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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. In comparison with unaffected iPSC-CMs, CMs containing the KLHL26 (p.R237C) variant exhibited aberrant morphology including distended endo/sarcoplasmic 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, while 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.

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.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.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).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.

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.

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

Multiple single-ventricle populations are noted to be at increased risk for mortality after the Norwood procedure. Preoperative risk factors include low birth weight, restrictive/intact atrial septum, obstructed pulmonary veins, ventricular dysfunction, and atrioventricular valve regurgitation. We report outcomes of the Norwood procedure in standard- and high-risk patients in the recent era.All patients born with hypoplastic left heart syndrome between 2006 and 2016 who underwent a Norwood procedure at our institution were included. Patient data were retrospectively reviewed, and Kaplan-Meier analysis was used to evaluate survival between groups.The cohort included 177 patients. Fifty patients were determined high-risk preoperatively: low birth weight (n = 18), ventricular dysfunction/atrioventricular valve regurgitation (n = 13), intact or restrictive atrial septum/obstructed anomalous pulmonary venous return (n = 14), and multiple factors (n = 5). There were 2 (1.6%) deaths before Glenn in the standard-risk group, with a total of 10 (20%) from the high-risk groups (P.0001). Survival at 1 year differed greatly between groups, with highest being standard risk at 89% and lowest in the intact septum/obstructed veins group at 54%. The difference between groups in long-term survival was significant (P.001).Outcomes after the Norwood procedure have improved for standard-risk patients. Those with preoperative risk factors account for most of the early deaths after the Norwood procedure. This high-risk status does not resolve after Glenn, because longer-term survival continues to diverge from the standard-risk group.

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.

Introduction: In adults, cerebrovascular accidents (CVA) are often the result of atherosclerotic disease, underlying cardiac arrhythmias, or hypertension. CVA are rarely seen in pediatric patients, but cyanotic congenital heart disease (CHD) patients are at increased risk of a thromboembolic event. Cyanotic CHD patients with a single ventricle undergo multiple procedures in the palliation of their heart lesions including the Glenn procedure, a direct anastomosis of the superior vena cava to the pulmonary arteries. These procedures improve but do not resolve underlying systemic cyanosis, which leaves patients susceptible to polycythemia, anemia, and reduced end-organ perfusion at …

Background Different methods have resulted in variable Z scores for echocardiographic measurements. Using the measurements from 3,215 healthy North American children in the Pediatric Heart Network (PHN) echocardiographic Z score database, the authors compared the PHN model with previously published Z score models. Methods Z scores were derived for cardiovascular measurements using four models (PHN, Boston, Italy, and Detroit). Model comparisons were performed by evaluating (1) overlaid graphs of measurement versus body surface area with curves at Z = −2, 0, and +2; (2) scatterplots of PHN versus other Z scores with correlation coefficients; (3) Bland-Altman plots of PHN versus other Z scores; and (4) comparison of median Z scores for each model. Results For most measurements, PHN Z score curves were similar to Boston and Italian curves but diverged from Detroit curves at high body surface areas. Correlation coefficients were high when comparing the PHN model with the others, highest with Boston (mean, 0.99) and lowest with Detroit (mean, 0.90). Scatterplots suggested systematic differences despite high correlations. Bland-Altman plots also revealed poor agreement at both extremes of size and a systematic bias for most when comparing PHN against Italian and Detroit Z scores. There were statistically significant differences when comparing median Z scores between the PHN and other models. Conclusions Z scores from the multicenter PHN model correlated well with previous single-center models, especially the Boston model, which also had a large sample size and similar methodology. The Detroit Z scores diverged from the PHN Z scores at high body surface area, possibly because there were more subjects in this category in the PHN database. Despite excellent correlation, significant differences in Z scores between the PHN model and others were seen for many measurements. This is important when comparing publications using different models and for clinical care, particularly when Z score thresholds are used to guide diagnosis and management.

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.

