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Background: Rejection remains an important cause of morbidity and mortality after pediatric heart transplantation (HT). Endomyocardial biopsy (EMB) is the gold standard for rejection diagnosis, but it comes with procedural risk. The frequency of EMB varies significantly across centers. Since April 2018, our center's surveillance EMB schedule is based on a rejection risk prediction score employing age, pre-HT diagnosis, and panel reactive antibodies (PRA). We aimed to evaluate outcomes in the 1st year post-HT before and after risk score implementation., Methods: Patients who underwent HT at our center at ≤ 18 years of age from January 2015 to December 2020 were reviewed. The primary endpoint was rejection-free survival at 1 year-post- HT. Clinical characteristics were compared for patients transplanted in Era 1 (January 2015-April 2018) and Era 2 (April 2018-December 2020). Cumulative 1-year survival free from rejection and from rejection with hemodynamic compromise (RHC) was compared between eras using Kaplan-Meier survival analysis., Results: 115 patients underwent HT during our study period (52 in Era 1 and 63 in Era 2). There was an increase in VAD utilization between eras (19% in Era 1 vs. 40% in Era 2, p = 0.025), but otherwise no significant difference in demographic or clinical variables between the two eras. No statistically significant difference in freedom from rejection or freedom from RHC was identified between the two eras. There was a 60% reduction in the median number of EMB per patient in the first year post-HT after employing the score (5 in Era 1 vs. 2 in Era 2, p < 0.001)., Conclusions: After employing a rejection risk prediction score, our center decreased the frequency of EMB without worsening early post-HT outcomes, thus establishing the clinical applicability of this tool., (© 2024 The Author(s). Pediatric Transplantation published by Wiley Periodicals LLC.)

Background: Waitlist mortality (WM) remains elevated in pediatric heart transplantation. Allocation policy is a potential tool to help improve WM. This study aims to identify patients at highest risk for WM to potentially inform future allocation policy changes., Methods: The Pediatric Heart Transplant Society database was queried for patients <18 years of age indicated for heart transplantation between January 1, 2010 to December 31, 2021. Waitlist mortality was defined as death while awaiting transplant or removal from the waitlist due to clinical deterioration. Because WM is low after the first year, analysis was limited to the first 12 months on the heart transplant list. Kaplan-Meier analysis and log-rank testing was conducted to compare unadjusted survival between groups. Cox proportional hazard models were created to determine risk factors for WM. Subgroup analysis was performed for status 1A patients based on body surface area (BSA) at time of listing, cardiac diagnosis, and presence of mechanical circulatory support., Results: In total 5974 children met study criteria of which 3928 were status 1A, 1012 were status 1B, 963 were listed status 2, and 65 were listed status 7. Because of the significant burden of WM experienced by 1A patients, further analysis was performed in only patients indicated as 1A. Within that group of patients, those with smaller size and lower eGFR had higher WM, whereas those patients without congenital heart disease or support from a ventricular assist device (VAD) at time of listing had decreased WM. In the smallest size cohort, cardiac diagnoses other than dilated cardiomyopathy were risk factors for WM. Previous cardiac surgery was a risk factor in the 0.3 to 0.7 m 2 and >0.7 m 2 BSA groups. VAD support was associated with lower WM other than in the single ventricle cohort, where VAD was associated with higher WM. Extracorporeal membrane oxygenation and mechanical ventilation were associated with increased risk of WM in all cohorts., Conclusions: There is significant variability in WM among status-1A patients. Potential refinements to current allocation system should factor in the increased WM risk we identified in patients supported by extracorporeal membrane oxygenation or mechanical ventilation, single ventricle congenital heart disease on VAD support and small children with congenital heart disease, restrictive cardiomyopathy, or hypertrophic cardiomyopathy., Competing Interests: None.

Background: The cardiovascular adaptations associated with structured exercise training in Fontan patients remain unknown. We hypothesised that short-term training causes cardiac remodelling and parallel improvement in maximal exercise capacity (VO2 max) in these patients., Methods and Results: Five patients, median age 19.5 (17.6-21.3) years, with a history of Fontan operation meeting inclusion/exclusion criteria, participated in a 3-month training programme designed to improve endurance. Magnetic resonance images for assessment of cardiac function, fibrosis, cardiac output, and liver elastography to assess stiffness were obtained at baseline and after training. Maximal exercise capacity (VO2 max) and cardiac output Qc (effective pulmonary blood flow) at rest and during exercise were measured (C2H2 rebreathing) at the same interval. VO2 max increased from median (IQR) 27.2 (26-28.7) to 29.6 (28.5-32.2) ml/min/kg (p = 0.04). There was an improvement in cardiac output (Qc) during maximal exercise testing from median (IQR) 10.3 (10.1-12.3) to 12.3 (10.9-14.9) l/min, but this change was variable (p = 0.14). Improvement in VO2 max correlated with an increase in ventricular mass (r = 0.95, p = 0.01), and improvement in Quality-of-life inventory (PedsQL) Cardiac scale scores for patient-reported symptoms (r = 0.90, p = 0.03) and cognitive problems (r = 0.89, p = 0.04). The correlation between VO2 max and Qc showed a positive trend but was not significant (r = 0.8, p = 0.08). No adverse cardiac or liver adaptations were noted., Conclusion: Short-term training improved exercise capacity in this Fontan pilot without any adverse cardiac or liver adaptations. These results warrant further study in a larger population and over a longer duration of time., Trial Registration Number: NCT03263312, Unique Protocol ID: STU 122016-037; Registration Date: 18 January, 2017.

