Search

Melissa S Engel,1 Lazaros K Kochilas2 1Division of Neonatology, University of Minnesota, Minneapolis, MN, 2Children’s Healthcare of Atlanta, Emory University, Atlanta, GA, USA Abstract: Congenital heart disease (CHD) is one of the most common birth defects, with an incidence of nine out of every 1,000 live births. The mortality of infants with CHD has decreased over the past 3 decades, but significant morbidity and mortality continue to occur if not diagnosed shortly after birth. Pulse oximetry was recommended as a screening tool to detect critical CHD in 2011 by the American Academy of Pediatrics and the American Heart Association. Pulse oximetry is a tool to measure oxygen saturation, and based on the presence of hypoxemia, many cardiac lesions are detected. Due to its ease of application to the patient, providing results in a timely manner and without the need for calibrating the sensor probe, pulse oximetry offers many advantages as a screening tool. However, pulse oximetry has also important limitations of which physicians should be aware to be able to assess the significance of the pulse oximetry measurement for a given patient. This review aims to highlight the benefits and shortcomings of pulse oximetry within the context of screening for critical CHD and suggests future avenues to cover existing gaps in current practices. Keywords: congenital heart disease, critical congenital heart disease, pulse oximetry, newborn, newborn screening

Background: With improved survival of adults with congenital heart disease (CHD) comes a need to understand the lifelong outcomes of this population. The aim of this paper is to describe the rationale and design of Congenital Heart Disease Project to Understand Lifelong Survivor Experience (CHD PULSE), a study to determine long-term medical, neurocognitive, and psychosocial outcomes among adults with a history of intervention for CHD and to identify factors associated with those outcomes., Methods: CHD PULSE is a cross-sectional survey conducted from September 2021 to April 2023 among adults aged 18 and older with a history of at least 1 intervention for CHD at 1 of 11 participating U.S. centers in the Pediatric Cardiac Care Consortium. Participants with CHD were asked to complete a 99-question survey on a variety of topics including: demographics, surgeries, health insurance, health care, heart doctors, general health, height and weight, education and work history, reproductive health (for women only), and COVID-19. To construct a control group for the study, siblings of survey respondents were invited to complete a similar survey. Descriptive statistics for demographics, disease severity, center, and method of survey completion were computed for participants and controls. Comparisons were made between participants and non-participants to assess for response bias and between CHD participants and sibling controls to assess for baseline differences., Results: Among the 14,322 eligible participants, there were 3,133 respondents (21.9%) from 48 U.S. states with surveys returned for inclusion in the study. Sibling contact information was provided by 691 respondents, with surveys returned by 326 siblings (47.2%). The median age of participants was 32.8 years at time of survey completion, with an interquartile range of 27.2 years to 39.7 years and an overall range of 20.1 to 82.9 years. Participants were predominantly female (55.1%) and of non-Hispanic White race/ethnicity (87.1%). There were no differences between participants and non-participants regarding severity of CHD. Compared to nonparticipants, participants were more likely to be female, of older age, and be of non-Hispanic White race/ethnicity. Enrolled siblings were more likely to be female and slightly younger than participants., Conclusions: With surveys from 3,133 participants from across the U.S., CHD PULSE is poised to provide keen insights into the lifelong journey of those living with CHD, extending beyond mere survival. These insights will offer opportunities for informing strategies to enhance and improve future outcomes for this population of patients., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Children with congenital heart defects (CHD) have shorter life expectancy than the general population. Previous studies also suggest that patients with CHD have higher risk of cancer. This study aims to describe cancer-related mortality among patients with a history of CHD interventions using the Pediatric Cardiac Care Consortium (PCCC), a large US cohort of such patients., Methods: We performed a retrospective cohort study of individuals (<21 years) who underwent interventions for CHD in the PCCC from 1982 to 2003. Patients surviving their first intervention were linked to the National Death Index through 2020. Multivariable models assessed risk of cancer-related death, adjusting for age, sex, race, and ethnicity. Patients with/without genetic abnormalities (mostly Down syndrome [DS]) were considered separately, due to expected differential risk in cancer., Results: Among the 57,601 eligible patients in this study, cancer was the underlying or contributing cause of death for 208; with 20% among those with DS. Significantly increased risk of cancer-related death was apparent among patients with DS compared to the non-genetic group (aHR: 3.63, 95% confidence interval [CI]: 2.52-5.24, p < .001). For the group with non-genetic abnormalities, the highest association with cancer-related death compared to those with mild CHD was found among those with more severe CHD (severe two-ventricle aHR: 1.82, 95% CI: 1.04-3.20, p = .036, single-ventricle aHR: 4.68, 95% CI: 2.77-7.91, p < .001)., Conclusions: Patients with more severe forms of CHD are at increased risk for cancer-related death. Despite our findings, we are unable to distinguish whether having CHD raises the risk of cancer or reduces survival., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: The Fontan operation is used to palliate single ventricle congenital heart defects (CHD) but poses significant morbidity and mortality risks. We present the design, planned analyses, and rationale for a long-term Fontan cohort study aiming to examine the association of patient characteristics at the time of Fontan with post-Fontan morbidity and mortality., Methods and Results: We used the Pediatric Cardiac Care Consortium (PCCC), a US-based, multicenter registry of pediatric cardiac surgeries to identify patients who underwent the Fontan procedure for single ventricle CHD between 1 and 21 years of age. The primary outcomes are in-hospital Fontan failure (death or takedown) and post-discharge mortality through 2022. A total of 1461 (males 62.1%) patients met eligibility criteria and were included in the analytical cohort. The median age at Fontan evaluation was 3.1 years (IQR: 2.4-4.3). While 95 patients experienced in-hospital Fontan failure (78 deaths and 17 Fontan takedown), 1366 (93.5%) survived to discharge with Fontan physiology and formed the long-term analysis cohort. Over a median follow-up of 21.2 years (IQR: 18.4-24.5) 184 post-discharge deaths occurred. Thirty-year post Fontan survival was 75.0% (95% CI: 72.3%-77.8%) for all Fontan types with higher rates for current techniques such as lateral tunnel and extracardiac conduit 77.1% (95% CI: 73.5-80.8)., Conclusion: The PCCC Fontan study aims to identify predictors for post-Fontan morbidity and mortality, enabling risk- stratification and informing surveillance practices. Additionally, the study may guide therapeutic interventions aiming to optimize hemodynamics and enhance Fontan longevity for individual patients., Competing Interests: Disclosure The authors have no relevant financial relationships or conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Primary supravalvar aortic stenosis (SVAS) is a rare congenital cardiovascular condition that can coexist with Williams-Beuren syndrome, coronary artery involvement, aortic coarctation, and pulmonary artery stenosis. SVAS repair can be achieved with low perioperative mortality, but long-term survival remains less well understood. We used the Pediatric Cardiac Care Consortium, a multicenter United States-based registry for pediatric cardiac operations, to assess long-term outcomes after SVAS repair., Methods: We used Kaplan-Meier plots and Cox proportional hazards regression to examine factors associated with postdischarge deaths. These included sex, age-group, weight z-score, coexisting conditions (Williams-Beuren syndrome, coronary artery involvement, coarctation, and pulmonary artery stenosis), surgical techniques, and era, defined as early (1982-1995) or late (1996-2003). Survival was assessed by matching with the National Death Index through 2021., Results: Of 333 patients who met inclusion criteria, 313 (94.0%) survived to discharge and 188 (60.1%) had identifiers for National Death Index matching. Over a median follow-up of 25.2 years (interquartile range, 21.1-29.4 years), 17 deaths occurred. The 30-year survival after discharge from SVAS repair was 88.7% (95% CI, 82.9%-94.8%). Infantile surgery and non-Williams-Beuren syndrome were associated with decreased 30-year survival. From the various repairs, the 2-sinus technique had better outcomes compared with all other types, except the 3-sinus technique (nonsignificant difference). Adjusted analysis revealed infantile age and type of repair as associated with postdischarge probability of death., Conclusions: These data demonstrate favorable long-term outcomes after SVAS repair, except for the infantile group that was associated with more diffuse arteriopathy. As techniques continue to evolve, future studies are warranted to investigate their long-term outcomes., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Cardiovascular conditions are considered risk factors for poor outcomes associated with COVID-19. However, the effect of the COVID-19 pandemic on the mortality of patients with congenital heart disease (CHD) is unclear. Our study aims to examine the trends in mortality risk of CHD patients during the COVID-19 pandemic., Methods: This is a retrospective cohort study from the Pediatric Cardiac Care Consortium, a US-based registry of interventions for CHD. We included patients having US residence and direct identifiers; death events were captured by matching with