paediatric cardiology. The Infant Single Ventricle (ISV) Trial results published in 2010 did not support routine use of the angiotensin-converting enzyme inhibitor enalapril in infants with single-ventricle physiology. We sought to assess the influence of these findings on clinical practice. METHODS: A web-based survey was distributed via e-mail to over 2000 paediatric cardiologists, intensivists, cardiothoracic surgeons, and cardiac advance practice nurses during three distribution periods. The results were analysed using McNemar's test for paired data and Fisher's exact test. RESULTS: The response rate was 31.5% (69% cardiologists and 65% with >10 years of experience). Among respondents familiar with trial results, 74% reported current practice consistent with trial findings versus 48% before trial publication (p<0.001); 19% used angiotensin-converting enzyme inhibitor in this population "almost always" versus 36% in the past (p<0.001), and 72% reported a change in management or improved confidence in treatment decisions involving this therapy based on the trial results. Respondents familiar with trial results (78%) were marginally more likely to practise consistent with the trial results than those unfamiliar (74 versus 67%, p=0.16). Among all respondents, 28% reported less frequent use of angiotensin-converting enzyme inhibitor over the last 3 years. CONCLUSIONS: Within 5 years of publication, the majority of respondents was familiar with the Infant Single Ventricle Trial results and reported less frequent use of angiotensin-converting enzyme inhibitor in single-ventricle infants; however, 28% reported not adjusting their clinical decisions based on the trial's findings.

Agenesis of the venous duct: two cases of extrahepatic drainage of the umbilical vein and extrahepatic portosystemic shunt with a review of the literature.

Agenesis of the venous duct is a rare congenital anomaly resulting in abnormal drainage of the umbilical vein into the foetal venous circulation. The clinical presentation and prognosis is variable, and may depend on the specific drainage pathways of the umbilical vein. We present two foetuses with agenesis of the venous duct, both associated with a postnatal portosystemic shunt, but with markedly different postnatal clinical courses. We also review all previously reported cases to better characterise this foetal disorder and the prognosis.

Leftward displacement of septum primum in hypoplastic left heart syndrome.

Embryologic development of atrial septum primum antedates formation of the atrioventricular and semilunar valves. Leftward displacement of the superior attachment of septum primum (LDSP) has only been described in hypoplastic left heart syndrome (HLHS). This study reports the frequency of LDSP in HLHS and correlates LDSP with other echocardiographic features of HLHS. Preoperative echocardiograms for 72 consecutive patients with classic HLHS from 1996 to 2002 at Children's Hospital of Wisconsin were reviewed. One patient was excluded for inadequate imaging. Data for the 71 patients included the following: size, location, and Doppler gradient across the atrial septal defect (ASD); location of attachment of septum primum; size and patency of the aortic valve (AoV) annulus; size and patency of the mitral valve (MV) annulus; ascending aorta diameter (AAD); and left-ventricular end diastolic dimension (LVEDD). Patients were categorized into three groups: aortic atresia/mitral atresia (AA/MA), aortic atresia/mitral stenosis (AA/MS), and aortic stenosis/mitral stenosis (AS/MS). LDSP was seen in 46 of 71 patients (64 %). By diagnostic group, 32 of 35 patients with AA/MA had LDSP (91 %) compared with 10 of 19 AA/MS patients (53 %) and 4 of 17 AS/MS patients (24 %), p < 0.05. AoV patency was seen in 4 of 46 (9 %) patients with LDSP compared with 13 of 25 (52 %) patients with normal atrial attachment, p < 0.005. Mean left heart dimensions in infants with LDSP compared with normal attachment were as follows: AoV annulus 2.24 versus 3.83 mm, AAD 2.34 versus 4.1 mm, MV annulus 3.21 versus 6.48 mm, and LVEDD 6.38 versus 13.83 mm. By two-way analysis of variance of diagnostic category versus atrial septal attachment with interaction, MV annulus and AAD were independently predicted smaller by LDSP versus normal atrial attachment, p < 0.05. Nonsignificant factors included AoV annulus, LVEDD, ASD size, and Doppler gradient. LDSP correlates with more severe maldevelopment of the left heart in patients with HLHS. Because formation of septum primum precedes development and growth of the intracardiac valves, we speculate that LDSP may be an initiating event in the development of HLHS. In addition, prenatal identification of LDSP may help direct planning of potential in utero therapies.

Abnormal mitral valve anatomy in d-transposition of the great arteries: anatomic characterization and surgical outcomes.