Pediatric patients with cardiovascular disease are at increased risk of cardiopulmonary arrest. Despite utilization of Cardiac Pediatric Early Warning Scores to identify patients at risk of decompensation, our institution had a twofold increase in cardiac arrests (CAs) in the acute care cardiology unit (ACCU) over 2 years. Through a quality improvement initiative, we developed a watcher program, HeartWatch, to reduce the CA arrest rate in the ACCU by 50% over the first year of implementation., Methods: HeartWatch aims to identify patients not adequately captured by Cardiac Pediatric Early Warning Scores who are at high risk for sudden decompensation. Inclusion criteria were developed and evaluated during pilot and implemented phases (April 2020-April 2021) and then monitored in a sustained phase through June 2022. Our primary outcome was the reduction in the out-of-ICU CA rate., Results: During the 13 months, we enrolled 169 patients, and the CA rate decreased from 0.7 to 0.33 per 1,000 patient days, a 53% reduction. The CA rate further decreased to 0.28 events per 1,000 patient days, a 60% reduction, by June 2022. The most common indications for HeartWatch inclusion were high-risk single-ventricle patients (31%) and patients with diminished ventricular function (20%)., Conclusions: Implementation of HeartWatch was associated with a meaningful reduction in CA in the ACCU. Creating shared mental models for high-risk patients is essential for patient safety. Future work will optimize local processes that focus on the sustainability of our gains. We will also evaluate opportunities to adapt and implement a similar framework in other institutions to assess reproducibility., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Abnormal dystrophin production due to mutations in the dystrophin gene causes Duchenne Muscular Dystrophy (DMD). Cases demonstrate considerable genetic and disease progression variability. It is unclear if specific gene mutations are prognostic of outcomes in this population. We conducted a retrospective cohort study of DMD patients followed at 17 centers across the USA and Canada from 2005 to 2015 with goal of understanding the genetic variability of DMD and its impact on clinical outcomes. Cumulative incidence of clinically relevant outcomes was stratified by genetic mutation type, exon mutation location, and extent of exon deletion. Of 436 males with DMD, 324 (74.3%) underwent genetic testing. Deletions were the most common mutation type (256, 79%), followed by point mutations (45, 13.9%) and duplications (23, 7.1%). There were 131 combinations of mutations with most mutations located along exons 45 to 52. The number of exons deleted varied between 1 and 52 with a median of 3 exons deleted (IQR 1-6). Subjects with mutations starting at exon positions 40-54 had a later onset of arrhythmias occurring at median age 25 years (95% CI 18-∞), p = 0.01. Loss of ambulation occurred later at median age of 13 years (95% CI 12-15) in subjects with mutations that started between exons 55-79, p = 0.01. There was no association between mutation type or location and onset of cardiac dysfunction. We report the genetic variability in DMD and its association with timing of clinical outcomes. Genetic modifiers may explain some phenotypic variability., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Adults with heart failure and transplant are at increased risk for psychiatric comorbidities. The prevalence and impact of psychiatric comorbidities have not been well studied in pediatric heart failure and transplant. This quality improvement project sought to evaluate the feasibility of utilizing electronic mental health screening measures during pediatric heart failure and transplant clinics and to explore the prevalence and severity of self-reported depressive, anxiety, and suicidal ideation symptoms. Patients aged 11 years and older who presented to a pediatric heart failure and transplant clinic were administered the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7). Medical chart review and a survey were used to examine additional variables of interest. There were no significant differences in moderate and severe mental health symptoms between gender, medical diagnoses, or those with recent hospitalizations. Pediatric patients with heart failure or transplant reported higher prevalence of anxiety and depressive symptoms, and similar suicidal ideation compared to the general adolescent population. Moreover, rates of depression and anxiety symptoms as well as suicidal ideation were comparable to pediatric patients with diabetes, lupus, inflammatory bowel disease, and cystic fibrosis. Results suggest electronic mental health screening is feasible for use during outpatient cardiology clinic visits and provides valuable mental health information., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Pediatric donor heart acceptability differs among transplant centers. However, the impact of center donor acceptance on waitlist and posttransplant outcomes has not been investigated. The aim of our study was to investigate associations between transplant center refusal rate (RR) and outcomes after listing., Methods: Retrospective analysis was performed using United Network for Organ Sharing/Organ Procurement and Transplant Network pediatric (<18 y) heart transplant data from 2007 to 2017. Center RR was defined as the median number of refusals per listed patient. Associations between RR center quartile and waitlist time, waitlist removal for death or clinical deterioration, posttransplant survival, and survival after listing were investigated., Results: There were 5552 listed patients in 59 centers who met inclusion criteria. The lowest quartile RR centers had a median RR of ≤1 per listed patient, and highest RR centers percentile had a median RR of ≥4. Highest RR centers had shorter time to first offer (19 versus 38 d; P < 0.001), with longer waitlist times (203 versus 145 d; P < 0.001), were more likely to remove patients from the waitlist due to death or deterioration (24.1% versus 14.6%; P < 0.001), less likely to transplant listed patients (63.1% versus 77.6%; P < 0.001), and had a lower likelihood of survival 1 year after listing (79.2% versus 91.6%; odds ratio, 1.6; 95% confidence interval, 1.2-2.0; P < 0.001) compared with low RR centers., Conclusions: Patients listed at high RR centers had worse survival from listing despite having shorter times to first offer., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Mechanical support of patients with superior cavopulmonary connection is challenging; multiple factors contribute to failure: elevated pulmonary vascular resistance, aortopulmonary collateral flow, venovenous collaterals, ventricular dysfunction, and atrioventricular valve regurgitation. We report 2 cases of conversion from a single ventricle circulation to biventricular mechanical support by reestablishing caval continuity. Both patients have demonstrated recovery of end-organ function and participation in rehabilitation. This method of support results in improved systemic venous pressures and pulmonary blood flow compared with systemic mechanical circulatory support with a cavopulmonary connection and transfers some of the complexity of the transplant to the ventricular assist device implant., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Pediatric heart transplant patients require cardiac catheterization to monitor for coronary allograft vasculopathy. Cardiac catheterization has no safe and consistent method for measuring microvascular disease. Stress perfusion cardiac magnetic resonance imaging (MRI) assessing microvascular disease has been performed in adults., Objective: To investigate the feasibility and safety of performing cardiac MRI with quantitative adenosine stress perfusion testing in pediatric heart transplant patients with and without coronary allograft vasculopathy., Materials and Methods: All pediatric heart transplant patients with coronary vasculopathy at our institution were asked to participate. Age- and gender-matched pediatric heart transplant patients without vasculopathy were recruited for comparison. Patients underwent cardiac MRI with adenosine stress perfusion testing., Results: Sixteen pediatric heart transplant patients, ages 6-22 years, underwent testing. Nine patients had vasculopathy by angiography. No heart block or other complications occurred during the study. The myocardial perfusion reserve for patients with vasculopathy showed no significant difference with comparison patients (median: 1.43 vs. 1.48; P=0.49). Values for both groups were lower than expected values based on previous adult studies. The patients were also analyzed for time after transplant and the number of rejection episodes. Patients within 6 years of transplantation had a nonsignificant trend toward a higher myocardial perfusion reserve (median: 1.57) versus patients with older transplants (median: 1.47; P=0.46). Intra- and interobserver reproducibility were 97% and 92%, respectively., Conclusion: Myocardial perfusion reserve is a safe and feasible method for estimating myocardial perfusion in pediatric heart transplant patients. There is no reliable way to monitor microvascular disease in pediatric patients. This method shows potential and deserves investigation in a larger cohort.

Objective: Patients with biventricular assist devices (BiVADs) have worse outcomes than those with left ventricular assist devices (LVADs). It is unclear whether these outcomes are due to device selection or patient factors. We used propensity score matching to reduce patient heterogeneity and compare outcomes in pediatric patients supported with BiVADs with a similar LVAD cohort., Methods: The Pedimacs registry was queried for patients who were supported with BiVAD or LVAD. Patients were analyzed by BiVAD or LVAD at primary implant and the 2 groups were compared before and after using propensity score matching., Results: Of 363 patients who met inclusion criteria, 63 (17%) underwent primary BiVAD support. After propensity score matching, differences between cohorts were reduced. Six months after implant, in the BiVAD cohort (LVAD cohort) 52.5% (42.5%) had been transplanted; 32.5% (40%) were alive with device, and 15% (10%) had died. Survival was similar between cohorts (P = .31, log-rank), but patients with BiVADs were more likely to experience a major adverse event in the form of bleeding (P = .04, log-rank). At 1 week and 1 and 3 months' postimplant, the percentage of patients on mechanical ventilation, on dialysis, or with elevated bilirubin was similar between the 2 groups., Conclusions: When propensity scores were used to reduce differences in patient characteristics, there were no differences in survival but more major adverse events in the patients with BiVADs, particularly bleeding. Differences in unmatched patient outcomes between LVAD and BiVAD cohorts likely represent differences in severity of illness rather than mode of support., (Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Significant inter- and intra-center practice variability is present in pediatric donor heart acceptability. This may contribute to variation in the donor refusal rate and may impact waitlist time, morbidity, mortality, and transplant rates. In order to reduce practice variability, our center developed and implemented a comprehensive strategy regarding donor acceptance in September 2017. The aim of this study was to assess the impact of this strategy on waitlist time and outcomes as well as early post-transplant outcomes. We performed a single-center, retrospective analysis of all pediatric (<18 years) patients listed for single-organ heart transplant at our center from September 2015 to September 2018. Patients were divided into those listed before (Group 1) and after implementation of the comprehensive strategy (Group 2). The primary end-point was waitlist time. Secondary end-points included waitlist removal due to death or clinical deterioration, donor refusals per listed patient, early post-transplant outcomes (graft failure, mechanical ventilation time, inotropic support, length of hospital stay) and 1-year post-transplant survival. Of 78 listed patients, 54 were transplanted (29 in Group 1), 9 were removed due to death or clinical deterioration (7 in Group 1) and 15 were removed due to clinical improvement (12 in Group 1). The waitlist time was significantly shorter in Group 2 (17 days, IQR 7-53) vs Group 1 (90 days, IQR 14-162); P = .006. The number of donor refusals was lower in Group 2 (1, IQR 0-2.2) vs Group 1 (4, IQR 2-19); P < .001. The percentage of refused donors with normal function (Left ventricular ejection fraction > 50%) was lower in Group 2 vs Group 1 (53% vs 84%; P < .001). Difference in removal from the waitlist for death or deterioration in Group 2 vs Group 1 (n = 2, 7% vs n = 7, 20%, P = .18) did not reach statistical significance. There was no difference in post-transplant outcomes between groups. The waitlist time and donor refusals significantly decreased after implementation of a comprehensive donor acceptance strategy without impacting transplant outcomes. This analysis supports the need for a comprehensive approach to donor organ acceptance within a pediatric transplant center., (© 2020 Wiley Periodicals LLC.)

Background: Hypertrophic cardiomyopathy is the leading cause of sudden cardiac death (SCD) in children and young adults. Our objective was to develop and validate a SCD risk prediction model in pediatric hypertrophic cardiomyopathy to guide SCD prevention strategies., Methods: In an international multicenter observational cohort study, phenotype-positive patients with isolated hypertrophic cardiomyopathy <18 years of age at diagnosis were eligible. The primary outcome variable was the time from diagnosis to a composite of SCD events at 5-year follow-up: SCD, resuscitated sudden cardiac arrest, and aborted SCD, that is, appropriate shock following primary prevention implantable cardioverter defibrillators. Competing risk models with cause-specific hazard regression were used to identify and quantify clinical and genetic factors associated with SCD. The cause-specific regression model was implemented using boosting, and tuned with 10 repeated 4-fold cross-validations. The final model was fitted using all data with the tuned hyperparameter value that maximizes the c-statistic, and its performance was characterized by using the c-statistic for competing risk models. The final model was validated in an independent external cohort (SHaRe [Sarcomeric Human Cardiomyopathy Registry], n=285)., Results: Overall, 572 patients met eligibility criteria with 2855 patient-years of follow-up. The 5-year cumulative proportion of SCD events was 9.1% (14 SCD, 25 resuscitated sudden cardiac arrests, and 14 aborted SCD). Risk predictors included age at diagnosis, documented nonsustained ventricular tachycardia, unexplained syncope, septal diameter z -score, left ventricular posterior wall diameter z score, left atrial diameter z score, peak left ventricular outflow tract gradient, and presence of a pathogenic variant. Unlike in adults, left ventricular outflow tract gradient had an inverse association, and family history of SCD had no association with SCD. Clinical and clinical/genetic models were developed to predict 5-year freedom from SCD. Both models adequately discriminated between patients with and without SCD events with a c-statistic of 0.75 and 0.76, respectively, and demonstrated good agreement between predicted and observed events in the primary and validation cohorts (validation c-statistic 0.71 and 0.72, respectively)., Conclusion: Our study provides a validated SCD risk prediction model with >70% prediction accuracy and incorporates risk factors that are unique to pediatric hypertrophic cardiomyopathy. An individualized risk prediction model has the potential to improve the application of clinical practice guidelines and shared decision making for implantable cardioverter defibrillator insertion. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT0403679.