the National Death Index. The observation window (2017-2022) was divided into pre-COVID-19 and COVID-19 era defined around the national onset of COVID-19 disease in 2020. Stratified Cox model was used to assess all-cause mortality between the pre- and the COVID-19 era., Results: Among 45,130 patients with CHD (median age in 2017: 23.3 years, IQR: 19.0-28.4), 503 deaths occurred during the pandemic with 44 deaths (8.7%) attributed to COVID-19 (COVID-19 mortality rate of 0.09%). The overall risk of death for patients with all types of CHD during the pandemic was significantly higher compared to the pre-COVID-19 era (aHR 1.28, 95%CI: 1.08-1.53), with a differential trend towards increased risk in patients with two-ventricle (aHR 1.44, 95% CI: 1.19-1.76) vs unchanged risk for those with single ventricle CHD (aHR = 0.83, 95% CI: 0.57-1.21). Adjusted subgroup analysis revealed a higher risk of death during the pandemic for CHD patients with male and chromosomal abnormalities. The excess deaths during the pandemic were attributed to COVID-19 itself rather than CHD or cardiovascular conditions., Conclusion: In this large CHD cohort study, there was a higher risk of death among CHD patients with male and chromosomal abnormalities. A differential trend towards higher risk for those with two vs. unchanged risk for single ventricle CHD was presented. The excess mortality was attributed to the COVID-19 itself and not to conditions potentially related to deferral of care. These results justify targeted protective measures towards the CHD population and may provide guidance for public health and medical care response in future epidemics., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Children with heart disease frequently require anticoagulation for thromboprophylaxis. Current standard of care (SOC), vitamin K antagonists or low-molecular-weight heparin, has significant disadvantages., Objectives: The authors sought to describe safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of apixaban, an oral, direct factor Xa inhibitor, for prevention of thromboembolism in children with congenital or acquired heart disease., Methods: Phase 2, open-label trial in children (ages, 28 days to <18 years) with heart disease requiring thromboprophylaxis. Randomization 2:1 apixaban or SOC for 1 year with intention-to-treat analysis., Primary Endpoint: a composite of adjudicated major or clinically relevant nonmajor bleeding. Secondary endpoints: PK, pharmacodynamics, quality of life, and exploration of efficacy., Results: From 2017 to 2021, 192 participants were randomized, 129 apixaban and 63 SOC. Diagnoses included single ventricle (74%), Kawasaki disease (14%), and other heart disease (12%). One apixaban participant (0.8%) and 3 with SOC (4.8%) had major or clinically relevant nonmajor bleeding (% difference -4.0 [95% CI: -12.8 to 0.8]). Apixaban incidence rate for all bleeding events was nearly twice the rate of SOC (100.0 vs 58.2 per 100 person-years), driven by 12 participants with ≥4 minor bleeding events. No thromboembolic events or deaths occurred in either arm. Apixaban pediatric PK steady-state exposures were consistent with adult levels., Conclusions: In this pediatric multinational, randomized trial, bleeding and thromboembolism were infrequent on apixaban and SOC. Apixaban PK data correlated well with adult trials that demonstrated efficacy. These results support the use of apixaban as an alternative to SOC for thromboprophylaxis in pediatric heart disease. (A Study of the Safety and Pharmacokinetics of Apixaban Versus Vitamin K Antagonist [VKA] or Low Molecular Weight Heparin [LMWH] in Pediatric Subjects With Congenital or Acquired Heart Disease Requiring Anticoagulation; NCT02981472)., Competing Interests: Funding Support and Author Disclosures This trial was supported by the Bristol Myers Squibb/Pfizer Alliance, in collaboration with the NHLBI-funded Pediatric Heart Network (grant numbers: HL135646, HL135665, HL135666, HL135678, HL135680, HL135682, HL135683, HL135685, HL135689, HL135691). Bristol Myers Squibb provided all financing and drugs for this trial; managed the trial data, adjudication process, and clinical sites; and was involved in the design of the study. The Pediatric Heart Network (PHN) provided scientific input on the trial design and contributed organizational infrastructure including the Data and Safety Monitoring Board, Protocol Review Committee, Publications and Presentations Committee, and additional logistical support for United States–based sites. Editorial support was provided by Caudex and was funded by Bristol Myers Squibb. Any publication-related fees will be funded by Bristol Myers Squibb. In collaboration with the trial steering committee, Bristol Myers Squibb was involved in the writing of this manuscript and decision to submit the paper for publication. Dr Payne has received grants or contracts from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI), Friedreich Ataxia Research Alliance, and Additional Ventures non-profit organization; has received royalties or license from inventions: Wake Forest University, Larimar Therapeutics, and Indiana University; has received consulting fees from Larimar Therapeutics Inc.; has received support for attending meetings or travel from Indiana University School of Medicine; has 2 patents pending at Indiana University School of Medicine; is chair or is on the Data and Safety Monitoring Board (DSMB) for NIH study on Friedreich Ataxia; has served on the scientific advisory board for Friedreich Ataxia Research Alliance; and has stock in Larimar Therapeutics, Inc. Dr Glatz has received grants or contracts from NIH/NHLBI. Dr Male has received payment or honoraria from Anthos, AstraZeneca, Bayer, Chiesi, Janssen, and Norgine; and has a leadership or fiduciary role in Pediatric Anti-thrombotic Trials Leadership & Steering (Pedi-ATLAS) Group. Dr Brandão has received participation in an advisory committee for AstraZeneca (Andexxa in pediatrics) and Boehringer Ingelheim (dabigatran in children). Dr VanderPluym has received grants or contracts from the Georgia Claire Bowen Foundation; has received consulting fees from AstraZeneca and Merck; and participates in an advisory committee for the Valor Trial (Veriguciat in pediatric heart failure), and Andexxa in pediatrics in Europe. Dr Kochilas has received grants or contracts from NIH/NHLBI, Department of Defense, and Novartis Pharma; and participates in the Mitochondrial transplant study: Boston Children’s Hospital. Dr Stiller has received consulting fees from Janssen and Novartis; and has received payment or honoraria from Bristol Myers Squibb. Dr Cnota has received grants or contracts from NIH/NHLBI and Additional Ventures nonprofit organization; has received support for attending meetings or travel from the American Heart Association CSSP committee; and has participated on the NIH-NHLBI DSMB, Advisory Board for Inozyme Pharma. Dr Rahkonen has received payment or honoraria from Bristol Myers Squibb. Dr Adorisio has received grants or contracts from HORIZON 2022, Ministry of Italian Public Health; and has received consulting fees and payment or honoraria from PTC Therapeutics. Dr Stoica has been a co-applicant on research grants from local charities, National Institute of Health Research, the Health Foundation, and industry (Livanova, Admedus); has received payment or honoraria from LeMaitre Vascular; has received payment for expert testimony; and was audit co-lead in the Society of Cardiothoracic Surgeons of Great Britain and Ireland and at the National Institute of Cardiovascular Outcomes and Research. Dr May has received institutional support for conference fees. Dr Saraiva has a conflict of interest with AstraZeneca, Novartis, Merck, Novo Nordisk, Boehringer, Janssen, and Bayer; has received consulting fees from AstraZeneca, Novartis, Merck, Novo Nordisk, Boehringer, Janssen, and Bayer; has received payment or honoraria from AstraZeneca, Novartis, Merck, Novo Nordisk, Boehringer, Janssen, and Bayer; has received payment for expert testimony from AstraZeneca; has received support for attending meetings or travel from Novo Nordisk, AstraZeneca, and Boehringer; and has participated in the Allbert Einstein Academic Research Organization, Brazil. Dr Rubio has stock in BMS (obtained in 2001). Dr Meador has Concurrent employment with AtriCure effective September 2022. Ms Wheaton has a contract between HealthCore (now known as Carelon Research) and BMS to conduct the SAXOPHONE study. Dr Ajavon-Hartmann and Ms Mills are employees of and have stock options in Bristol Myers Squibb. Drs Jarugula, Reedy, and Dyme and Ms Carlson-Taneja are employees of Bristol Myers Squibb. Dr Monagle has received patents planned, issued, or pending from University of Melbourne and McMaster University: No commercial interests or connections since 2011. No current licensing agreements and no ongoing negotiations to license. Expect patents to expire in the next couple of years - Thrombin generation assay. Inventors: Berry LR, Ignjatovic V, Monagle PT, Chan AKC. U.S. patent, patent no. 8138308, “Modified Peptide Substrate”, issued 20 March 2012 “Enzyme Measurement Assay Using a Modified Substrate Comprising a Substrate Attached to a Macromolecule via a Spacer”: India patent no. 244241, issued November 25, 2010; Europe patent application, serial no. 06840527.3, issued October 2019; China patent application, serial no. 200680053447, filed December 21, 2006; and Japan patent application, serial no. 2008-547812, filed December 21, 2006. Dr Monagle has participated in Bayer Einstein junior suite of studies (Rivaroxaban in children): steering committee and writing committee; is an unpaid site investigator for the Bristol Myers Squibb SAXOPHONE study (apixaban in children): steering committee and writing committee; has been a site investigator (Unpaid, Ongoing) for Janssen; is an unpaid advisory board member for Milvexian; is an unpaid advisory board member for Takeda; is an unpaid advisory board member for Ceprotinin; and is an Associate Investigator for AstraZeneca, Takeda, Stago, Bayer, Janssen, and Pfizer. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, the U.S. Department of Health and Human Services, or Bristol Myers Squibb/Pfizer Alliance. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. All rights reserved.)