Mitral valve anomalies can occur with S,D,D-transposition of the great arteries (d-TGA). Their influence on surgical technique and outcome after an arterial switch operation (ASO) has not been well described. Patients with d-TGA who underwent ASO from February 1990 to January 2011 were identified. Echocardiograms, operative reports, hospital course, and latest follow-up evaluation were reviewed. A total of 218 infants underwent ASO at a median age of 15.8 days. Survival was 95 % during a mean follow-up period of 60 months. Nine patients (4 %) were found to have similar mitral valve anomalies including anterior malalignment conoventricular septal defect, anterior displacement of the mitral valve toward the left ventricular outflow tract (LVOT), malpositioning of the posteromedial papillary muscle, unusual rotation of the mitral valve leaflets orienting the commissure toward the anterior ventricular septum, and redundant mitral valve tissue extending into the LVOT. Coarctation was more frequent in this subgroup (33 vs. 10 %; p = 0.05). Preoperative echocardiography consistently indicated suspicion of a cleft mitral valve with chordal attachments to the ventricular septum causing potential LVOT obstruction. Operative inspection did not identify a cleft or anomalous attachments in any patient, and no valvuloplasty or chordal manipulation was performed. The average hospital length of stay were similar (30.7 vs. 25.3 days; p = 0.54). One patient died late due to progressive LVOT obstruction, and one required heart transplantation. No patient had significant mitral valve regurgitation. We conclude that mitral valve anomalies associated with d-TGA are rare but present with consistent anatomic features and higher risk of coarctation. Unusual mitral valve apparatus positioning and chordal redundancy can suggest the need for valvuloplasty and chordal resection preoperatively, but this is rarely needed.

Impact of Reintervention During Stage 1 Palliation Hospitalization: A National, Multicenter Study.

BACKGROUND: Stage 1 palliation (S1P) for hypoplastic left heart syndrome remains associated with high morbidity and mortality. Previous studies on burden of reinterventions did not include patients who remain hospitalized before stage 2 palliation (S2P). This study described the rate of reintervention during S1P hospitalization and sought to determine the impact of reintervention on outcomes. METHODS: All participants enrolled in phase II of the National Pediatric Cardiology Quality Improvement Collaborative after S1P were included in this study. The primary outcome was the rate of reintervention during hospitalization after S1P and before hospital discharge or S2P. Reintervention was defined as 1 or more unplanned interventional cardiac catheterizations or surgical reoperations. RESULTS: Between March 1, 2016 and October 1, 2019, 1367 participants underwent S1P and 339 (24.8%) had a reintervention; most commonly to address the source of pulmonary blood flow. Gestational age, weight at S1P, atrioventricular septal defect, heterotaxy, preoperative pulmonary artery bands, hybrid S1P, and an additional bypass run or early extracorporeal membrane oxygenation were significantly associated with reintervention. Participants in the reintervention group experienced higher rates of nearly all postoperative complications, were less likely to be discharged before S2P (57.1% vs 86%; P < .001), and more likely to experience in-hospital mortality (17% vs 5%; P < .001). CONCLUSIONS: Unplanned reintervention during hospitalization after S1P palliation occurred in 25% of participants in a large, registry-based national cohort. Participants who underwent reintervention were more likely to remain as inpatient and were less likely to survive to S2P. Reintervention was associated with a multitude of postoperative complications that affect survival and long-term outcome.

Association of Potentially Damaging De Novo Gene Variants With Neurologic Outcomes in Congenital Heart Disease.