Duchenne muscular dystrophy (DMD) is characterized by myocardial fibrosis and left ventricular (LV) dysfunction. Implantable cardioverter defibrillator (ICD) use has not been characterized in this population but is considered for symptomatic patients with severe LV dysfunction (SLVD) receiving guideline-directed medical therapy (GDMT). We evaluated ICD utilization and efficacy in patients with DMD. Retrospective cohort study of DMD patients from 17 centers across North America between January 2, 2005 and December 31, 2015. ICD use and its effect on survival were evaluated in patients with SLVD defined as ejection fraction (EF) < 35% and/ or shortening fraction (SF) < 16% on final echocardiogram. SLVD was present in 57/436 (13.1%) patients, of which 12 (21.1%) died during the study period. Of these 12, (mean EF 20.9 ± 6.2% and SF 13.7 ± 7.2%), 8 received GDMT, 5 received steroids, and none received an ICD. ICDs were placed in 9/57 (15.8%) patients with SLVD (mean EF 31.2 ± 8.5% and SF 10.3 ± 4.9%) at a mean age of 20.4 ± 6.3 years; 8/9 received GDMT, 7 received steroids, and all were alive at study end; mean ICD duration was 36.1 ± 26.2 months. Nine ICDs were implanted at six different institutions, associated with two appropriate shocks for ventricular tachycardia in two patients, no inappropriate shocks, and one lead fracture. ICD use may be associated with improved survival and minimal complications in DMD cardiomyopathy with SLVD. However, inconsistent GDMT utilization may be a significant confounder. Future studies should define optimal indications for ICD implantation in patients with DMD cardiomyopathy.

Background: Acute decompensated heart failure (ADHF) is a highly morbid condition among adults. Little is known about outcomes in children with ADHF. We analyzed the Pediatric Cardiac Critical Care Consortium registry to determine the epidemiology, contemporary treatments, and predictors of mortality in critically ill children with ADHF., Methods: Cardiac intensive care unit (CICU) patients ≤18 years of age meeting Pediatric Cardiac Critical Care Consortium criteria for ADHF were included. ADHF was defined as systolic or diastolic dysfunction requiring continuous vasoactive or diuretic infusion, respiratory support, or mechanical circulatory support. Demographics, diagnosis, therapies, complications, and mortality are described for the cohort. Predictors of CICU mortality were identified using logistic regression., Results: Among 26 294 consecutive admissions (23 centers), 1494 (6%) met criteria for analysis. Median age was 0.93 years (interquartile range, 0.1-9.3 years). Patients with congenital heart disease (CHD) comprised 57% of the cohort. Common therapies included the following: vasoactive infusions (88%), central venous catheters (86%), mechanical ventilation (59%), and high flow nasal cannula (46%). Common complications were arrhythmias (19%), cardiac arrest (10%), sepsis (7%), and acute renal failure requiring dialysis (3%). Median length of CICU stay was 7.9 days (interquartile range, 3-18 days) and the CICU readmission rate was 22%. Overall, CICU mortality was 15% although higher for patients with CHD versus non-CHD (19% versus 11%; P <0.001). Independent risk factors associated with CICU mortality included age <30 days, CHD, vasoactive infusions, ventricular tachycardia, mechanical ventilation, sepsis, pulmonary hypertension, extracorporeal membrane oxygenation, and cardiac arrest., Conclusions: ADHF in children is characterized by comorbidities, high mortality rates, and frequent readmission, especially among patients with CHD. Opportunities exist to determine best practices around appropriate use of mechanical support, cardiac arrest prevention, and optimal heart transplantation candidacy to improve outcomes for these patients.

As survival and neuromuscular function in Duchenne muscular dystrophy (DMD) have improved with glucocorticoid (GC) therapy and ventilatory support, cardiac deaths are increasing. Little is known about risk factors for cardiac and non-cardiac causes of death in DMD. A multi-center retrospective cohort study of 408 males with DMD, followed from January 1, 2005 to December 31, 2015, was conducted to identify risk factors for death. Those dying of cardiac causes were compared to those dying of non-cardiac causes and to those alive at study end. There were 29 (7.1%) deaths at a median age of 19.5 (IQR: 16.9-24.6) years; 8 (27.6%) cardiac, and 21 non-cardiac. Those living were younger [14.9 (IQR: 11.0-19.1) years] than those dying of cardiac [18 (IQR 15.5-24) years, p = 0.03] and non-cardiac [19 (IQR: 16.5-23) years, p = 0.002] causes. GC use was lower for those dying of cardiac causes compared to those living [2/8 (25%) vs. 304/378 (80.4%), p = 0.001]. Last ejection fraction prior to death/study end was lower for those dying of cardiac causes compared to those living (37.5% ± 12.8 vs. 54.5% ± 10.8, p = 0.01) but not compared to those dying of non-cardiac causes (37.5% ± 12.8 vs. 41.2% ± 19.3, p = 0.58). In a large DMD cohort, approximately 30% of deaths were cardiac. Lack of GC use was associated with cardiac causes of death, while systolic dysfunction was associated with death from any cause. Further work is needed to ensure guideline adherence and to define optimal management of systolic dysfunction in males with DMD with hopes of extending survival.

For decades, physicians have administered corticosteroids in the perioperative period to infants undergoing heart surgery with cardiopulmonary bypass (CPB) to reduce the postoperative systemic inflammatory response to CPB. Some question this practice because steroid efficacy has not been conclusively demonstrated and because some studies indicate that steroids could have harmful effects. STRESS is a randomized, placebo-controlled, double-blind, multicenter trial designed to evaluate safety and efficacy of perioperative steroids in infants (age < 1 year) undergoing heart surgery with CPB. Participants (planned enrollment = 1,200) are randomized 1:1 to methylprednisolone (30 mg/kg) administered into the CPB pump prime versus placebo. The trial is nested within the existing infrastructure of the Society of Thoracic Surgeons Congenital Heart Surgery Database. The primary outcome is a global rank score of mortality, major morbidities, and hospital length of stay with components ranked commensurate with their clinical severity. Secondary outcomes include several measures of major postoperative morbidity, postoperative hospital length of stay, and steroid-related safety outcomes including prevalence of hyperglycemia and postoperative infectious complications. STRESS will be one of the largest trials ever conducted in children with heart disease and will answer a decades-old question related to safety and efficacy of perioperative steroids in infants undergoing heart surgery with CPB. The pragmatic "trial within a registry" design may provide a mechanism for conducting low-cost, high-efficiency trials in a heretofore-understudied patient population., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Transition to adult health care has become a mainstream focus in pediatric health care as a higher percentage of patients are surviving into adulthood. This study investigated the success of a structured educational transition program in improving pediatric heart transplant patients' overall medical knowledge, medication adherence, readiness to transition, as well as parental perceptions of their child's readiness to transition to aid in the successful transition to an adult heart transplant program. Patients underwent a structured transition program over 2 years that included a total of seven 2-hour educational sessions hosted quarterly. This study comprised of a retrospective review of 12 heart transplant patients between the ages of 16-22 years. Test results indicated a statistically significant increase in overall medical knowledge scores from presession assessment compared to post-session assessment. Participants remained confident in their ability to transition throughout the program. Further, a statistically significant decrease in participant non-adherence was observed, as percentage of calcineurin inhibitor levels determined to be out of range decreased over the course of the program. Results suggest that a structured transition program is effective in improving overall patient medical knowledge in relation to their heart transplant and enhancing patient medication adherence. To effectively facilitate transition, pediatric providers, caregivers, and patients must communicate to provide a purposeful planned transition experience from pediatric to adult health care., (© 2019 Wiley Periodicals, Inc.)