Williams-Beuren syndrome (WBS) is a genetic condition frequently requiring interventions for associated congenital heart disease (CHD). Long-term survival data after cardiac interventions for children with WBS are sparse. This is a retrospective cohort study aiming to describe the 30-year survival outcomes of children with WBS after interventions for CHD using the Pediatric Cardiac Care Consortium (PCCC), a large North American-based registry of interventions for pediatric heart diseases, between 1982 and 2009. Outcomes were obtained from the PCCC and by linkage with the National Death Index through 2020. Survival of patients with WBS and their major subgroups was assessed by Kaplan-Meier survival curves and Cox regression. A total of 200 patients met the inclusion criteria of having their first intervention for CHD at a US PCCC center and age <21 years at time of intervention. The most common lesions were left heart obstructive lesions (LHOL), either in isolation (37%) or in combination with right heart obstructive lesions (RHOL) (49.0%), whereas isolated RHOL accounted for 11% of the total. The first procedure was surgery for 85.5% of the group, and the remainder underwent a transcatheter procedure. There were 5 in-hospital deaths (2.5%), and among survivors to hospital discharge, 164 had sufficient identifiers for National Death Index linkage. Over a median period of postdischarge follow-up of 23.7 years (interquartile range 18.7 to 27.3), 16 deaths occurred, with an overall 30-year survival rate of 90%. Survival rates ranged from 96.1% for isolated LHOL or RHOL to 83.4% for patients with combined disease (adjusted hazard ratio 4.7, 95% confidence intervals 1.35 to 16.59)., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Connective tissue disorders can be associated with significant cardiovascular morbidity needing cardiac surgery during childhood. In this retrospective study, we used the Pediatric Cardiac Care Consortium, a multicenter United States-based registry of pediatric cardiac interventions, to describe the long-term outcomes of patients who underwent their first surgery for connective tissue-related cardiovascular conditions aged <21 years. Between 1982 and 2003, a total of 103 patients were enrolled who underwent cardiac surgery for a connective tissue-related cardiovascular disorder, including 3 severe infantile cases operated on within the first year of life. Most patients underwent aortic site surgery (n = 85) as a composite graft (n = 50), valve-sparing (n = 33), or other aortic surgery (n = 2). The remaining patients underwent atrioventricular valve surgery (mitral 17, tricuspid 1). Of the 99 patients surviving to discharge, 80 (including the 3 infantile) had adequate identifiers for tracking long-term outcomes through 2019 through linkage with the National Death Index and the Organ Procurement. Over a median period of 19.5 years (interquartile range 16.0 to 23.1), 29 deaths and 1 transplant occurred in the noninfantile group, whereas all 3 infantile patients died before the age of 4 years. The postdischarge survival for the noninfantile group was 92.2%, 68.2%, and 56.7% at 10, 20, and 25 years, respectively. Cardiovascular-related pathology contributed to all deaths in the infantile and 89% (n = 27) of deaths for the noninfantile cases after hospital discharge. The significant late attrition from cardiovascular causes emphasizes the need for close monitoring and ongoing management in this population., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Although resilience and high quality of life are demonstrated by many individuals with congenital heart disease, a range of significant psychological challenges exists across the life span for this growing patient population. Psychiatric disorders represent the most common comorbidity among people with congenital heart disease. Clinicians are becoming increasingly aware of the magnitude of this problem and its interplay with patients' physical health, and many seek guidance and resources to improve emotional, behavioral' and social outcomes. This American Heart Association scientific statement summarizes the psychological outcomes of patients with congenital heart disease across the life span and reviews age-appropriate mental health interventions, including psychotherapy and pharmacotherapy. Data from studies on psychotherapeutic, educational' and pharmacological interventions for this population are scarce but promising. Models for the integration of mental health professionals within both pediatric and adult congenital heart disease care teams exist and have shown benefit. Despite strong advocacy by patients, families' and health care professionals, however, initiatives have been slow to move forward in the clinical setting. It is the goal of this scientific statement to serve as a catalyst to spur efforts for large-scale research studies examining psychological experiences, outcomes, and interventions tailored to this population and for integrating mental health professionals within congenital heart disease interdisciplinary teams to implement a care model that offers patients the best possible quality of life.

Objective: The ideal valve substitute for surgical intervention of congenital aortic valve disease in children remains unclear. Data on outcomes beyond 10-15 years after valve replacement are limited but important for evaluating substitute longevity. We aimed to describe up to 25-year death/cardiac transplant by type of valve substitute and assess the potential impact of treatment centre. Our hypothesis was that patients with pulmonic valve autograft would have better survival than mechanical prosthetic., Methods: This is a retrospective cohort study from the Pediatric Cardiac Care Consortium, a multi-institutional US-based registry of paediatric cardiac interventions, linked with the National Death Index and United Network for Organ Sharing through 2019. Children (0-20 years old) receiving aortic valve replacement (AVR) from 1982 to 2003 were identified. Kaplan-Meier transplant-free survival was calculated, and Cox proportional hazard models estimated hazard ratios for mechanical AVR (M-AVR) versus pulmonic valve autograft., Results: Among 911 children, the median age at AVR was 13.4 years (IQR=8.4-16.5) and 73% were male. There were 10 cardiac transplants and 153 deaths, 5 after transplant. The 25-year transplant-free survival post AVR was 87.1% for autograft vs 76.2% for M-AVR and 72.0% for tissue (bioprosthetic or homograft). After adjustment, M-AVR remained related to increased mortality/transplant versus autograft (HR=1.9, 95% CI=1.1 to 3.4). Surprisingly, survival for patients with M-AVR, but not autograft, was lower for those treated in centres with higher in-hospital mortality., Conclusion: Pulmonic valve autograft provides the best long-term outcomes for children with aortic valve disease, but AVR results may depend on a centre's experience or patient selection., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Bicuspid aortic valve (BAV) with ~1%-2% prevalence is the most common congenital heart defect (CHD). It frequently results in valve disease and aorta dilation and is a major cause of adult cardiac surgery. BAV is genetically linked to rare left-heart obstructions (left ventricular outflow tract obstructions [LVOTOs]), including hypoplastic left heart syndrome (HLHS) and coarctation of the aorta (CoA). Mouse and human studies indicate LVOTO is genetically heterogeneous with a complex genetic etiology. Homozygous mutation in the Pcdha protocadherin gene cluster in mice can cause BAV, and also HLHS and other LVOTO phenotypes when accompanied by a second mutation. Here we show two common deletion copy number variants (delCNVs) within the PCDHA gene cluster are associated with LVOTO. Analysis of 1,218 white individuals with LVOTO versus 463 disease-free local control individuals yielded odds ratios (ORs) at 1.47 (95% confidence interval [CI], 1.13-1.92; p = 4.2 × 10 -3 ) for LVOTO, 1.47 (95% CI, 1.10-1.97; p = 0.01) for BAV, 6.13 (95% CI, 2.75-13.7; p = 9.7 × 10 -6 ) for CoA, and 1.49 (95% CI, 1.07-2.08; p = 0.019) for HLHS. Increased OR was observed for all LVOTO phenotypes in homozygous or compound heterozygous PCDHA delCNV genotype comparison versus wild type. Analysis of an independent white cohort (381 affected individuals, 1,352 control individuals) replicated the PCDHA delCNV association with LVOTO. Generalizability of these findings is suggested by similar observations in Black and Chinese individuals with LVOTO. Analysis of Pcdha mutant mice showed reduced PCDHA expression at regions of cell-cell contact in aortic smooth muscle and cushion mesenchyme, suggesting potential mechanisms for BAV pathogenesis and aortopathy. Together, these findings indicate common variants causing PCDHA deficiency play a significant role in the genetic etiology of common and rare LVOTO-CHD.