Background Intramural anomalous aortic origin of a coronary artery (AAOCA) is associated with an increased risk of sudden cardiac death. This is amenable to surgical coronary unroofing, but outcomes studies are lacking. Objective To perform a comprehensive review of our institutional experience with pediatric patients with AAOCA who underwent surgical repair with unroofing of the intramural segment, focusing on preoperative and postoperative course and testing as well as intraoperative findings. Methods A retrospective cohort study was conducted to evaluate patients with AAOCA status post–coronary unroofing at Children's Hospital of Wisconsin. Data extraction included symptoms, preoperative and postoperative imaging and testing, surgical findings, and postoperative clinical course. Results From January 1999 to December 12, 2015, 63 patients underwent unroofing at a median age of 13 years (0.5-18 years). The majority underwent unroofing of an intramural right coronary (79%); 21% had an intramural left AAOCA. Symptoms suggestive of possible ischemia were present in about 50%. Additional structural cardiac anomalies were present in 33%. Transthoracic echocardiography was diagnostic in 60 of 63 (95%) and correlated with surgical findings in all cases. There was no surgical mortality associated with the unroofing, and no additional coronary reinterventions were performed. The median duration of postoperative follow-up was 3.1 years (7 days to 13.6 years). Symptoms either persisted or developed in 46% postoperatively. Postoperative exercise stress testing, stress echocardiography, and cardiac magnetic resonance imaging were performed in 76%, 8%, and 20%, respectively, of the cohort. None identified findings consistent with reversible coronary ischemia. Three patients had sudden cardiac arrest (1 death) after surgery without an identified residual coronary abnormality. Conclusions Transthoracic echocardiography, with carefully designed coronary imaging protocols, can be diagnostic in accurately identifying intramural AAOCA in pediatric patients. Unroofing can be performed safely with no early morbidity, but symptoms can persist (including rare life-threatening events) without evidence of ischemia by postoperative provocative testing.

Background Anomalous left coronary artery from the pulmonary artery (ALCAPA) is a rare condition that can be difficult to diagnose by echocardiography alone. The purpose of this study was to describe the clinical and echocardiographic presentation of ALCAPA, create a set of critical echocardiographic diagnostic criteria, and report outcomes. Methods A retrospective review was conducted of all patients diagnosed with isolated ALCAPA at two major cardiac centers between 1990 and 2015. Results Of the 37 patients identified, only 54% presented in infancy. The anomalous coronary artery (CA) origin was clearly imaged in only 54% of echocardiographic examinations. However, other consistently identified echocardiographic markers were found, including left CA flow reversal (91%), collateral CA flow (85%), right CA dilation (81%), abnormal pulmonary artery flow (79%), mitral regurgitation (74%), left ventricular dysfunction (66%) and endocardial fibroelastosis (57%). Presenting echocardiograms had five of seven markers in 85% of patients. Left ventricular dysfunction was the most common marker in infants (89% vs 38%, P = .005); older children were more likely to have collateral formation visualized by color Doppler (100% vs 75%, P = .04). Following surgery, there were no early surgical deaths. The median follow-up duration was 10.3 years. At last follow-up, 92% had normal left ventricular function, 3% had moderate or worse mitral regurgitation, and 17% had required reintervention. Conclusions Echocardiographic markers can reliably identify ALCAPA; these markers vary with the age of presentation. Surgical outcomes are excellent, and most patients will recover left ventricular and mitral valve function.

BackgroundA 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.MethodsA 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.ResultsThe 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 (pConclusionsWithin 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.

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.

Background Ebstein's anomaly (EA) is a rare congenital heart disease of the tricuspid valve and right ventricle. Patients with EA often manifest with left ventricular noncompaction (LVNC), a cardiomyopathy. Despite implication of cardiac sarcomere genes in some cases, very little is understood regarding the genetic etiology of EA/LVNC. Our study describes a multigenerational family with at least 10 of 17 members affected by EA/LVNC. Methods We performed echocardiography on all family members and conducted exome sequencing of six individuals. After identifying candidate variants using two different bioinformatic strategies, we confirmed segregation with phenotype using Sanger sequencing. We investigated structural implications of candidate variants using protein prediction models. Results Exome sequencing analysis of four affected and two unaffected members identified a novel, rare, and damaging coding variant in the Kelch‐like family member 26 (KLHL26) gene located on chromosome 19 at position 237 of the protein (GRCh37). This variant region was confirmed by Sanger sequencing in the remaining family members. KLHL26 (c.709C > T p.R237C) segregates only with EA/LVNC‐affected individuals (FBAT p, Patient's Ebstein's anomaly (EA), a rare congenital heart disease of the tricuspid valve and right ventricle often manifest with left ventricular noncompaction (LVNC), a cardiomyopathy. Our study identifies a novel, rare, and damaging coding variant c.709C > T (p.R237C) in the Kelch‐like family member 26 (KLHL26) gene with 10 affected out of 17 affected members using Sanger sequencing. Through structural modeling, we show that the KLHL26 variant may affect protein binding to Cullin3 (CUL3), a component of E3 ubiquitin ligase in the ubiquitin‐mediated protein degradation.