Background: As survival and neuromuscular function in Duchenne Muscular Dystrophy (DMD) improve with glucocorticoid therapy and respiratory advances, the proportion of cardiac deaths is increasing. Little is known about the use and outcomes of advanced heart failure (HF) therapies in this population., Methods: A retrospective cohort study of 436 males with DMD was performed, from January 1, 2005-January 1, 2018, with the primary outcome being use of advanced HF therapies including: implantable cardioverter defibrillator (ICD), left ventricular assist device (LVAD), and heart transplantation (HTX)., Results: Nine subjects had an ICD placed, 2 of whom (22.2%) had appropriate shocks for ventricular tachycardia; 1 and 968 days after implant, and all of whom were alive at last follow-up; median 18 (IQR: 12.5-25.5) months from implant. Four subjects had a LVAD implanted with post-LVAD survival of 75% at 1 year; 2 remaining on support and 1 undergoing HTX. One subject was bridged to HTX with ICD and LVAD and was alive at last follow-up, 53 months after HTX., Conclusion: Advanced HF therapies may be used effectively in select subjects with DMD. Further studies are needed to better understand risk stratification for ICD use and optimal candidacy for LVAD implantation and HTX, with hopes of improving cardiac outcomes., Competing Interests: Declaration of interest Carol A. Wittlieb-Weber, MD: None. Chet R. Villa, MD: None. Matthew J. Bock, MD: None. Katheryn E. Gambetta, MD: None. Jonathan N. Johnson, MD: None. Ashwin K. Lal, MD: None. Kurt R. Schumacher, MD: None. Sabrina P. Law, MD: None. Shriprasad R. Deshpande, MD, MS: None. Shawn C. West, MD, MSc: None. Joshua M. Friedland-Little, MD: None. Irene D. Lytrivi, MD: None. Michael A. McCulloch, MD: None. Ryan J. Butts, MD: None. David R. Weber, MD, MSCE: Consulted for Marathon Pharmaceuticals. Kenneth R. Knecht, MD: None.

Background: Pediatric heart transplant waitlist mortality remains significant but allograft offer refusals are common and allografts continue to be discarded. Our aim in this study was to assess the impact of donor organ refusals on mortality after listing using a multi-institutional data set., Methods: In this study we conducted a retrospective review of donor offers made to pediatric (<18 years) recipients in the United States in the period from 2007 to 2017. Candidates were stratified by whether they refused an acceptable donor offer (ADO). Acceptance was defined as an offer from a donor <40 years old and within 1,000 miles that was ultimately accepted by a waitlist candidate. Candidate survival after an offer was assessed., Results: There were 12,447 hearts offered at least once to a pediatric candidate. Most candidates (n = 4,282, 84.4%) refused the first offer, and 677 (15.4%) of these subsequently died or were removed from the list for deterioration. Refusal of an ADO was associated with higher mortality after listing, independent of transplant, in both univariate (1 year: 92% vs 87%, p = 0.002) and multivariate (hazard ratio 1.5, 95% CI 1.2 to 1.7, p < 0.0001) Cox regression analyses. ADO refusals were not correlated with improved post-transplant survival and >8 ADO refusals was associated with higher risk-adjusted post-transplant mortality (odds ratio 1.7, 95% confidence interval 1.0 to 2.9, p = 0.04)., Conclusions: Refusal of ADOs is associated with higher risk-adjusted mortality after listing (independent of transplantation), without improvement in post-transplant outcomes. So, although a "perfect" organ would be ideal, acceptance of one that is "good enough" has the potential to improve survival among pediatric candidates for heart transplantation., (Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: The first pediatric heart transplant died 5 hours after transplant and the case was published by Kantrowitz. There is no report of the first successful case in the medical literature, nor indeed the outcome of children transplanted prior to 1982. However, we recently discovered that children from this period were entered retrospectively into the ISHLT Registry when it began and they form the basis of this report., Methods: A retrospective review of the ISHLT Thoracic Registry was undertaken for pediatric heart transplants prior to 1982. Demographic and descriptive data, and patient and graft survival were analyzed., Results: Thirty children (24 male) had a median age of 13 years (IQR 12-16) at the time of primary transplant. The underlying cardiac diagnosis was cardiomyopathy (18), congenital heart disease (7), not reported (5). The median follow-up was 2.63 years (IQR 0.1-7.2). Twenty-two patients are known to have died, and eight underwent retransplantation. Median patient survival was 3.5 years. The first patient to survive for more than one year was transplanted in 1968 and survived 6 years., Conclusion: The definition of a successful transplant is debatable; however, the first child reported to the registry to survive beyond one year was transplanted in 1968. Survival for these early patients was considerably less than the subsequent eras and retransplantation more common; however, the experience in managing these children laid the foundation for the future., (© 2019 Wiley Periodicals, Inc.)

This study aims to compare 2 common induction strategies, basiliximab and ATG. Analysis of the ISHLT transplant registry was performed. The database was queried for pediatric heart transplants from January 1, 2000, to June 30, 2015, who had received induction with basiliximab or ATG. Primary end-point was graft survival. Secondary end-points included 1-year survival and 1-year conditional survival. There were 3158 heart transplants who received induction with basiliximab or ATG. The ATG cohort was younger, more likely to have congenital heart disease or be a retransplant, have a higher PRA, longer ischemic time, and been transplanted earlier in the study period (all P<.01). There was no difference in graft loss in the basiliximab cohort compared to the ATG cohort (HR 1.18 P=.06). On conditional 1-year survival analysis, basiliximab induction was associated with graft loss (HR=1.35 95% CI 1.1-1.7, P<.01), and in the propensity-matched cohort, the basiliximab cohort was more likely to experience rejection prior to discharge (P=.04). Infection prior to discharge was more common in the antithymocyte cohort. Induction with ATG is associated with improved late graft survival compared to basiliximab., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aims: The relationship between echocardiographic measures of left ventricular (LV) systolic function and reference-standard measures have not been assessed in children. The objective of this study was to assess the validity of echocardiographic indices of LV systolic function via direct comparison to a novel composite measure of contractility derived from pressure-volume loop (PVL) analysis., Methods and Results: Children with normal loading conditions undergoing routine left heart catheterization were prospectively enrolled. PVLs were obtained via conductance catheters. A composite invasive composite contractility index (ICCI) was developed using data reduction strategies to combine four measures of contractility derived from PVL analysis. Echocardiograms were performed immediately after PVL analysis under the same anesthetic conditions. Conventional and speckle-tracking echocardiographic measures of systolic function were measured. Of 24 patients, 18 patients were heart transplant recipients, 6 patients had a small patent ductus arteriosus or small coronary fistula. Mean age was 9.1 ± 5.6 years. Upon multivariable regression, longitudinal strain was associated with ICCI (β = -0.54, P = 0.02) while controlling for indices of preload, afterload, heart rate, and LV mass under baseline conditions. Ejection fraction and shortening fraction were associated with LV mass and load indices, but not contractility., Conclusion: Speckle-tracking derived longitudinal strain is associated ICCI in children with normal loading conditions. Longitudinal measures of deformation appear to accurately assess LV contractility in children.

Background: Pediatric heart transplant recipients are at risk for increased left ventricular (LV) diastolic stiffness. However, the noninvasive evaluation of LV stiffness has remained elusive in this population. The objective of this study was to compare novel echocardiographic measures of LV diastolic stiffness versus gold-standard measures derived from pressure-volume loop (PVL) analysis in pediatric heart transplant recipients., Methods: Patients undergoing left heart catheterization were prospectively enrolled. PVLs were obtained via conductance. The end-diastolic pressure-volume relationship was obtained via balloon occlusion. The stiffness constant, β, was calculated. Echocardiographic measures of diastolic function were derived from spectral and tissue Doppler and two-dimensional speckle-tracking. Ventricular volumes were measured using three-dimensional echocardiography. The novel echocardiographic estimates of ventricular stiffness included E:e'/end-diastolic volume (EDV) and E:early diastolic strain rate/EDV., Results: Of 24 children, 18 were heart transplant recipients. Six control patients had hemodynamically insignificant patent ductus arteriosus or coronary fistula. The mean age was 9.1 ± 5.6 years. Median end-diastolic pressure was 9 mm Hg (interquartile range, 8-13 mm Hg). Lateral E:e'/EDV (r = 0.59, P < .01), septal E:e'/EDV (r = 0.57, P < .01), and (E:circumferential early diastolic strain rate)/EDV (r = 0.54, P < .01) correlated with β. Lateral E:e'/EDV displayed a C statistic of 0.93 in detecting patients with abnormal LV stiffness (β > 0.015 mL -1 ). A lateral E:e'/EDV of >0.15 mL -1 had 89% sensitivity and 93% specificity in detecting an abnormal β., Conclusions: Echocardiographic estimates of ventricular stiffness may be accurate compared with the gold standard in pediatric heart transplant recipients. The clinical usefulness of these noninvasive measures in assessing LV stiffness merits further study in children., (Copyright © 2017 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Our objective was to understand the scope of pediatric heart failure (HF) and the current staffing environment of HF programs. An online survey was distributed to members of the Pediatric Heart Transplant Study and the Pediatric Council of the International Society for Heart and Lung Transplantation. All participants received the primary 23-question survey. Additionally, HF program directors received a 32-question supplemental survey. Of 235 invitations sent, there were 69 (29%) primary surveys and 34 program director surveys completed (24 U.S. programs, 9 outside non-U.S., and one non-specified location). A formal HF program was reported by 88% of directors. There were 150 [IQR 50-200] outpatients/institution and 40% [25-50] of patients had congenital heart disease. Inpatient HF census was 3 [2-4] patients. Most programs (70%) used a consulting service model to provide HF specialty care, while only 10 (30%) utilized an inpatient HF service. Inpatient HF service programs had a higher daily inpatient census versus consult service model programs (4 [3-7] vs. 2 [1-4], respectively; p = 0.022) and had a higher number of full-time equivalents dedicated to HF (5.5 [2-7] vs. 2.5 [1-4], respectively; p = 0.024). Only 47% of programs report a general fellowship rotation devoted to HF. Advanced practice providers (APP) were utilized in 15 programs, nurse coordinators in 2, and both in 3. Most HF programs are formalized, utilize APP, and have inadequate HF staffing to utilize a separate inpatient HF service. Exposure of general pediatric cardiology fellows to HF care is variable between institutions.