Objective: To evaluate long-term transplant-free survival and causes of death in the trisomy 21 (T21) population after surgery for congenital heart disease (CHD) in comparison with patients who are euploidic., Study Design: This is a retrospective cohort study from the Pediatric Cardiac Care Consortium, enriched with prospectively collected data from the National Death Index and the Organ Procurement and Transplantation Network for patients with sufficient direct identifiers. Kaplan-Meier survival plots were generated and multivariable Cox proportional hazards models were used to examine risk factors for mortality between patients with T21 and 1:1 matched patients with comparable CHD who are euploidic., Results: A long-term survival analysis was completed for 3376 patients with T21 (75 155 person-years) who met inclusion criteria. The 30-year survival rate for patients with T21 ranged from 92.1% for ventricular septal defect to 65.3% for complex common atrioventricular canal. Of these, 2185 patients with T21 were successfully matched with a patient who was euploidic. After a median follow-up of 22.86 years (IQR, 19.45-27.14 years), 213 deaths occurred in the T21 group (9.7%) compared with 123 (5.6%) in the euploidic comparators. After adjustment for age, sex, era, CHD complexity, and initial palliation, the hazard ratio of CHD-related mortality was 1.34 times higher in patients with T21 (95% CI, 0.92-1.97; P = .127)., Conclusions: CHD-related mortality for patients with T21 after cardiac surgical intervention is comparable with euploidic comparators. Children with T21 require lifelong surveillance for co-occurring conditions associated with their chromosomal abnormality., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: This is a cross-sectional study aiming to understand the early characteristics and background of bone health impairment in clinically well children with Fontan circulation., Methods: We enrolled 10 clinically well children with Fontan palliation (operated >5 years before study entrance, Tanner stage ≤3, age 12.1 ± 1.77 years, 7 males) and 11 healthy controls (age 12.0 ± 1.45 years, 9 males) at two children's hospitals. All patients underwent peripheral quantitative CT. For the Fontan group, we obtained clinical characteristics, NYHA class, cardiac index by MRI, dual x-ray absorptiometry, and biochemical studies. Linear regression was used to compare radius and tibia peripheral quantitative CT measures between Fontan patients and controls., Results: All Fontan patients were clinically well (NYHA class 1 or 2, cardiac index 4.85 ± 1.51 L/min/m2) and without significant comorbidities. Adjusted trabecular bone mineral density, cortical thickness, and bone strength index at the radius were significantly decreased in Fontan patients compared to controls with mean differences -30.13 mg/cm3 (p = 0.041), -0.31 mm (p = 0.043), and -6.65 mg2/mm4 (p = 0.036), respectively. No differences were found for tibial measures. In Fontan patients, the mean height-adjusted lumbar bone mineral density and total body less head z scores were -0.46 ± 1.1 and -0.63 ± 1.1, respectively, which are below the average, but within normal range for age and sex., Conclusions: In a clinically well Fontan cohort, we found significant bone deficits by peripheral quantitative CT in the radius but not the tibia, suggesting non-weight-bearing bones may be more vulnerable to the unique haemodynamics of the Fontan circulation.

Patients who undergo coarctation repair during infancy have excellent early survival but long-term survival is unknown. We aimed to describe the long-term survival of patients with coarctation repaired during infancy and determine predictors of mortality. We performed a retrospective cohort study using data from the Pediatric Cardiac Care Consortium for patients with coarctation who underwent surgical repair before 12 months of age between 1982 and 2003. Long-term transplant-free survival was obtained by linkage with the National Death Index and the Organ Sharing Procurement Network. Kaplan Meier survival plots were constructed, and univariate and multivariable analyses were performed to determine predictors of mortality. We identified 2,424 coarctation patients who met inclusion criteria. At 20 years postoperatively, 94.5% of all patients and 95.8% of those discharged after initial operation remained alive, respectively. Significant multivariable predictors of mortality included surgical weight <2.5 kg (hazard ratio [HR] 3.70, 95% confidence interval [CI] 2.19 to 6.24), presence of a genetic syndrome (HR 2.40, 95% CI 1.13 to 5.10), and repair before 1990 (HR 1.91, 95% CI 1.09 to 3.34). None of the other factors examined including age at repair, gender, coarctation type, or surgical approach were found to be statistically significant. Over half of the deaths were due to the underlying congenital heart disease or other cardiovascular etiology. Overall long-term survival of patients who undergo coarctation repair during infancy is excellent. However, patients do experience small continued survival attrition throughout early adulthood. Ongoing monitoring of this cohort is necessary to assess late mortality risk., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Patients with Trisomy 21 (T21) and single ventricle (SV) physiology present unique challenges compared to euploidic counterparts. This study reports postoperative and long-term outcomes in patients with T21 and SV palliation., Design: This retrospective cohort study from the Pediatric Cardiac Care Consortium (PCCC) included patients with T21 (<21 years old) that underwent surgical palliation for SV between 1982 and 2008 and control patients without known genetic anomaly following Fontan palliation for similar diagnoses. Kaplan-Meier survival plots were created based on death events obtained from the PCCC and by linkage with the National Death Index (NDI) and the Organ Procurement and Transplantation Network (OPTN) through 2014 for patients with adequate identifiers., Results: We identified 118 children with T21 who underwent initial surgical SV palliation. Among 90 (75.6%) patients surviving their first surgery, 66 (73.3%) underwent Glenn anastomosis and 25 (27.8%) completed Fontan palliation with in-hospital survival of 80.3% and 76.0%, respectively. Fifty-three patients had sufficient identifiers for PCCC-NDI-OPTN linkage. Ten-year survival, conditioned on discharge alive after the Fontan procedure, was 66.7% compared to 92.2% for 51 controls without genetic anomaly (P = .001). Median age at death for T21 patients following initial surgical SV palliation was 2.69 years (IQR 1.34-7.12) with most deaths (89.2%) attributed to the underlying congenital heart disease (CHD)., Conclusions: Children with T21 and SV are at high risk for procedural and long-term mortality related to their genetic condition and underlying CHD. Nevertheless, a select group of patients can successfully complete Glenn or Fontan palliation, reaching satisfactory long-term survival., (© 2019 Wiley Periodicals, Inc.)