BACKGROUND: The reliability of LV systolic functional indices calculated from blinded echocardiographic measurements of LV size has not been tested in a large cohort of healthy children. The objective of this study was to estimate interobserver variability in standard measurements of left ventricular (LV) size and systolic function in children with normal cardiac anatomy and qualitatively normal function. METHODS: The Pediatric Heart Network Normal Echocardiogram Database collected normal echocardiograms from healthy children ≤18 years old distributed equally by age, gender, and race. A core lab used 2-dimensional echocardiograms to measure LV dimensions from which a separate data coordinating center calculated LV volumes and systolic functional indices. To evaluate interobserver variability, two independent expert pediatric echocardiographic observers re-measured LV dimensions on a subset of studies, while blinded to calculated volumes and functional indices. RESULTS: Of 3215 subjects with measurable images, 552 (17%) had a calculated LV shortening fraction (SF)

We report our intermediate-term results after Norwood procedure, including use of an interstage inpatient management strategy for high-risk patients, and seek to create a predictive model for probability of discharge.A single-site retrospective review was conducted for all patients undergoing Norwood procedure from 2006 to 2016 (N = 177). We compared those discharged home with those who either remained hospitalized until Glenn procedure or died before Norwood procedure discharge. Multivariable logistic regression was used to develop a predictive model for discharge.During the study period, 120 (68%) patients were discharged home, 45 (25%) remained hospitalized, and 12 (7%) died before Glenn procedure (median age: 71 days). Interstage survival for those discharged after Norwood procedure was 100%. Longitudinal survival for the cohort was 86%, 81%, and 77% at 1, 5, and 10 years, resepectively. Ten-year survival was significantly greater for the discharged group compared with the interstage inpatients (86% vs 56%, P.001). A reduced predictive model of discharge included lower gestational age (odds ratio [OR]: 0.95), lower median income for ZIP code (OR: 0.4), lower birth-weight-for-age z-score (OR: 0.56), longer cardiopulmonary bypass time (OR: 0.45), and Blalock-Taussig shunt (OR: 0.32).Survival up to 10 years after Norwood procedure is good using a strategy of inpatient care for a subset of high-risk patients to mitigate home interstage mortality. A probabilistic model used after Norwood procedure was able to predict interstage discharge with good accuracy, but will require external validation to ensure generalizability. Further work is also needed to determine optimal palliative pathways for the high-risk patients because of the notable attrition beyond successful bidirectional Glenn procedure.

BACKGROUND AND OBJECTIVES: Children with congenital heart disease (CHD) are at risk for neurodevelopmental (ND) delays. The purpose of this study is to compare the ND testing results of children with CHD at 2 and 4 years of age and determine if rates of ND delays change over time. METHODS: Children with CHD completed the Bayley Scales of Infant Development – III (BSID-III) at 2 years of age, and standardized neuropsychological measures at 4 years. Scores were compared to test norms and were classified as: average (within one SD of test mean); at risk (1-2 SDs from the test mean); and delayed (>2SD from test mean). Pearson correlations and McNemar’s exact tests were performed to determine the relationship between test scores at the two times of assessment. RESULTS: Sixty-four patients completed evaluations at 24±3 months of age and 4 years of age. BSID-III cognitive and fine motor scores were correlated with preschool IQ and fine motor scores, r = 0.75 to 0.87, p