Importance: Neurodevelopmental disabilities are commonly associated with congenital heart disease (CHD), but medical and sociodemographic factors explain only one-third of the variance in outcomes. Objective: To examine whether potentially damaging de novo variants (dDNVs) in genes not previously linked to neurodevelopmental disability are associated with neurologic outcomes in CHD and, post hoc, whether some dDNVs or rare putative loss-of-function variants (pLOFs) in specific gene categories are associated with outcomes. Design, Setting, and Participants: This cross-sectional study was conducted from September 2017 to June 2020 in 8 US centers. Inclusion criteria were CHD, age 8 years or older, and available exome sequencing data. Individuals with pathogenic gene variants in known CHD- or neurodevelopment-related genes were excluded. Cases and controls were frequency-matched for CHD class, age group, and sex. Exposures: Heterozygous for (cases) or lacking (controls) dDNVs in genes not previously associated with neurodevelopmental disability. Participants were separately stratified as heterozygous or not heterozygous for dDNVs and/or pLOFs in 4 gene categories: chromatin modifying, constrained, high level of brain expression, and neurodevelopmental risk. Main Outcomes and Measures: Main outcomes were neurodevelopmental assessments of academic achievement, intelligence, fine motor skills, executive function, attention, memory, social cognition, language, adaptive functioning, and anxiety and depression, as well as 7 structural, diffusion, and functional brain magnetic resonance imaging metrics. Results: The study cohort included 221 participants in the post hoc analysis and 219 in the case-control analysis (109 cases [49.8%] and 110 controls [50.2%]). Of those 219 participants (median age, 15.0 years [IQR, 10.0-21.2 years]), 120 (54.8%) were male. Cases and controls had similar primary outcomes (reading composite, spelling, and math computation on the Wide Range Achievement Test, Fourth Edition) and secondary outcomes. dDNVs and/or pLOFs in chromatin-modifying genes were associated with lower mean (SD) verbal comprehension index scores (91.4 [20.4] vs 103.4 [17.8]; P = .01), Social Responsiveness Scale, Second Edition, scores (57.3 [17.2] vs 49.4 [11.2]; P = .03), and Wechsler Adult Intelligence Scale, Fourth Edition, working memory scores (73.8 [16.4] vs 97.2 [15.7]; P = .03), as well as higher likelihood of autism spectrum disorder (28.6% vs 5.2%; P = .01). dDNVs and/or pLOFs in constrained genes were associated with lower mean (SD) scores on the Wide Range Assessment of Memory and Learning, Second Edition (immediate story memory: 9.7 [3.7] vs 10.7 [3.0]; P = .03; immediate picture memory: 7.8 [3.1] vs 9.0 [2.9]; P = .008). Adults with dDNVs and/or pLOFs in genes with a high level of brain expression had greater Conners adult attention-deficit hyperactivity disorder rating scale scores (mean [SD], 55.5 [15.4] vs 46.6 [12.3]; P = .007). Conclusions and Relevance: The study findings suggest neurodevelopmental outcomes are not associated with dDNVs as a group but may be worse in individuals with dDNVs and/or pLOFs in some gene sets, such as chromatin-modifying genes. Future studies should confirm the importance of specific gene variants to brain function and structure.

Normal interstage growth after the norwood operation associated with interstage home monitoring.

After stage 1 palliation (S1P) with a Norwood operation, infants commonly experience growth failure during the initial interstage period. Growth failure during this high-risk period is associated with worse outcomes. This study evaluated the growth patterns of patients enrolled in the authors' interstage home-monitoring program (HMP), which uses a multidisciplinary team approach to nutrition management. From 2000 to 2009, 148 infants were enrolled in the HMP after S1P. Families recorded daily weights during the interstage period and alerted the interstage monitoring team about protocol violations of nutritional goals. Interstage monitoring and inpatient data from the S1P hospitalization were reviewed to identify risk factors for poor growth. Growth outcomes were compared with published norms from the Centers for Disease Control. Interstage survival for patients in the HMP was 98 % (145/148). Growth velocity during the interstage period was 26 ± 8 g/day. The weight-for-age z-scores decreased from birth to discharge after S1P (-0.4 ± 0.9 to -1.3 ± 0.9; p < 0.001) but then increased during the interstage period to the time of S2P (-0.9 ± 1; p < 0.001). The factors associated with improved growth during the interstage period included male gender, greater birth weight, full oral feeding at S1P discharge, and a later birth era. After S1P, infants enrolled in an HMP experienced normal growth velocity during the interstage period. Daily observation of oxygen saturation, weight change, and enteral intake together with implementation of a multidisciplinary feeding protocol is associated with excellent interstage growth and survival.

A Systematic Review of Ebstein's Anomaly with Left Ventricular Noncompaction.

Traditional definitions of Ebstein's anomaly (EA) and left ventricular noncompaction (LVNC), two rare congenital heart defects (CHDs), confine disease to either the right or left heart, respectively. Around 15-29% of patients with EA, which has a prevalence of 1 in 20,000 live births, commonly manifest with LVNC. While individual EA or LVNC literature is extensive, relatively little discussion is devoted to the joint appearance of EA and LVNC (EA/LVNC), which poses a higher risk of poor clinical outcomes. We queried PubMed, Medline, and Web of Science for all peer-reviewed publications from inception to February 2022 that discuss EA/LVNC and found 58 unique articles written in English. Here, we summarize and extrapolate commonalities in clinical and genetic understanding of EA/LVNC to date. We additionally postulate involvement of shared developmental pathways that may lead to this combined disease. Anatomical variation in EA/LVNC encompasses characteristics of both CHDs, including tricuspid valve displacement, right heart dilatation, and left ventricular trabeculation, and dictates clinical presentation in both age and severity. Disease treatment is non-specific, ranging from symptomatic management to invasive surgery. Apart from a few variant associations, mainly in sarcomeric genes MYH7 and TPM1, the genetic etiology and pathogenesis of EA/LVNC remain largely unknown.