Objective: Pulmonary atresia with intact ventricular septum (PA/IVS) can be treated by various operative and catheter-based interventions. We aim to understand the long-term transplant-free survival of patients with PA/IVS by treatment strategy., Methods: Cohort study from the Pediatric Cardiac Care Consortium, a multi-institutional registry with prospectively acquired outcome data after linkage with the National Death Index and the Organ Procurement and Transplantation Network., Results: Eligible patients underwent neonatal surgery or catheter-based intervention for PA/IVS between 1982 and 2003 (median follow-up of 16.7 years, IQR: 12.6-22.7). Over the study period, 616 patients with PA/IVS underwent one of three initial interventions: aortopulmonary shunt, right ventricular decompression or both. Risk factors for death at initial intervention included earlier birth era (1982-1992), chromosomal abnormality and atresia of one or both coronary ostia. Among survivors of neonatal hospitalisation (n=491), there were 99 deaths (4 post-transplant) and 10 transplants (median age of death or transplant 0.7 years, IQR: 0.3-1.8 years). Definite repair or last-stage palliation was achieved in the form of completed two-ventricle repair (n=201), one-and-a-half ventricle (n=39) or Fontan (n=96). Overall 20-year survival was 66%, but for patients discharged alive after definitive repair, it reached 97.6% for single-ventricle patients, 90.9% for those with one-and-a-half ventricle and 98.0% for those with complete two-ventricle repair (log-rank p=0.052)., Conclusions: Transplant-free survival in PA/IVS is poor due to significant infantile and interstage mortality. Survival into early adulthood is excellent for patients reaching completion of their intended path independent of type of repair., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Several advances have led to improved hospital survival following neonatal palliation (NP) of single ventricle (SV) anomalies. Nonetheless, a number of patients continue to suffer from interstage mortality (ISM) prior to subsequent Glenn. We aim to study patients' characteristics and anatomic, surgical, and clinical details associated with ISM., Methods: A total of 453 SV neonates survived to hospital discharge following NP. Competing risk analysis modeled events after NP (Glenn, transplantation, or death) and examined variables associated with ISM., Results: Competing risk analysis showed that one year following NP, 10% of patients had died, 87% had progressed to Glenn, 1% had received heart transplantation, and 2% were alive without subsequent surgery. On multivariable analysis, factors associated with ISM were as follows: weight ≤2.5 kg (hazard ratio, HR = 2.4 [1.2-4.6], P = .013), premature birth ≤36 weeks (HR = 2.0 [1.0-4.0], P = .05), genetic syndromes (HR = 3.2 [1.7-6.1], P < .001), unplanned cardiac reoperation (HR = 2.1 [1.0-4.4], P = .05), and prolonged intensive care unit (ICU) stay >30 days following NP (HR = 2.5 [1.4-4.5], P < .001). Palliative surgery type (shunt, Norwood, band) was not associated with ISM, although aortopulmonary shunt circulation after Norwood was (HR = 5.4 [1.5-19.2] P = .01). Of interest, underlying SV anatomy was not associated with ISM (HR = 1.1 [0.6-2.2], P = .749)., Conclusions: In our series, ISM following NP occurred in 10% of hospital survivors. As opposed to hospital death, underlying SV anomaly was not associated with ISM. Conversely, several patient factors (prematurity, low weight, and genetic syndromes) and clinical factors (unplanned reoperation and prolonged ICU stay following NP) were associated with ISM. Vigilant outpatient management that is individualized to specific clinical and social needs, taking into account all associated factors, is warranted to improve survival in high-risk patients.

Objective: Surgical coronary revascularisation in children with congenital heart disease (CHD) is a rare event for which limited information is available. In this study, we review the indications and outcomes of surgical coronary revascularisation from the Pediatric Cardiac Care Consortium, a large US-based multicentre registry of interventions for CHD., Methods: This is a retrospective cohort study of children (<18 years old) with CHD who underwent surgical coronary revascularisation between 1982 and 2011. In-hospital mortality and graft patency data were obtained from the registry. Long-term transplant-free survival through 2014 was achieved for patients with adequate identifiers via linkage with the US National Death Index and the Organ Procurement and Transplantation Network., Results: Coronary revascularisation was accomplished by bypass grafting (n=72, median age 6.8 years, range 3 days-17.4 years) or other operations (n=65, median age 2.6 years, range 5 days-16.7 years) in 137 patients. Most revascularisations were related to the aortic root (61.3%) or coronary anomalies (27.7%), but 10.9% of them were unrelated to either of them. Twenty in-hospital deaths occurred, 70% of them after urgent 'rescue' revascularisation in association with another operation. Long-term outcomes were available by external linkage for 54 patients surviving to hospital discharge (median follow-up time 15.0 years, max follow-up 29.8 years) with a 15-year transplant-free survival of 91% (95% CI 83% to 99%)., Conclusions: Surgical coronary revascularisation can be performed in children with CHD with acceptable immediate and long-term survival. Outcomes are dependent on indication, with the highest mortality in rescue procedures., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

: media-1vid110.1542/5727212367001PEDS-VA&#95;2017-4065 Video Abstract OBJECTIVES: Determine the performance of the American Academy of Pediatrics (AAP) critical congenital heart disease (CCHD) newborn screening algorithm and the impact of an alternative algorithm., Methods: Screening was performed on term infants without a known CCHD diagnosis at or near 24 hours of age at a tertiary birth hospital by using the AAP algorithm from 2013 to 2016. Retrospective review from the birth hospital and the area's sole pediatric cardiac center identified true- and false-positives and true- and false-negatives. A simulation study modeled the results of a modified screening algorithm with a single repeat pulse oximetry test instead of 2., Results: Screening results were collected on 77 148 newborns . By using the current AAP algorithm, 77 114 (99.96%) infants passed screening, 18 infants failed for an initial saturation of <90%, and 16 failed after not attaining a passing pulse oximetry level after 3 tests. There was 1 true-positive (total anomalous pulmonary venous return), 33 false-positives, and 6 false-negatives, yielding an overall specificity of 99.96%, a sensitivity of 14.3%, and a false-positive rate of 0.043%. Among false-positives, 10 (31.3%) had significant non-CCHD disease. Simulating the modified algorithm, sensitivity remained at 14.3%, and the false-positive rate increased to 0.054%., Conclusions: Although CCHD screening in a tertiary care birth hospital may not detect many new cases of CCHD, it can detect other important diseases in newborns. Modifying the screening algorithm to 1 repeat pulse oximetry test instead of 2 may detect additional infants with significant disease without a substantial increase in the false-positive rate., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Background: Long-term survival, risk of transplantation, and causes of death after repair of total anomalous pulmonary venous connection (TAPVC) remain unknown. By linking the Pediatric Cardiac Care Consortium with the National Death Index and the United Network for Organ Sharing, we evaluated long-term transplant-free survival in children undergoing repair of TAPVC., Methods: We identified 777 infants within the Pediatric Cardiac Care Consortium who underwent TAPVC repair (median 21 days; interquartile range, 5 to 80) and had sufficient personal identifiers for linkage with the National Death Index and United Network for Organ Sharing. Sixty-six deaths, ten cardiac transplantations, and one bilateral lung transplantation had occurred by the end of 2014. Data collected included age and weight at time of procedure, TAPVC type, associated cardiac lesions, and postoperative length of stay. The study cohort was divided into simple and complex TAPVC based on the presence of an associated cardiac lesion. Parametric survival plots were constructed, and risk factor analyses were performed to identify demographic and clinical characteristics associated with long-term outcomes., Results: Mortality or need for transplantation was 9.7% with a median follow-up of 18.4 years and a median age of death or transplant of 0.74 years. The risk of mortality and transplant after TAPVC repair was highest during the first 18 months after hospital discharge. Cardiac causes accounted for the majority of deaths. Multivariate regression models for transplant-free survival demonstrated that complex TAPVC, mixed TAPVC, and postoperative length of stay were associated with increased risk of death/transplant., Conclusions: Transplant-free survival after TAPVC repair is excellent, with most deaths or transplant events occurring early. Factors associated with the worst long-term outcomes included complex TAPVC, mixed TAPVC, and prolonged postoperative length of stay., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Ultrasound imaging of adults with heart failure and increased central venous pressure (CVP) has shown significant thoracic duct (TD) dilation from impedance in lymphatic drainage. Elevated CVP and abnormal lymphatic drainage are implicated in severe Fontan complications, including protein losing enteropathy (PLE) and plastic bronchitis (PB). Systematic studies of TD and lymphatic circulation in children are limited, and their cervical TD normative values have not been established., Methods: Thoracic duct imaging was attempted prospectively during routine echocardiograms performed 7/2014-9/2016 in children 5-21 years old with normal cardiovascular physiology and Fontan palliation. TD insertion to the central venous system (lympho-venous junction) was assessed with an S12-4 MHz transducer. For the first 34 patients, only TD ostia were measured, but ostium shape variability at the lympho-venous junction led to including the TD arch 5-10 mm proximal to the ostium for the remaining cohort., Results: Seventy-nine total subjects were studied: 58 controls, 13 Fontan patients with normal systemic ventricular ejection fraction (EF) (>50%), and 8 Fontan patients with decreased EF (≤50%). Combined Fontan subjects had larger TD ostial diameters compared to controls when normalized by body surface area (median 2.6 mm/m 2 vs. 2 mm/m 2 ) (P=.04)., Conclusion: To our knowledge, this is the first systematic study of ultrasonographic TD imaging in children. Fontan patients have larger TD diameters, reflecting the impaired lymphatic circulation in patients with this physiology. Further research may provide important associations between sonographic TD features with the functional status of patients with Fontan circulation., (© 2017, Wiley Periodicals, Inc.)