Introduction Isomerism, or heterotaxy syndrome, affects many organ systems anatomically and functionally. Intestinal malrotation is common in patients with isomerism. Despite a low reported risk of volvulus, some physicians perform routine screening and prophylactic Ladd procedures on asymptomatic patients with isomerism who are found to have intestinal malrotation. The primary aim of this study was to determine if isomerism is an independent risk factor for volvulus. Methods Kid's Inpatient Database data from 1997 to 2012 was utilized for this study. Characteristics of admissions with and without isomerism were compared with a particular focus on intestinal malrotation, volvulus, and Ladd procedure. A logistic regression was conducted to determine independent risk factors for volvulus with respect to isomerism. Results 15,962,403 inpatient admissions were included in the analysis, of which 7970 (0.05%) patients had isomerism, and 6 patients (0.1%) developed volvulus. Isomerism was associated with a 52-fold increase in the odds of intestinal malrotation by univariate analysis. Of 251 with isomerism and intestinal malrotation, only 2.4% experienced volvulus. Logistic regression demonstrated that isomerism was not an independent risk factor for volvulus. Conclusion Isomerism is associated with an increased risk of intestinal malrotation but is not an independent risk factor for volvulus. Type of Study Prognosis study. Level of Evidence Level III.

Background— Published nomograms of pediatric echocardiographic measurements are limited by insufficient sample size to assess the effects of age, sex, race, and ethnicity. Variable methodologies have resulted in a wide range of Z scores for a single measurement. This multicenter study sought to determine Z scores for common measurements adjusted for body surface area (BSA) and stratified by age, sex, race, and ethnicity. Methods and Results— Data collected from healthy nonobese children ≤18 years of age at 19 centers with a normal echocardiogram included age, sex, race, ethnicity, height, weight, echocardiographic images, and measurements performed at the Core Laboratory. Z score models involved indexed parameters (X/BSA α ) that were normally distributed without residual dependence on BSA. The models were tested for the effects of age, sex, race, and ethnicity. Raw measurements from models with and without these effects were compared, and α ) were selected for each measurement. Multivariable regression revealed statistically significant effects by age, sex, race, and ethnicity for all outcomes, but all effects were clinically insignificant based on comparisons of models with and without the effects, resulting in Z scores independent of age, sex, race, and ethnicity for each measurement. Conclusions— Echocardiographic Z scores based on BSA were derived from a large, diverse, and healthy North American population. Age, sex, race, and ethnicity have small effects on the Z scores that are statistically significant but not clinically important.

Newborns with hypoplastic left heart syndrome and other single right ventricular variants require substantial health care resources. Weekend acute care has been associated with worse outcomes and increased resource use in other populations but has not been studied in patients with single ventricle. Subjects of the Single Ventricle Reconstruction trial were classified by whether they had a weekend admission and by day of the week of Norwood procedure. The primary outcome was hospital length of stay (LOS); secondary outcomes included transplant-free survival, intensive care unit (ICU) LOS, and days of mechanical ventilation. The Student's t test with log transformation and the Wilcoxon rank-sum test were used to analyze associations. Admission day was categorized for 533 of 549 subjects (13% weekend). The day of the Norwood was Thursday/Friday in 39%. There was no difference in median hospital LOS, transplant-free survival, ICU LOS, or days ventilated for weekend versus non-weekend admissions. Day of the Norwood procedure was not associated with a difference in hospital LOS, transplant-free survival, ICU LOS, or days ventilated. Prenatally diagnosed infants born on the weekend had lower mean birth weight, younger gestational age, and were more likely to be intubated but did not have a difference in measured outcomes. In conclusion, in this cohort of patients with single right ventricle, neither weekend admission nor end-of-the-week Norwood procedure was associated with increased use of hospital resources or poorer outcomes. We speculate that the complex postoperative course following the Norwood procedure outweighs any impact that day of admission or operation may have on these outcomes.

Background Invasive fetal cardiac intervention (FCI) has been reported in single-institution series, promoting technical and physiologic success. Objectives This study describes the creation of an international registry of cases presenting for FCI, intended to compile technical and outcome data from a multicenter cohort. Methods For this initial analysis, the entire database of the International Fetal Cardiac Intervention Registry (IFCIR) was queried for details of diagnoses, procedures, and outcomes. Maternal-fetal dyads from January 2001 through June 2014 were included. Results Eighteen institutions submitted data by data harvest. Of 370 cases entered, 245 underwent FCI: 100 aortic valvuloplasties from a previous single-center report (excluded from additional reporting here), an additional 86 aortic and 16 pulmonary valvuloplasties, 37 atrial septal cases, and 6 unclassified cases. FCI did not appear to affect overall survival to hospital discharge. Among live-born infants with a fetal diagnosis of aortic stenosis/evolving hypoplastic left heart syndrome, more than twice as many were discharged with biventricular circulation after successful FCI versus those meeting institutional criteria but without any or successful FCI (42.8% vs. 19.4%, respectively). When fetal deaths were counted as treatment failures, the percentages were similar: biventricular circulation at discharge was 31.3% versus 18.5% for those discharged with univentricular palliation. Survival to discharge for live-born fetuses with atrial restriction was similar to that of those undergoing technically successful versus unsuccessful FCI (63.6% vs. 46.7%, respectively), although criteria for diagnosis were nonuniform. Conclusions We describe the contents of the IFCIR and present post-natal data to suggest potential benefit to fetal therapy among pregnancies considered for possible intervention and support proposals for additional work.