Background: The purpose of this study was to investigate the associations between clinical factors and cardiac function as measured by pressure-volume loops (PVLs) in a pediatric heart transplant cohort., Methods: Patients (age < 20 years) who underwent heart transplantation presenting for a clinically indicated catheterization were enrolled. PVLs were recorded using microconductance catheters (CD Leycom ® , Zoetermeer, Netherlands). Demographic data, serum B-type natriuretic peptide (BNP), time from transplant, ischemic time, presence of transplant coronary artery disease, donor-specific antibodies, and history of rejection were recorded at the time of catheterization. PVL data included contractility indices: end-systolic elastance and preload recruitable stroke work; ventricular-arterial coupling index; ventricular stiffness constant, Beta; and isovolumic relaxation time constant, tau. Associations between PVL measures and clinical data were investigated using non-parametric statistical tests., Results: A total of 18 patients were enrolled. Median age was 8.7 years (IQR 5-14 years). There were ten males and eight females. Six patients had a history of rejection and ten had positive donor-specific antibodies. There was no transplant coronary artery disease. Median BNP was 100 pg/mL (IQR 46-140). Time from transplant to PVL obtained during catheterization procedure was 4.1 years (IQR 1.7-7.8 year). No single clinical characteristic was statistically significant when correlated with PVL data. However, longer ischemic time was associated with worse Beta (r = 0.49, p = 0.05)., Conclusions: Our study found that longer ischemic times are associated with increased left ventricular stiffness. No other single clinical variable is associated with cardiac dysfunction as determined by PVL analysis.

Objective: Speckle tracking echocardiography (STE) may be a useful modality for assessing ventricular performance in patients with single ventricle physiology. However, STE's ability to accurately assess ventricular performance in this population is unknown. The objective of this study was to perform a preliminary comparison of STE measures of myocardial deformation to reference standard measures of function derived from pressure-volume loop (PVL) analysis., Design: This was a secondary analysis of a prospective study investigating PVLs in patients with Fontan physiology. PVLs were recorded using microconductance catheters. PVL indices included end-systolic elastance (Ees), arterial elastance (Ea), ventriculo-arterial coupling (Ea/Ees), and the isovolumic relaxation time constant (tau). Patients were included if they had an echocardiogram within 1 month of their catheterization. STE was performed retrospectively using vendor independent software., Results: Seventeen patients had echocardiograms available for analysis, 12 were right ventricular (RV) dominant. The median age was 8 years (IQR 5-17 years). Circumferential strain (r=-.72, P≤.01) and strain rate (r=-.61, P=.04) correlated with Ea/Ees in those with RV-dominant morphology. Longitudinal strain rate correlated with Ees in those with LV-dominant morphology (r=-.98, P≤.01). Longitudinal EDSR correlated with tau in those with LV-dominant morphology (r=-.90, P=.04)., Conclusions: In this limited sample, circumferential measures of deformation correlated with PVL measures better in patients with RV morphology, while longitudinal measures correlated better with PVL measures in patients with LV morphology. Further validation and investigation into the clinical usefulness of these measures are warranted., (© 2017, Wiley Periodicals, Inc.)

The objective of this study was to describe a contemporary cohort of pediatric patients hospitalized for clinically suspected myocarditis. A retrospective chart review was performed at seven tertiary pediatric hospitals. Electronic medical records were searched between 2008 and 2012 for patients ≤18 years admitted with an ICD-9 code consistent with myocarditis. Patients were excluded if the admitting or consulting cardiologist did not suspect myocarditis during the admission or an alternative diagnosis was determined. One hundred seventy-one patients were discharged or died with a primary diagnosis of myocarditis. Median age was 13.1 years (IQR 2.1, 15.9), with a bimodal distribution; 24% <2 years and 46% between 13 and 18 years. Patients with moderate or severe systolic dysfunction were younger, had higher BNPs at admission, but had lower troponin. Mortality, heart transplantation, and readmission did not differ between patients who received only IVIG, only steroids, IVIG and steroids, and no immunotherapy. Ninety-four patients (55%) were discharged on heart failure medications, 16 were transplanted, and seven died. The presence at the time of admission of gastrointestinal (GI) symptoms (p = 0.01) and lower echo shortening fraction (SF) (p < 0.01) was associated with death/transplant. Within one year 16% had a readmission, one underwent heart transplant, and 39% received heart failure therapy. Pediatric myocarditis has a bimodal age distribution. The use of IVIG and steroids is not associated with mortality/heart transplantation. The presence of GI symptoms and lower echo SF may identify patients at risk for death and/or transplantation during the admission.

Cardiopulmonary exercise testing (CPET) aids in clinical assessment of patients with Fontan circulation. Effects of persistent fenestration on CPET variables have not been clearly defined. Associations between fenestration and CPET variables at anaerobic threshold (AT) and peak exercise were explored in the Pediatric Heart Network Fontan Cross-Sectional Study cohort. Fenestration patency was associated with a greater decrease in oxygen saturation from rest to peak exercise (fenestration -4.9 ± 3.8 v. nonfenestration -3 ± 3.5; P < .001). Physiological dead space at peak exercise was higher in fenestrated v. nonfenestrated (25.2 ± 16.1 v. 21.4 ± 15.2; P = .03). There was a weak association between fenestration patency and maximal work and heart rate. Fenestration patency was also weakly correlated with oxygen pulse, work and VE/VCO2 at AT. The effect of persistent fenestration on CPET measurements was minimal in this study, likely due to the cross-sectional design., (© 2017 Wiley Periodicals, Inc.)

Echocardiography is frequently performed under anesthesia during procedures such as cardiac catheterization with EMB in pediatric HTx recipients. Anesthetic agents may depress ventricular function, resulting in concern for rejection. The aim of this study was to compare ventricular function as measured by echocardiography before and during GA in 17 pediatric HTx recipients. Nearly all markers of ventricular systolic function were significantly decreased under GA, including EF (-4.2% ±1.2, P < .01) and RV FAC (-0.05 ± 0.02, P = .04). Subjects in the first post-transplant year (n = 9) trended toward a more significant decrease in EF vs those beyond the first post-transplant year (n = 8; -6.0% ±1.2 vs -2.1 ± 2.0, P = .1). This information quantifies a decline in biventricular function that should be expected in pediatric HTx recipients while under GA and can assist the transplant clinician in avoiding unnecessary treatment of transient GA-induced ventricular dysfunction., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The accuracy of echocardiography in evaluating left ventricular contractility has not been validated in children. The objective of this study was to compare echocardiographic measures of contractility with those derived from pressure-volume loop (PVL) analysis in children., Methods: Patients with relatively normal loading conditions undergoing routine left heart catheterization were prospectively enrolled. PVLs were obtained via conductance catheters. The gold-standard measure of contractility, end-systolic elastance (Ees), was obtained via balloon occlusion of one or both vena cavae. Echocardiograms were performed immediately after PVL analysis under the same anesthetic conditions. Single-beat estimations of echocardiographic Ees were calculated using four different methods. These estimates were calculated using a combination of noninvasive blood pressure readings, ventricular volumes derived from three-dimensional echocardiography, and Doppler time intervals., Results: Of 24 patients, 18 patients were heart transplant recipients, and six patients had small patent ductus arteriosus or small coronary fistulae. The mean age was 9.1 ± 5.6 years. The average invasive Ees was 3.04 ± 1.65 mm Hg/mL. Invasive Ees correlated best with echocardiographic Ees by the method of Tanoue (r = 0.85, P < .01), with a mean difference of -0.07 mm Hg/mL (95% limits of agreement, -2.0 to 1.4 mm Hg/mL)., Conclusions: Echocardiographic estimates of Ees correlate well with gold-standard measures obtained via conductance catheters in children with relatively normal loading conditions. The use of these noninvasive measures in accurately assessing left ventricular contractility appears promising and merits further study in children., (Copyright © 2016 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