Background: The purpose of this study is to report short- and long-term outcomes after congenital heart defect (CHD) interventions in patients with trisomy 13 or 18., Methods: A retrospective review of the Pediatric Cardiac Care Consortium (PCCC) identified children with trisomy 13 or 18 with interventions for CHD between 1982 and 2008. Long-term survival and cause of death were obtained through linkage with the National Death Index., Results: A total of 50 patients with trisomy 13 and 121 patients with trisomy 18 were enrolled in PCCC between 1982 and 2008; among them 29 patients with trisomy 13 and 69 patients with trisomy 18 underwent intervention for CHD. In-hospital mortality rates for patients with trisomy 13 or trisomy 18 were 27.6% and 13%, respectively. Causes of in-hospital death were primarily cardiac (64.7%) or multiple organ system failure (17.6%). National Death Index linkage confirmed 23 deaths after discharge. Median survival (conditioned to hospital discharge) was 14.8 years (95% confidence interval [CI]: 12.3 to 25.6 years) for patients with trisomy 13 and 16.2 years (95% CI: 12 to 20.4 years) for patients with trisomy 18. Causes of late death included cardiac (43.5%), respiratory (26.1%), and pulmonary hypertension (13%)., Conclusions: In-hospital mortality rate for all surgical risk categories was higher in patients with trisomy 13 or 18 than that reported for the general population. However, patients with trisomy 13 or 18, who were selected as acceptable candidates for cardiac intervention and who survived CHD intervention, demonstrated longer survival than previously reported. These findings can be used to counsel families and make program-level decisions on offering intervention to carefully selected patients., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Fontan survivors have depressed cardiac index that worsens over time. Serum biomarker measurement is minimally invasive, rapid, widely available, and may be useful for serial monitoring. The purpose of this study was to identify biomarkers that correlate with lower cardiac index in Fontan patients. Methods and results This study was a multi-centre case series assessing the correlations between biomarkers and cardiac magnetic resonance-derived cardiac index in Fontan patients ⩾6 years of age with biochemical and haematopoietic biomarkers obtained ±12 months from cardiac magnetic resonance. Medical history and biomarker values were obtained by chart review. Spearman's Rank correlation assessed associations between biomarker z-scores and cardiac index. Biomarkers with significant correlations had receiver operating characteristic curves and area under the curve estimated. In total, 97 cardiac magnetic resonances in 87 patients met inclusion criteria: median age at cardiac magnetic resonance was 15 (6-33) years. Significant correlations were found between cardiac index and total alkaline phosphatase (-0.26, p=0.04), estimated creatinine clearance (0.26, p=0.02), and mean corpuscular volume (-0.32, p<0.01). Area under the curve for the three individual biomarkers was 0.63-0.69. Area under the curve for the three-biomarker panel was 0.75. Comparison of cardiac index above and below the receiver operating characteristic curve-identified cut-off points revealed significant differences for each biomarker (p<0.01) and for the composite panel [median cardiac index for higher-risk group=2.17 L/minute/m2 versus lower-risk group=2.96 L/minute/m2, (p<0.01)]., Conclusions: Higher total alkaline phosphatase and mean corpuscular volume as well as lower estimated creatinine clearance identify Fontan patients with lower cardiac index. Using biomarkers to monitor haemodynamics and organ-specific effects warrants prospective investigation.

Background: The long-term outcomes of patients undergoing interventions for congenital heart disease (CHD) remain largely unknown. We linked the Pediatric Cardiac Care Consortium (PCCC) with the National Death Index (NDI) and the United Network for Organ Sharing Dataset (UNOS) registries to study mortality and transplant occurring up to 32 years postintervention. The objective of the current analysis was to determine the sensitivity of this linkage in identifying patients who are known to have died or undergone heart transplant., Methods and Results: We used direct identifiers from 59 324 subjects registered in the PCCC between 1982 and 2003 to test for completeness of case ascertainment of subjects with known vital and heart transplant status by linkage with the NDI and UNOS registries. Of the 4612 in-hospital deaths, 3873 were identified by the NDI as "true" matches for a sensitivity of 84.0% (95% CI, 82.9-85.0). There was no difference in sensitivity across 25 congenital cardiovascular conditions after adjustment for age, sex, race, presence of first name, death year, and residence at death. Of 455 known heart transplants in the PCCC, there were 408 matches in the UNOS registry, for a sensitivity of 89.7% (95% CI, 86.9-92.3). An additional 4851 deaths and 363 transplants that occurred outside the PCCC were identified through 2014., Conclusions: The linkage of the PCCC with the NDI and UNOS national registries is feasible with a satisfactory sensitivity. This linkage provides a conservative estimate of the long-term death and heart transplant events in this cohort., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: The surgical mortality associated with repair of coarctation of the aorta (CoA) over a 25-year period was examined. Risk factors for discharge mortality were evaluated as well as the surgical techniques and its evolution over the period studied., Methods: Utilizing the pediatric cardiac care consortium, we conducted a retrospective review of patients less than 18 years of age submitted between 1982 and 2007. Variables reviewed included weight at birth, age and weight at the operation, type of coarctation repair, associated cardiac anomalies, year of repair, center-specific volume, postoperative length of stay, and in-hospital mortality., Results: There were 7,860 patients submitted with the procedural code for repair of CoA. Forty-five percent underwent repair within 30 days of life (n = 3,549), including 1,444 patients who were operated upon within the first 7 days of life (18% of all patients). Seventy percent (n = 5,528) of patients had an isolated CoA (iCoA). The overall mortality for the entire group was 4.2% (n = 331), decreasing to 2.0% (n = 114) for iCoA (P < .0001). A hypoplastic aortic arch occurred in 4.6%, with a mortality of 10.6%. Coarctectomy with an end-to-end reconstruction was the most common procedure performed. Multivariable modeling for discharge mortality was significant for diagnosis of ventricular septal defect, operative weight, operative year, and diagnosis of aortic arch hypoplasia., Conclusions: Operative repair of CoA is accomplished with a low mortality, although certain subgroups have persistently inferior outcomes. The techniques utilized for aortic reconstruction have evolved, with coarctectomy and an end-to-end anastomosis becoming the dominant surgical procedures., (© The Author(s) 2015.)

Prior to state-wide implementation of newborn screening for critical congenital heart disease (CCHD) in Minnesota, a pilot program was completed using the protocol recommended by the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC). This report compares the retesting rates for newborn screening for CCHDs using the SACHDNC protocol and four alternative algorithms used in large published CCHD screening studies. Data from the original Minnesota study were reanalyzed using the passing values from these four alternative protocols. The retesting rate for the first pulse oximeter measurement ranged from 1.1 % in the SACHDNC protocol to 9.6 % in the Ewer protocol. The SACHDNC protocol generated the lowest rate of retesting among all tested algorithms. Our data suggest that even minor modifications of CCHD screening protocol would significantly impact screening retesting rate. In addition, we provide support for including lower extremity oxygen saturations in the screening algorithm.