Objectives Prenatal diagnosis of critical congenital heart disease, which requires surgical or catheter intervention in the first 30 days of life, allows for delivery at a specialized center and can reduce preoperative morbidity and mortality. We sought to identify the risk factors for a missed prenatal diagnosis of critical congenital heart disease. Methods Patients presenting to the Children's Hospital of Wisconsin with critical congenital heart disease from 2007 to 2013 were included. Those with a prenatal diagnosis were compared with those with a postnatal diagnosis. Results The cohort included 535 patients with prenatal diagnosis made in 326 (61%). The prenatal diagnostic rate improved from 44% in 2007 to 69% in 2013. Independent factors associated with a postnatal diagnosis were a lesion that required a view other than a four chamber view to make the diagnosis (p

Today, almost 70% of babies with hypoplastic left heart syndrome (HLHS) will survive into adulthood, although significant long-term morbidity and mortality still exists. Prenatal diagnosis of HLHS is increasingly common, allowing improved counseling, and the potential for fetal intervention if indicated. Exciting progress continues to be made in the area of fetal diagnosis and intervention, specifically catheter intervention for intact atrial septum or severe aortic stenosis. Pediatric cardiologists should be keenly aware of the flaws of staged palliation for the treatment of HLHS, and need to keep abreast of the emerging data regarding fetal diagnosis and intervention.

Infants with hypoplastic left heart syndrome and an intact or highly restrictive atrial septum (HLHS-IAS) represent a high-risk subset. Fetal cardiac intervention (FCI) for fetuses with HLHS-IAS has been reported in single-institution series as a therapy that may improve outcomes. This study uses the International Fetal Cardiac Intervention Registry (IFCIR) to examine fetal and maternal characteristics and pregnancy and neonatal outcome data for FCI in this population. For this descriptive analysis, the IFCIR was queried for fetuses with HLHS-IAS evaluated between 2001 and March 2015 for possible FCI and felt to be candidates at the referral center by a variety of published criteria including foramen ovale (FO) size, shunt flow direction across the FO, and pulmonary venous Doppler flow patterns. It includes those who were determined not to be candidates because of other fetal noncardiac conditions, maternal conditions, or maternal preferences, or because FCI was not performed at the participating institution. Further details on the methodology of the IFCIR registry are found in the initial report.1 Participating IFCIR member sites obtained local institutional review board and ethics board approval or a waiver, as governed …

We describe the case of a 10-year-old male with a history of repaired Tetralogy of Fallot and known intramural right coronary artery (RCA) who presented for bioprosthetic pulmonary valve replacement. The operation was complicated by postoperative ventricular fibrillation arrest. Selective coronary angiography revealed external compression of the mid-RCA by a mediastinal chest tube that improved immediately upon removal of the tube. Ultimately, the patient required additional unroofing of the intramural coronary for full recovery. This case highlights the need to thoroughly investigate malignant ventricular dysrhythmias following pediatric cardiac surgery and to rule out coronary insufficiency, which may be due to both extrinsic and/or intrinsic lesions.

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

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.

Infants who undergo Norwood stage 1 palliation (S1P) continue with high-risk circulation until stage 2 palliation (S2P). Routine care during the interstage period is associated with 10% to 20% mortality. This report illustrates the sustained reduction of interstage mortality over 10 years associated with use of home monitoring.Daily monitoring of oxygen saturation and weight was done for all patients discharged to home after S1P. Notification of the care team occurred for oxygen saturation75% or90%, weight gain20 g over 3 days, weight loss30 g, or intake100 cc/kg/d. Breach of these criteria marked an interstage event. Interstage outcomes are reported. Patient characteristics and perioperative variables were compared between patients with and without interstage events.Over 10 years, 157 patients were discharged after S1P with home monitoring. Interstage survival was 98%. Breach of home criteria occurred in 59% (93 out of 157), with violation of oxygen saturation75% the most common event. Patient characteristics, operative data, and early postoperative morbidity did not differ between patients with and without events.Home monitoring after S1P is associated with excellent interstage survival. Although a breach of monitoring criteria occurred in more than half of patients, our analysis failed to identify independent predictors of interstage events. Analysis of variables predicting mortality could not be assessed due to the low frequency of death in this cohort. Failure to identify specific variables for interstage events suggests that home monitoring, as part of an interstage surveillance program, should be applied to all S1P hospital survivors.