The ability to quantify patient-specific hospital mortality risk before the Norwood procedure remains elusive. This study aimed to develop an accurate and clinically feasible score to assess the risk of hospital mortality in neonates undergoing the Norwood procedure. All patients (n = 549) in the publically available Pediatric Heart Network Single Ventricle Reconstruction trial database were included in the analysis. Patients were randomly divided into a derivation (75%) and validation (25%) cohort. Preoperative factors found to be associated with mortality upon univariable analysis (P < 0.2) were included in the logistic regression model. The score was derived by including variables independently associated with mortality (P < 0.05). A 20-point score using 6 variables (birth weight, clinical syndrome or abnormal karyotype, surgeon Norwood volume or year, anatomic subtype, ascending aorta size, and obstructed pulmonary venous return) was developed using relative magnitudes of the covariates׳ odds ratio. The score was then tested in the validation cohort. In weighted regression analysis, model predicted risk of mortality correlated closely with actual rates of mortality in the derivation (R 2 = 0.87, P < 0.01) and validation cohorts (R 2 = 0.82, P < 0.01). Patients were classified as low (score: 0-5), medium (6-10), or high risk (>10). Mortality differed significantly between risk groups in both the derivation (6% vs 22% vs 77%, P < 0.01) and validation (4% vs 30% vs 53%, P < 0.01) cohorts. This mortality score is accurate in determining risk of hospital mortality in neonates undergoing planned Norwood operations. The score has the potential to be used in clinical practice to aid in risk assessment before surgery. Clinical trial registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00115934., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Ventricular assist devices (VADs) have been used in children on an increasing basis in recent years. One-year survival rates are now >80% in multiple reports. In this report we describe adverse events experienced by children with durable ventricular assist devices, using a national-level registry (PediMACS, a component of INTERMACS) METHODS: PediMACS is a national registry that contains clinical data on patients who are <19 years of age at the time of VAD implantation. Data collection concludes at the time of VAD explantation. All FDA-approved devices are included. PediMACS was launched on September 1, 2012, and this report includes all data from launch until August 2014. Adverse events were coded with a uniform, pre-specified set of definitions., Results: This report comprises data from 200 patients with a median age of 11 years (range 11 days to 18 years), and total follow-up of 783 patient-months. The diagnoses were cardiomyopathy (n = 146, 73%), myocarditis (n = 17, 9%), congenital heart disease (n = 35, 18%) and other (n = 2, 1%). Pulsatile-flow devices were used in 91 patients (45%) and continuous-flow devices in 109 patients (55%). Actuarial survival was 81% at 6 months. There were 418 adverse events reported. The most frequent events were device malfunction (n = 79), infection (n = 78), neurologic dysfunction (n = 52) and bleeding (n = 68). Together, these accounted for 277 events, 66% of the total. Although 38% of patients had no reported adverse event and 16% of patients had ≥5 adverse events. Adverse events occurred at all time-points after implantation, but were most likely to occur in the first 30 days. For continuous-flow devices, there were broad similarities in adverse event rates between this cohort and historic rates from the INTERMACS population., Conclusions: In this study cohort, the overall rate of early adverse events (within 90 days of implantation) was 86.3 events per 100 patient-months, and of late adverse events it was 20.4 events per 100 patient-months. The most common adverse events in recipients of pulsatile VADs were device malfunction, neurologic dysfunction, bleeding and infection. For continuous-flow VADs, the most common adverse events were infection, bleeding, cardiac arrhythmia, neurologic dysfunction and respiratory failure. Compared with an adult INTERMACS cohort, the overall rate and distribution of adverse events appears similar., (Copyright © 2016 International Society for Heart and Lung Transplantation. All rights reserved.)

Unlabelled: Sildenafil has been reported to improve exercise capacity in Fontan patients, but the physiologic mechanisms behind these findings are not completely understood. The objective of this study was to study the acute effect of sildenafil on pressure-volume loop (PVL) measures of ventricular function in Fontan patients. Patients after Fontan operation who were presenting for a clinically indicated catheterization were enrolled. Patients were randomized in a double-blinded fashion to receive placebo (n = 9) or sildenafil (n = 10) 30-90 min prior to catheterization. PVLs were recorded using microconductance catheters at baseline and after infusion of dobutamine (10 mcg/kg/min). The primary outcome was change in ventriculoarterial (VA) coupling. For the entire cohort, VA coupling trended toward improvement with dobutamine (1.4 ± 0.4 to 1.8 ± 0.9, p = 0.07). End-systolic elastance showed improvement (2.6 ± 0.9 to 3.8 ± 1.4 mmHg m(2)/ml, p < 0.01) with dobutamine infusion. The cohorts had similar VA coupling at baseline (p = 0.32), but the sildenafil cohort trended toward having less of an improvement in VA coupling with dobutamine stress (p = 0.06). There were no differences between PVL measures of systolic or diastolic function between treatment groups, both at baseline and after dobutamine infusion. Patients with Fontan circulation had improved contractility and trended toward improvement in VA coupling with dobutamine stress. Acute sildenafil administration was not associated with improved PVL measurements of ventricular function in this population. These results suggest that clinical improvements seen with administration of sildenafil in Fontan patients are not associated with an acute improvement in ventricular function., Clinical Trial Registration: www.clinicaltrials.gov ; Clinicaltrials.gov Identifier: NCT01815502.

Objectives: This study aimed to develop a reliable and feasible score to assess the risk of rejection in pediatric heart transplantation recipients during the first post-transplant year., Background: The first post-transplant year is the most likely time for rejection to occur in pediatric heart transplantation. Rejection during this period is associated with worse outcomes., Methods: The United Network for Organ Sharing database was queried for pediatric patients (age <18 years) who underwent isolated orthotopic heart transplantation from January 1, 2000 to December 31, 2012. Transplantations were divided into a derivation cohort (n = 2,686) and a validation (n = 509) cohort. The validation cohort was randomly selected from 20% of transplantations from 2005 to 2012. Covariates found to be associated with rejection (p < 0.2) were included in the initial multivariable logistic regression model. The final model was derived by including only variables independently associated with rejection. A risk score was then developed using relative magnitudes of the covariates' odds ratio. The score was then tested in the validation cohort., Results: A 9-point risk score using 3 variables (age, cardiac diagnosis, and panel reactive antibody) was developed. Mean score in the derivation and validation cohorts were 4.5 ± 2.6 and 4.8 ± 2.7, respectively. A higher score was associated with an increased rate of rejection (score = 0, 10.6% in the validation cohort vs. score = 9, 40%; p < 0.01). In weighted regression analysis, the model-predicted risk of rejection correlated closely with the actual rates of rejection in the validation cohort (R(2) = 0.86; p < 0.01)., Conclusions: The rejection score is accurate in determining the risk of early rejection in pediatric heart transplantation recipients. The score has the potential to be used in clinical practice to aid in determining the immunosuppressant regimen and the frequency of rejection surveillance in the first post-transplant year., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Cardiopulmonary exercise testing (CPET) is a common method of evaluating patients with a Fontan circulation. Equations to calculate predicted CPET values are based on children with normal circulation. This study aims to create predictive equations for CPET variables solely based on patients with Fontan circulation. Patients who performed CPET in the multicenter Pediatric Heart Network Fontan Cross-Sectional Study were screened. Peak variable equations were calculated using patients who performed a maximal test (RER > 1.1) and anaerobic threshold (AT) variable equations on patients where AT was adequately calculated. Eighty percent of each cohort was randomly selected to derive the predictive equation and the remaining served as a validation cohort. Linear regression analysis was performed for each CPET variable within the derivation cohort. The resulting equations were applied to calculate predicted values in the validation cohort. Observed versus predicted variables were compared in the validation cohort using linear regression. 411 patients underwent CPET, 166 performed maximal exercise tests and 317 had adequately calculated AT. Predictive equations for peak CPET variables had good performance; peak VO2, R (2) = 0.61; maximum work, R (2) = 0.61; maximum O2 pulse, R (2) = 0.59. The equations for CPET variables at AT explained less of the variability; VO2 at AT, R (2) = 0.15; work at AT, R (2) = 0.39; O2 pulse at AT, R (2) = 0.34; VE/VCO2 at AT, R (2) = 0.18; VE/VO2 at AT, R (2) = 0.14. Only the models for VE/VCO2 and VE/VO2 at AT had significantly worse performance in validation cohort. Of the 8 equations for commonly measured CPET variables, six were able to be validated. The equations for peak variables were more robust in explaining variation in values than AT equations.