Conditions that increase central venous pressure lead to secondary dilation of the thoracic duct and impaired lymphatic circulation. We report the use of ultrasound to directly image the cervical part of the thoracic duct in children without the need for invasive techniques or contrast agents. Systematic evaluation of the thoracic duct may be useful in cardiovascular conditions with congestion of the lymphatic system such as single ventricle following Glenn or Fontan procedures., (© 2014, Wiley Periodicals, Inc.)

Background: Management of a ventricular septal defect (VSD) at time of coarctation of the aorta (CoA) repair remains controversial, with recent studies advocating concomitant repair of both defects. We evaluated the surgical management and mortality for patients undergoing CoA repair associated with a VSD., Methods: We retrospectively reviewed data submitted to the Pediatric Cardiac Care Consortium of patients undergoing repair of CoA from 1982 to 2007. The cohort was divided into three groups: CoA repair plus VSD closure (group 1); CoA repair plus pulmonary artery band (group 2); and CoA repair without repair of VSD (group 3). Variables reviewed included era, age, and weight at repair, and in-hospital mortality., Results: There were 7,860 patients who underwent repair of CoA, of whom 2,022 had an associated VSD (25.7%). Mortality after CoA repair with and without an associated diagnosis of VSD was 8.3% versus 2.1% (p < 0.001). Mean age at repair for group 1 (n = 286) and group 2 (n = 472) was 87.4 days and 21.6 days, respectively (p = 0.004), and median weight was 3.31 kg and 3.30 kg, respectively (p = 0.130). Discharge mortality for group 1 and group 2 was similar, at 8.7% and 9.1%, respectively (p = 0.852). Patients with CoA/VSD who had neither VSD closure nor pulmonary artery banding (group 3) had a hospital mortality of 7.9%., Conclusions: The association of CoA and VSD is common. A strategy of concomitant VSD closure at CoA repair does not result in worse discharge mortality when compared with pulmonary banding with anticipated staged repair of the VSD. These outcomes support continued evaluation of a one-stage approach., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

We describe an atypical case of an atrioventricular septal defect with a common atrioventricular junction in which the right-sided component of the common atrioventricular valve was imperforate, producing tricuspid atresia with a severely hypoplastic right ventricle and an ostium primum defect. We discuss the implications of the anatomic findings with regard to concepts of cardiac development, drawing a comparison with similar cases previously reported.

Background: Sex has been linked to differential outcomes for cardiovascular disease in adults. We examined potential sex differences in outcomes after pediatric cardiac surgery., Methods and Results: We retrospectively analyzed data from the Pediatric Cardiac Care Consortium (1982-2007) by using logistic regression to evaluate the effects of sex on 30-day within-hospital mortality after pediatric (<18 years old) cardiac operations and its interaction with age, risk category, z-score for weight, and surgical year for the whole cohort. Of 76 312 operations, 55% were in boys. Unadjusted mortality was similar for boys and girls (5.2% versus 5.0%, P=0.313), but boys were more likely to have cardiac surgery as a neonate and to have more complex operations. After adjustment, the overall test of any association between postsurgical mortality and sex was significant (P=0.002), but the overall test of any interaction was not (P=0.503). However, a potential age-dependent sex effect on postsurgical mortality was observed among infants subjected to high-risk operations, with girls doing worse during the first 6 months of life., Conclusions: Patient sex has a significant effect on mortality after pediatric cardiac operations, with an increased risk of death in early infancy for girls after high-risk cardiac operations. This age-dependent relationship supports a sex-related biological effect on postoperative cardiovascular stress.

Objective: To assess the level of preparedness and resources needed in Minnesota for the implementation of newborn screening for critical congenital heart diseases (CCHDs)., Methods: A cross sectional survey of all birth centers in Minnesota was performed to assess the capacity to deliver care essential for the CCHD screening program. Compliance with the screening algorithm, nursing workload, and cost were assessed by using a pilot program implemented in 6 normal newborn nurseries., Results: Ninety-one of 99 eligible centers participated in the survey and 90 reported the ability to screen newborns in accordance with recommendations. Only 22 centers, with 63% of births, had access to echocardiography and routinely stocked prostaglandins for neonatal use. Our pilot study screened 7549 newborns with 6 failed screens and 1 CCHD diagnosis. Two of the failed screens were due to misinterpretation of the algorithm, 1 failed screen was not reported, and 4 failed screens were not recognized. Repeated screens were required for 115 newborns, with 29% of retesting due to misinterpretation of the algorithm. The mean nursing time required was 5.5 minutes, and the cost was $5.10 per screen., Conclusions: In Minnesota, two-thirds of newborns are born in centers with resources for initial diagnosis and management of CCHD. Implementation of a pilot screening program demonstrated minimal increase in nursing workload, but identified problems with interpretation of the algorithm and data reporting. This pilot project suggests the need for simplification of the algorithm, additional training of health care providers, and development of a centralized reporting mechanism.

The risk factors for superior vena cava (SVC) obstruction after pediatric orthotopic heart transplantation (OHT) have not been identified. This study tested the hypothesis that pretransplant superior cavopulmonary anastomosis (CPA) predisposes patients to SVC obstruction. A retrospective review of the Pediatric Cardiac Care Consortium registry from 1982 through 2007 was performed. Previous CPA, other cardiac surgeries, gender, age at transplantation, and weight at transplantation were assessed for the risk of developing SVC obstruction. Death, subsequent OHT, or reoperation involving the SVC were treated as competing risks. Of the 894 pediatric OHT patients identified, 3.1% (n = 28) developed SVC obstruction during median follow-up of 1.0 year (range: 0 to 19.5 years). Among patients who developed SVC obstruction, 32% (n = 9) had pretransplant CPA. SVC surgery before OHT was associated with posttransplant development of SVC obstruction (p <0.001) after adjustment for gender, age, and weight at OHT and year of OHT. Patients with previous CPA had increased risk for SVC obstruction compared with patients with no history of previous cardiac surgery (hazard ratio 10.6, 95% confidence interval: 3.5 to 31.7) and to patients with history of non-CPA cardiac surgery (hazard ratio 4.7, 95% confidence interval: 1.8 to 12.5). In conclusion, previous CPA is a significant risk factor for the development of post-heart transplant SVC obstruction., (Published by Elsevier Inc.)

Mortality after pediatric cardiac surgery varies among centers. Previous research suggests that surgical volume is an important predictor of this variation. This report characterizes the relative contribution of patient factors, center surgical volume, and a volume-independent center effect on early postoperative mortality in a retrospective cohort study of North American centers in the Pediatric Cardiac Care Consortium (up to 500 cases/center/year). From 1982 to 2007, 49 centers reported 109,475 operations, 85,023 of which were analyzed using hierarchical multivariate logistic regression analysis. Patient characteristics varied significantly among the centers. The adjusted odds ratio (OR) for mortality decreased more than 10-fold during the study period (1982 vs. 2007: OR, 12.27, 95 % confidence interval [CI], 8.52-17.66; p < 0.0001). Surgical volume was associated inversely with odds of death (additional 100 cases/year: OR, 0.84; 95 % CI, 0.78-0.90; p < 0.0001). In the analysis of interactions, this effect was fairly consistent across age groups, risk categories (except the lowest), and time periods. However, a volume-independent center effect contributed substantially more to the risk model than did the volume. The Risk Adjusted Classification for Congenital Heart Surgery, version 1 (RACHS-1) risk category remains the strongest predictor of postoperative mortality through the 25-year study period. In conclusion, center-specific variation exists but is only partially explained by operative volume. Low-risk operations are safely performed at centers in all volume categories, whereas regionalization or other quality improvement strategies appear to be warranted for moderate- and high-risk operations. Potentially preventable mortality occurs at centers in all volume categories studied, so referral or regionalization strategies must target centers by observed outcomes rather than assume that volume predicts quality.