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.

Optimal timing for elective repair of total anomalous pulmonary venous return (TAPVR) in the case of an unobstructed anomalous pathway is unclear. All infants with a diagnosis of TAPVR as an isolated lesion who underwent surgical repair at Children's Hospital of Wisconsin from 1991 to 2007 were reviewed to assess location of drainage, presence of obstruction, age at presentation, age at surgery, death, need for extracorporeal membrane oxygenation (ECMO), length of hospital stay, length of mechanical ventilation (MV), and late pulmonary venous obstruction. A total of 65 patients were identified: 38 (59%) with supracardiac drainage, 10 (15%) with cardiac drainage, 11 (17%) with infracardiac drainage, and 6 (9%) with mixed drainage. For 39 (60%) of the 65 patients, obstruction was identified preoperatively. Three early and five late deaths occurred after surgery (12%), all involving patients with preoperative obstruction. Most of the late deaths (80%) involved patients who experienced recurrent obstruction. Of the 65 patients, 26 (40%) had no obstruction preoperatively, and none died, required ECMO support, or experienced late obstruction. For the 26 patients without obstruction, the timing of surgery was elective at the discretion of the supervising cardiologist. Among these 26 patients, 15 had surgery less than 10 days after presentation (median age, 18 days), and 53% of these 15 patients (8/15) had MV less than 5 days. In contrast, all 11 patients who had elective surgery more than 10 days after presentation (median age, 56 days) required MV for more than 5 days (p = 0.007). Isolated TAPVR appears to be at the highest risk for death and late postoperative obstruction when obstruction is present preoperatively. Patients with unobstructive TAPVR do very well, but potential morbidity related to prolonged MV appears to be significantly reduced by early elective surgery.

Background Persistent pulmonary hypertension of the newborn (PPHN) causes morbidity and mortality in neonates. High-frequency ventilation (HFV), inhaled nitric oxide (iNO), and extracorporeal membrane oxygenation (ECMO) are used when conventional treatment fails. This study aimed to identify echocardiographic predictors of progression to these therapies before clinical deterioration. Methods Echocardiographic parameters were compared for survival and need for ECMO, HFV, iNO, and prolonged mechanical ventilation (MV, ≥10 days). Results Of 63 neonates, 95% survived, with 14% requiring ECMO, 52% requiring HFV, 67% requiring iNO, and 35% requiring MV. The following echocardiographic indices reflecting left ventricular output were decreased in sicker infants: (1) A decreased ascending aortic velocity time integral indicated an increased likelihood of ECMO (p = 0.02), iNO (p = 0.01), or MV (p = 0.05), (2) Shorter transverse aortic arch antegrade ejection time indicated HFV (p < 0.01), iNO (p < 0.01), and MV (p = 0.03), (3) Absent or retrograde transverse aortic diastolic flow correlated with HFV (p = 0.01, iNO (p = 0.01), and MV (p < 0.01). These sicker patients were more likely to have smaller left ventricular end-diastolic areas (p < 0.03 for all) and right-to-left atrial shunting (ECMO, HFV, and MV). There were no differences in survival. Conclusions Decreased left ventricular size and output correlates with the need for advanced therapies in infants with PPHN. Early identification may allow more effective management and placement of neonates at risk.