Background: Differences in ventricular geometry and physiology of patients with single ventricle anatomy complicate the application of traditional, noninvasive measurements of systolic function. We compared noninvasive measures of ventricular systolic function in single ventricle patients with invasive measures to evaluate their validity in this population., Methods: A secondary analysis of patients with single ventricle physiology enrolled in the multi-institutional research project, "multi-scale modeling of single ventricle hearts," was performed. Pressure-volume loops (PVLs) were recorded using microconductance catheters. Transthoracic echocardiogram and cardiac magnetic resonance imaging were performed on the same day. PVL indices of systolic function including end-systolic elastance (Ees), maximal rate of pressure increase (dP/dTmax), and stroke work indexed to end-diastolic volume (SW/EDV) were compared with noninvasive measures, including echocardiographic myocardial performance index (MPI), rate of pressure rise (AV valve dP/dT), isovolumic acceleration, longitudinal shortening fraction (longSF), and fractional area change (FAC)., Results: Fifteen patients had PVLs available for analysis. Eleven had a dominant right ventricle, three were status poststage 1 repair, five had superior cavopulmonary anastomosis, and seven had a total cavopulmonary anastomosis. FAC correlated with Ees (r = 0.69, P < .01), SW/EDV (r = 0.64, P = .01), and dP/dTmax (r = 0.59, P = .03). LongSF correlated with dP/dTmax (r = 0.61, P = .02) MPI, AV valve dP/dT, and isovolumic acceleration did not correlate with pressure-volume loop indices of systolic function., Conclusions: Obtaining PVLs via microconductance catheters can reliably be performed in the single ventricle population and serve as a method to validate echocardiographic indices in this high-risk population. Of the echocardiographic variables, FAC showed the best correlation with PVL indices. Future studies controlling for stage of palliation should be performed to further validate echocardiographic measures of systolic function in this patient population., (© 2014 Wiley Periodicals, Inc.)

Background: A higher degree of human leukocyte antigen (HLA) matching at the A, B, and DR loci has been associated with improved long-term survival after pediatric heart transplantation in multiple International Society for Heart and Lung Transplantation registry reports. The aim of this study was to investigate the association of HLA matching at the C and DQ loci with pediatric graft survival., Methods: The United Network of Organ Sharing database was queried for isolated heart transplants that occurred from 1988 to 2012 with a recipient age of 17 or younger and at least 1 postoperative follow-up encounter. When HLA matching at the C or DQ loci were analyzed, only transplants with complete typing of donor and recipient at the respective loci were included. Transplants were divided into patients with at least 1 match at the C locus (C-match) vs no match (C-no), and at least 1 match at the DQ (DQ-match) locus vs no match (DQ-no). Primary outcome was graft loss. Univariate analysis was performed with the log-rank test. Cox regression analysis was performed with the following patient factors included in the model: recipient age, ischemic time; recipient on ventilator, extracorporeal membrane oxygenation, ventricular assist device, or inotropes at transplant; recipient serum bilirubin and creatinine closest to transplant, ratio of donor weight to recipient weight, underlying cardiac diagnosis, crossmatch results, transplant year, and HLA matching at the A, B, and DR loci., Results: Complete typing at the C locus occurred in 2,429 of 4,731 transplants (51%), and complete typing at the DQ locus occurred in 3,498 of 4,731 transplants (74%). Patient factors were similar in C-match and C-no, except for year of transplant (median year, 2007 [interquartile range, 1997-2010] vs year 2005 [interquartile range, 1996-2009], respectively; p = 0.03) and the degree of HLA matching at the A, B, and DR loci (high level of HLA matching in 11.9% vs 3%, respectively; p < 0.01). Matching at the C locus was not associated with a decreased risk of graft loss (median graft survival: 13.1 years [95% confidence interval {CI}, 11.5-14.8] in C-no vs 15.1 years [95% CI, 13.5-16.6) in C-match, p = 0.44 log-rank; hazard ratio, 0.93; 95% CI, 0.76-1.15; p = 0.52). DQ-match did not differ from DQ-no in any of the analyzed patient factors, except DQ-match was more likely to have high degree of matching at the A, B, and DR loci vs DQ-no (9.8% vs 3.2%, p < 0.01). Matching at the DQ locus was not associated with decreased risk of graft loss (median graft survival: DQ-no, 13.1 years [95% CI, 11.7-14.6) vs DQ-match, 13.0 years [95% CI, 11.4-14.6], p = 0.80, log-rank; hazard ratio, 0.95; 95% CI, 0.81-1.1; p = 0.51., Conclusions: Complete typing at the C locus of both donor and recipient occurs less often then typing at the DQ locus. A higher degree of donor-recipient HLA matching at the C locus or the DQ locus appears not to confer any graft survival advantage., (Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Echocardiographic measurements of diastolic function have not been validated against invasive pressure-volume loop (PVL) analysis in the single-ventricle population. The authors hypothesized that echocardiographic measures of diastolic function would correlate with PVL indices of diastolic function in patients with a single-ventricle physiology. The conductance-derived PVL measures of diastolic function included the isovolumic relaxation time constant (τ), the maximum rate of ventricular pressure decline (peak -dP/dt), and a measure of passive diastolic stiffness (μ). The echocardiographic measures included Doppler inflow patterns of the dominant atrioventricular valve (DAVV), tissue Doppler velocities (TDI) at the lateral (ventricular free wall) component of the DAVV annulus, and the TDI-derived isovolumic relaxation time (IVRT'). The correlation between PVL and echocardiographic measures was examined. The study enrolled 13 patients at various stages of surgical palliation. The median age of the patients was 3 years (range 3 months to 19 years). τ correlated well with Doppler E:A (r = 0.832; p = 0.005), lateral E:E' (r = 0.747; p = 0.033), and IVRT' (r = 0.831; p = 0.001). Peak -dP/dt also was correlated with IVRT' (r = 0.609; p = 0.036), and μ also was correlated with IVRT' (r = 0.884; p = 0.001). This study represents the first-ever comparison of diastolic echocardiographic and PVL indices in a single-ventricle population. The findings show that Doppler E:A, lateral E:E', and IVRT' correlate well with PVL measures of diastolic function. This study supports further validation of echocardiographic measures of diastolic function versus PVL measures of diastolic function in the single-ventricle population.

Background: The effect of donor-recipient human leukocyte antigen (HLA) matching on outcomes remains relatively unexplored in pediatric patients. The objective of this study was to investigate the effects of donor-recipient HLA matching on graft survival in pediatric heart transplantation., Methods and Results: The UNOS (United Network for Organ Sharing) database was queried for heart transplants occurring between October 31, 1987, and December 31, 2012, in a recipient aged ≤17 years with ≥1 postoperative follow-up visit. Retransplants were excluded. Transplants were divided into 3 donor-recipient matching groups: no HLA matches (HLA-no), 1 or 2 HLA matches (HLA-low), and 3 to 6 HLA matches (HLA-high). Primary outcome was graft loss. Four thousand four hundred seventy-one heart transplants met the study inclusion criteria. High degree of donor-recipient HLA matching occurred infrequently: HLA-high (n=269; 6%) versus HLA-low (n=2683; 60%) versus HLA-no (n=1495; 34%). There were no differences between HLA matching groups in the frequency of coronary vasculopathy (P=0.19) or rejection in the first post-transplant year (P=0.76). Improved graft survival was associated with a greater degree of HLA donor-recipient matching: HLA-high median survival, 17.1 (95% confidence interval, 14.0-20.2) years; HLA-low median survival, 14.2 (13.1-15.4) years; and HLA-no median survival, 12.1 (10.9-13.3 years) years; P<0.01, log-rank test. In Cox-regression analysis, HLA matching was independently associated with decreased graft loss: HLA-low versus HLA-no hazard ratio, 0.86 (95% confidence interval, 0.74-0.99), P=0.04; HLA-high versus HLA-no, 0.62 (95% confidence interval, 0.43-0.90), P<0.01., Conclusions: Decreased graft loss in pediatric heart transplantation was associated with a higher degree of donor-recipient HLA matching, although a difference in the frequency of early rejection or development of coronary artery vasculopathy was not seen., (© 2014 American Heart Association, Inc.)