Pseudocoarctation of the aorta (PCOA) is an unusual congenital malformation of the aortic arch characterized by an acute anterior angulation of the aortic arch at the level of the ligamentum arteriosum with little or no obstruction. This report describes the occurrence of PCOA and other aortic arch abnormalities including true coarctation, right aortic arch, and aneurysms of the proximal and distal aortic arch in three generations of a single family. To our knowledge, a familial form of PCOA has not been described.

Objectives: Few studies have described the survival of low-birth-weight infants weighing less than 1.5 kg at operation for a cardiac malformation. Our goal was to determine if body weight at surgery affects survival., Methods: This was a retrospective cohort study using outcome data from the Pediatric Cardiac Care Consortium between 1982 and 2006., Results: We reviewed the outcomes of 450 consecutive infants with a cardiac anomaly and a birth weight of less than 1.5 kg, and weight of less than 2.5 kg at surgery. Of these, 179 patients had undergone surgery with a weight of less than 1.5 kg and 271 patients weighed 1.5 to 2.5 kg at surgery. The 30-day survival rate was 83% for cohort 1 and 86% for cohort 2. For patients not requiring cardiopulmonary bypass, the 30-day survival rate was 86% for cohort 1 and 92% for cohort 2. For patients requiring cardiopulmonary bypass, the 30-day survival rate was 69% for cohort 1 and 73% for cohort 2. No notable improvement in the outcomes occurred over time., Conclusions: For low-birth-weight infants (weight < 1.5 kg) undergoing a major cardiac procedure, the survival of infants weighing less than 1.5 kg at surgery is comparable to that of infants who weighed 1.5 to 2.5 kg. We conclude that, in our series, weight was not an independent risk factor for mortality, and, therefore, operative delay because of patient weight might be unwarranted., (Copyright © 2010 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

We report a series of children with clinical myocarditis presenting with chest pain and elevated cardiac troponin I mimicking coronary syndrome. Our series illustrates the complementary role the magnetic resonance imaging and computed tomographic angiography can play in the evaluation of these patients. Elevated cardiac troponin I levels were found to be related to the extent of myocardial involvement, but did not necessarily indicate poor prognosis in children with myocarditis.

Background: Myocardial hypoxic-ischemic injury is the cause of significant morbidity and mortality worldwide. The cardiomyocyte response to hypoxic-ischemic injury is known to include changes in cell cycle regulators. The cyclin-dependent kinase inhibitor p57Kip2 is involved in cell cycle control, differentiation, stress signaling and apoptosis. In contrast to other cyclin-dependent kinase inhibitors, p57Kip2 expression diminishes during postnatal life and is reactivated in the adult heart under conditions of cardiac stress. Overexpression of p57Kip2 has been previously shown to prevent apoptotic cell death in vitro by inhibiting stress-activated kinases. Therefore, we hypothesized that p57Kip2 has a protective role in cardiomyocytes under hypoxic conditions. To investigate this hypothesis, we created a transgenic mouse (R26loxpTA-p57k/+) that expresses p57Kip2 specifically in cardiac tissue under the ventricular cardiomyocyte promoter Mlc2v., Results: Transgenic mice with cardiac specific overexpression of p57Kip2 are viable, fertile and normally active and their hearts are morphologically indistinguishable from the control hearts and have similar heart weight/body weight ratio. The baseline functional parameters, including left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), LVdp/dtmax, heart rate (HR) and rate pressure product (RPR) were not significantly different between the different groups as assessed by the Langendorff perfused heart preparation. However, after subjecting the heart ex vivo to 30 minutes of ischemia-reperfusion injury, the p57Kip2 overexpressing hearts demonstrated preserved cardiac function compared to control mice with higher left ventricular developed pressure (63 +/- 15 vs 30 +/- 6 mmHg, p = 0.05), rate pressure product (22.8 +/- 4.86 vs 10.4 +/- 2.1 x 103bpm x mmHg, p < 0.05) and coronary flow (3.5 +/- 0.5 vs 2.38 +/- 0.24 ml/min, p <0.05)., Conclusion: These data suggest that forced cardiac expression of p57Kip2 does not affect myocardial growth, differentiation and baseline function but attenuates injury from ischemia-reperfusion in the adult mouse heart.

Here we report a patient with partial trisomy 2p and congenital dysplasia of the semilunar valves. To our knowledge, this is the first case of 2p duplication with developmental defects of both semilunar valves and suggests that genes on this region contribute to the formation of the semilunar valves.

Tbx1 is one of the genes within the DiGeorge Critical Region (DGCR) and has been recently identified as the critical gene for the cardiovascular anomalies in the DiGeorge mouse models. We have cloned, sequenced and analyzed the zebrafish (Danio rerio) tbx1 cDNA. It encodes a protein of 460 amino acids that shares 64% identity and 67% similarity with the human TBX1 orthologue at the amino acid level. Although maternal expression was detected by RT-PCR, only zygotic expression could be detected by whole-mount in situ hybridization. Expression of zebrafish tbx1 by whole-mount in situ hybridization was first detected at 40% epiboly, 5.0 hours post fertilization (hpf) in the dorsal blastoderm margin. Through the stage of embryonic shield formation, tbx1 expression is restricted to the hypoblast, in the region of cells fated to become head and lateral plate mesoderm and pharyngeal endoderm. At 18 hpf, when the heart tube is beginning to assemble, three domains of tbx1 expression can be seen: cardiac precursors, pharyngeal arch precursors and otic vesicle. These three domains will remain the sites of tbx1 expression to varying degrees through at least 72 hpf. By 51 hpf, tbx1 expression can be seen in the cardiac outflow tract, the ventricle and the atrium, although by 72 hpf cardiac expression is strongest in the cardiac outflow tract. This newly identified tbx1 expression pattern in cardiac regions other than the cardiac outflow tract offers a new insight into the role of the tbx1 transcription factor in cardiac development.

Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) is a congenital anomaly disorder associated with hemizygous 22q11 deletions. We previously showed that bacterial artificial chromosome (BAC) transgenic mice overexpressing four transgenes, PNUTL1, (CDCrel-1), GP1B beta, TBX1 and WDR14, had reduced viability, cardiovascular malformations and thymus gland hypoplasia. Since these are hallmark features of VCFS/DGS, we analyzed the mice for additional anomalies. We found that the mice have important defects in the middle and inner ear that are directly relevant to the disorder. The most striking defect was the presence of chronic otitis media, a common finding in VCFS/DGS patients. In addition, the mice had a hyperactive circling behavior and sensorineural hearing loss. This was associated with middle and inner ear malformations, analogous to Mondini dysplasia in humans reported to occur in VCFS/DGS patients. We propose that overexpression of one or more of the transgenes is responsible for the etiology of the ear defects in the mice. Based upon its pattern of expression in the ear and functional studies of the gene, TbX1 likely plays a central role. Haploinsufficiency of TBX1 may be responsible for ear disorders in VCFS/DGS patients.

During embryonic development the heart is required to grow in size and cell number, undergo complex morphologic alterations, and function to circulate the blood. Between embryonic d 10.5 (E10.5) and E11.5, cardiac myocytes undergo rapid cell division, resulting in doubling of cardiac mass, while metabolic requirements are increased and contraction force is enhanced. Accelerated cardiomyocyte differentiation is accompanied by a significant increase in trabeculation of ventricular myocardium. Many single gene mutations in the mouse result in a "thinned myocardium" and embryonic lethality between E10.5 and E13.5 secondary to heart failure. This is the case in the Splotch mouse in which a mutation of the Pax3 gene results in neural crest and cardiac defects. Nevertheless, the molecular events governing these important developmental steps remain largely unknown. Here, we describe the use of suppression subtractive hybridization to identify mRNA transcripts whose expression is enhanced during this critical period in normal hearts. These genes encode functions related to maturation of the contractile apparatus, cardiomyocyte differentiation, altered cellular metabolism, and transcriptional regulation. One of the genes that we identified, p57Kip2, encodes a cyclin-dependent kinase inhibitor of the p21 family. We show that p57Kip2 is normally expressed in the inner trabecular layer of the developing heart. In Splotch embryos, expression of p57Kip2 is expanded to encompass the entire thickness of the myocardium. This result and further structural analysis suggests that the myocardial defect of Splotch embryos is associated with precocious cardiomyocyte differentiation.