Objectives The study objective was to compare echocardiographic indices in infants with hypoplastic left heart syndrome (HLHS) randomized to different surgical pathways. Background Initial surgical palliation for HLHS has evolved to two strategies that vary by source of pulmonary blood flow: a modified Blalock-Taussig (BT) shunt or a right ventricle to pulmonary artery (RV-PA) conduit. Methods Seventeen patients were randomized to either a BT shunt or RV-PA as their first-stage palliation, and 15 survived through bidirectional Glenn (BDG) (seven BT shunts/eight RV-PAs). Echocardiography was performed pre-stage 1 palliation (S1P), early post-S1P, pre-BDG, and post-BDG. Echocardiographic measurements included indices of right ventricle function and shape, right ventricle myocardial performance index, neoaortic Doppler flow patterns and cardiac output, Doppler inflow and tissue imaging, and conduit/neoaortic regurgitant fraction. Results There were no significant differences in right ventricle size, shape, or estimates of systolic and diastolic function between groups. Patterns of changes in neoaortic Doppler flow in the RV-PA conduit group showed a decrease in all indices of systemic flow early after initial palliation, but these measures consistently increase later post-S1P and post-BDG. In contrast, the BT shunt group increases these same indices post-S1P and pre-BDG with a decrease after shunt removal. Conclusions Right ventricle size and function do not appear significantly affected by surgical type of initial palliation for HLHS, and this correlates with early outcome. Echocardiographic Doppler findings correlate well with the expected physiologies of the different shunts as these infants progress through initial palliative strategies.

Fetal echocardiography has clearly made a difference in the world of pediatric cardiology today. It has taught us much about the natural history of fetal cardiac disease, and with ongoing collaborative studies, it should continue to enhance our knowledge base. Fetal echocardiography has enabled us to identify potential candidates for fetal cardiac intervention and has promoted the development of an exciting new discipline within pediatric cardiology. We hope that the recognition of critical congenital heart disease in utero improves the long-term outcome of our patients, including neurodevelopmental outcome and quality of life.

Between August 1991 and September 2000, 15 patients received a diagnosis of the anomalous origin of the coronary artery from the pulmonary artery, at the Children's Hospital of Wisconsin. All were evaluated initially by transthoracic echocardiography, with subsequent diagnosis confirmation at cardiac catheterization and/or surgery. Seven of the 15 patients were referred in infancy (mean age 4.3 months) with symptoms of congestive heart failure. The remaining 8 patients were older (mean age 7.0 years) at the time of diagnosis, and 7 of those 8 patients were clinically asymptomatic and were referred for evaluation of a heart murmur and/or cardiomegaly on chest radiograph. One older patient, previously healthy, was referred at age 18 for an episode of sudden death while playing basketball. All the older asymptomatic patients had echocardiographic detection of multiple unusual color flow Doppler signals within the ventricular septum, believed to represent septal coronary collaterals, which raised suspicion of a coronary artery abnormality and led to more detailed imaging of the coronary artery anatomy. In the younger infants with congestive heart failure, septal coronary collaterals were less frequent, but did aid in the diagnosis of an anomalous coronary artery when present.

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.

Objectives Achieving adequate growth after stage 1 palliation for children with single-ventricle heart defects often requires supplemental nutrition through enteral tubes. Significant practice variability exists between centers in the choice of feeding tube. The impact of feeding modality on the growth of patients with a single ventricle after stage 1 palliation was examined using the multiinstitutional National Pediatric Cardiology Quality Improvement Collaborative data registry. Methods Characteristics of patients were compared by feeding modality, defined as oral only, nasogastric tube only, oral and nasogastric tube, gastrostomy tube only, and oral and gastrostomy tube. The impact of feeding modality on change in weight for age z-score during the interstage period, from stage 1 palliation discharge to stage 2 palliation, was evaluated by multivariable linear regression, adjusting for important patient characteristics and postoperative morbidities. Results In this cohort of 465 patients, all groups demonstrated improved weight for age z-score during the interstage period with a mean increase of 0.3 ± 0.8. In multivariable analysis, feeding modality was not associated with differences in the change in weight for age z-score during the interstage period ( P = .72). Risk factors for poor growth were a diagnosis of hypoplastic left heart syndrome ( P = .003), vocal cord injury ( P = .007), and lower target caloric goal at discharge ( P = .001). Conclusions In this large multicenter cohort, interstage growth improved for all groups and did not differ by feeding modality. With appropriate caloric goals and interstage monitoring, adequate growth may be achieved regardless of feeding modality and therefore local comfort and complication risk should dictate feeding modality.