Individuals suffering from motor impairments often require physical therapy (PT) to help improve their level of function. Previous investigations suggest that both intermittent theta burst stimulation (iTBS) and bihemispheric transcranial direct current stimulation (tDCS) may increase the speed and extent of motor learning/relearning. The purpose of the current study was to explore the feasibility and effectiveness of a novel, non-invasive brain stimulation approach that combined an iTBS primer, and bihemispheric stimulation coupled with motor training. We hypothesized that individuals exposed to this novel treatment would make greater functional improvements than individuals undergoing sham stimulation when tested immediately following, 24-h, and 7-days post-training. A total of 26 right-handed, healthy young adults were randomly assigned to either a treatment (n = 15) or control group (n = 12). iTBS (20 trains of 10 pulse triplets each delivered at 80% active motor threshold (AMT) / 50 Hz over 191.84 s) and bihemispheric tDCS (1.0 ma for 20 min) were used as a primer to, and in conjunction with, 20 min of motor training, respectively. Our primary outcome measure was performance on the Jebsen-Taylor Hand Function (JTHF) test. Participants tolerated the combined iTBS/bihemispheric stimulation treatment without complaint. While performance gains in the sham and stimulation group were not significant immediately after training, they were nearly significant 24-h post training (p = 0.055), and were significant at 7-days post training (p < 0.05). These results suggest that the combined iTBS/bihemispheric stimulation protocol is both feasible and effective. Future research should examine the mechanistic explanation of this approach as well as the potential of using this approach in clinical populations.

Data regarding the value of B-type natriuretic peptide (BNP) measurements in infants with a single-ventricle (SV) physiology are lacking. This analysis aimed to describe the BNP level changes in infants with an SV physiology before and after superior cavopulmonary connection (SCPC) surgery. Levels of BNP were measured by a core laboratory before SCPC (at 5.0 ± 1.6 months) and at the age of 14 months during a multicenter trial of angiotensin-converting enzyme inhibition therapy for infants with SV. Multivariable longitudinal analysis was used to model the associations between BNP levels and three sets of grouped variables (echocardiography, catheterization, growth). Multivariable analysis was performed to assess associations with patient characteristics at both visits. Associations between BNP levels and neurodevelopmental variables were investigated at the 14 month visit because neurodevelopmental assessment was performed only at this visit. The BNP level was significantly higher before SCPC (n = 173) than at the age of 14 months (n = 134). The respective median levels were 80.8 pg/ml (interquartile range [IQR], 35-187 pg/ml) and 34.5 pg/ml (IQR, 17-67 pg/ml) (p < 0.01). A BNP level higher than 100 pg/ml was present in 72 subjects (42 %) before SCPC and in 21 subjects (16 %) at the age of 14 months. In the 117 patients who had BNP measurements at both visits, the median BNP level decreased 32 pg/ml (IQR, 1-79 pg/ml) (p < 0.01). In the longitudinal multivariable analysis, higher BNP levels were associated with a higher end-systolic volume z-score (p = 0.01), a greater degree of atrioventricular (AV) valve regurgitation (p < 0.01), a lower weight z-score (p < 0.01), and a lower length z-score (p = 0.02). In multivariable analyses, a higher BNP level at the age of 14 months was associated with arrhythmia after SCPC surgery (p < 0.01), a prior Norwood procedure (p < 0.01), a longer hospital stay after SCPC surgery (p = 0.04), and a lower Bayley psychomotor developmental index (p = 0.02). The levels of BNP decreases in infants with SV from the pre-SCPC visit to the age of 14 months. A higher BNP level is associated with increased ventricular dilation in systole, increased AV valve regurgitation, impaired growth, and poorer neurodevelopmental outcomes. Therefore, BNP level may be a useful seromarker for identifying infants with SV at risk for worse outcomes.

Objective: Neonatal cardiac surgery requiring cardiopulmonary bypass results in a heightened inflammatory response. Perioperative glucocorticoid administration is commonly used in an attempt to reduce the inflammatory cascade, although characterization of the cytokine response to steroids in neonatal cardiac surgery remains elusive because of highly variable approaches in administration. This randomized trial was designed to prospectively evaluate the effect of specific glucocorticoid dosing protocols on inflammatory markers in neonatal cardiac surgery requiring cardiopulmonary bypass., Methods: Neonates scheduled for cardiac surgery were randomly assigned to receive either 2-dose (8 hours preoperatively and operatively, n = 36) or single-dose (operatively, n = 32) methylprednisolone at 30 mg/kg per dose in a prospective double-blind trial. The primary outcome was the effect of these steroid regimens on markers of inflammation. Secondary analyses evaluated the association of specific cytokine profiles with postoperative clinical outcomes., Results: Patient demographics, perioperative variables, and preoperative indices of inflammation were similar between the single- and 2-dose groups. Preoperative cytokine response after the 2-dose methylprednisolone protocol was consistent with an anti-inflammatory effect, although this did not persist into the postoperative period. Premedication baseline levels of interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor α were predictive of postoperative intensive care unit and hospital length of stay. Only interleukin-8 demonstrated a postoperative response associated with duration of intensive care unit and hospital stay., Conclusions: The addition of a preoperative dose of methylprednisolone to a standard intraoperative methylprednisolone dose does not improve markers of inflammation after neonatal cardiac surgery. The routine administration of preoperative glucocorticoids in neonatal cardiac surgery should be reconsidered., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: The objective of this study was to determine whether a composite outcome, derived of objective signs of inadequate cardiac output, would be associated with other important measures of outcomes and therefore be an appropriate end point for clinical trials in neonatal cardiac surgery., Methods: Neonates (n = 76) undergoing cardiac operations requiring cardiopulmonary bypass were prospectively enrolled. Patients were defined to have met the composite outcome if they had any of the following events before hospital discharge: death, the use of mechanical circulatory support, cardiac arrest requiring chest compressions, hepatic injury (2 times the upper limit of normal for aspartate aminotransferase or alanine aminotransferase), renal injury (creatinine >1.5 mg/dL), or lactic acidosis (an increasing lactate >5 mmol/L in the postoperative period). Associations between the composite outcome and the duration of mechanical ventilation, intensive care unit stay, hospital stay, and total hospital charges were determined., Results: The median age at the time of surgery was 7 days, and the median weight was 3.2 kg. The composite outcome was met in 39% of patients (30/76). Patients who met the composite outcome compared with those who did not had a longer duration of mechanical ventilation (4.9 vs 2.9 days, P < .01), intensive care unit stay (8.8 vs 5.7 days, P < .01), hospital stay (23 vs 12 days, P < .01), and increased hospital charges ($258,000 vs $170,000, P < .01). In linear regression analysis, controlling for surgical complexity, these differences remained significant (R(2) = 0.29-0.42, P < .01)., Conclusions: The composite outcome is highly associated with important early operative outcomes and may serve as a useful end point for future clinical research in neonates undergoing cardiac operations., (Published by Mosby, Inc.)

We present pressure–volume loops obtained from two patients with single-ventricle physiology, one with a modified Blalock–Taussig shunt and one with a right ventricle-to-pulmonary artery shunt. The dissimilarities in pressure–volume loop contour and related indices highlight potentially important differences in ventricular mechanics between the shunt types.

New evidence of increased phosphodiesterase-5 (PDE-5) in hypertrophied human myocardium suggests that sildenafil, a selective PDE-5 inhibitor, may improve muscle contraction and therefore improve ventricular function. The purpose of this study was to compare ventricular function as assessed by echocardiography in 10 surgically palliated single-ventricle patients at baseline and again after a single dose of sildenafil. The velocity time integral of the ventricular outflow tract was increased 2 h after sildenafil administration (p = 0.01), thus suggesting an improvement in cardiac output.

Acute right ventricular failure post heart transplantation in the pediatric population has not been well documented. Treatment using medical therapies including inotropes and nitric oxide are often inefficient for pediatric patients. Extracorporeal membrane oxygenation has been traditionally used in children until a long-term decision can be made. As a result of the emergence of smaller assist devices, pediatric practitioners now have more options available to treat this patient population. We describe the successful use of the Thoratec CentriMag in a pediatric patient posttransplantation with acute right ventricular failure.

Objective: To study the effects of duration of preoperative prostaglandin E1 (PGE) exposure on perioperative outcomes of the arterial switch operation in patients with transposition of the great arteries with an intact ventricular septum., Design: Retrospective chart review., Setting: Pediatric cardiac intensive care unit in a tertiary care children's hospital., Patients: All patients with transposition of the great arteries with an intact ventricular septum from 1995 to 2008., Outcome Measures: Inotropic score was calculated for all patients in the first 5 postoperative days and maximum inotropic score was recorded. Length of postoperative mechanical ventilation, fluid balance, mechanical ventilation time, as well as intensive care unit and hospital stay were recorded for all patients., Results: Study population included 59 patients, 41 (69%) underwent balloon atrial septostomy. PGE was used in 52 patients, median exposure of 59 hours, range 0 to 272 hours. Longer preoperative PGE exposure was associated with longer preoperative mechanical ventilation (P < .001). There was no association between preoperative PGE duration and cardiopulmonary bypass time, cross-clamp time, or total hospital stay. Patients with longer preoperative PGE exposure had a lower postoperative inotrope score (10 vs. 15 P = .02)., Conclusion: Greater preoperative PGE exposure was associated with prolonged preoperative mechanical ventilation. Longer PGE exposure was associated with lower postoperative inotrope requirements. Aggressive efforts to avoid or shorten PGE infusion duration may not be warranted in this population., (© 2012 Wiley Periodicals, Inc.)