Background. To determine factors predicting mortality and morbidity after repair of complete atrioventricular septal defect, we retrospectively analyzed preoperative, operative, and postrepair factors on the outcome of 115 consecutive complete atrioventricular septal defect repairs at The Children's Hospital of Wisconsin between January 1974 and December 1993. Methods. For the entire experience the operative mortality was 13.9% (16 patients). During the most recent era, January 1988 to December 1993, operative mortality was 3.6% (2 of 55 patients). This was significantly improved from the two previous eras, January 1974 to December 1980, 28% (7 of 25) and January 1981 to December 1987, 20% (7 of 35 patients) ( p = 0.02). There were seven late deaths; 10-year actuarial survival, including operative mortality was 81%. Age at complete repair decreased; before 1982 all patients were more than 12 months of age, whereas after 1982 64% (56 of 88 patients) were 12 months of age or less. Results. Moderate or severe preoperative left atrioventricular valve regurgitation was not a risk factor for operative mortality. For operative survivors with moderate to severe preoperative left atrioventricular valve regurgitation (n = 17), late postoperative left atrioventricular valve regurgitation (follow-up data available on 15 patients) was significantly reduced (severe = 1, moderate=5, mild=9; p = 0.007). Conclusions. Early mortality was predicted by the era of surgical repair. Conversion to routine repair during infancy was achieved with a simultaneous decrease in operative mortality. For patients with moderate to severe preoperative left atrioventricular valve regurgitation, significant improvement in the degree of left atrioventricular valve regurgitation can be expected without an increase in operative or late mortality or morbidity.

Background The bidirectional cavopulmonary shunt has become an important intermediate step in the treatment of pediatric patients with single ventricle physiology who are ultimately destined for palliative surgery. We wanted to know whether there would be risks or benefits if an additional source of pulmonary blood flow was left after a bidirectional cavopulmonary shunt. Methods and Results We retrospectively reviewed the medical and surgical records of all patients who underwent a bidirectional cavopulmonary shunt at the Children’s Hospital of Wisconsin between January 1991 and December 1993. A total of 43 patients were identified. Anatomic diagnoses included double inlet left ventricle (14 patients), tricuspid atresia (8 patients), pulmonary atresia with intact septum (6 patients), single right ventricle (5 patients), hypoplastic left heart (3 patients), unbalanced atrioventricular septal defect (3 patients), and other complex lesions (4 patients). We then divided the patients into two groups for purposes of analysis. Group 1 had only the cavopulmonary shunt as a source of pulmonary flow (22 patients); group 2 had an additional source of pulmonary flow (21 patients). Patient age at the time of cavopulmonary shunt ranged from 6 months to 12 years, with group 1 patients being younger (31 versus 45 months, P =.05). Group 2 patients had higher postoperative central venous pressures (17.8 versus 14.1 mm Hg, P P P Conclusions We conclude that patients with an additional source of pulmonary blood flow after bidirectional cavopulmonary shunt have higher postoperative central venous pressures, have higher oxygen saturations, and are at risk for the late development of a chylothorax.

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.

We investigated medium-term outcomes in single-ventricle heart disease palliated with a Kawashima procedure (KP) compared with matched patients who had a standard Fontan procedure (FP).Clinical characteristics, oxygen saturation as measured by pulse oximetry (SpO(2)) trends, and survival in 18 KP cases were compared with 36 matched controls who underwent a standard FP. Records of surgical procedures, catheterizations, noninvasive imaging, and clinical follow-up were reviewed.The median duration of follow-up after KP was 6.7 years. The mean SpO(2) (%) in the KP group over the follow-up period before completion Fontan was 85.1 ± 6, and differed significantly from the control FP group (90.7 ± 5.1, p0.001). Thirteen of the 18 KP patients underwent completion Fontan at a median age of 3.3 years (1.1 to 8.6) and median interval of 2.61 years (0.61 to 7.35) after KP. Mean SpO(2) after completion Fontan following KP was 88.7 ± 7.6%. The SpO(2) in Fontan after KP was not as high as after control FP. Low SpO(2) with upward trend was noted throughout the postoperative follow-up. The overall survival in the KP group after Fontan estimated by the Kaplan-Meier method was 87% at 5 years and at 7 years.The KP and subsequent Fontan completion results in acceptable medium-term survival, and remains the approach of choice for single-ventricle heart disease with interrupted inferior vena cava. The KP has to be undertaken with expectation for somewhat lower early SpO(2) relative to standard Fontan patients, but in anticipation that SpO(2) is likely to rise gradually with time.