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Purpose: Acute cellular (ACR) and antibody-mediated (AMR) rejection are risk factors for allograft loss in heart transplant (HT) recipients. Endomyocardial biopsy (EMB), although considered the gold standard for rejection surveillance, is invasive and has high interobserver variability. Noninvasive donor-derived cell-free DNA (dd-cfDNA) sampling has a high negative predictive value (NPV) for rejection in adults and is increasingly used in pediatrics. This single center study aimed to test the performance of dd-cfDNA in screening for acute rejection (AR) and donor-specific antibodies (DSAs) in pediatric HT recipients., Methods: Blood samples for dd-cfDNA were obtained per clinical protocol for all eligible HT recipients in our center from July 1, 2022 to December 31, 2023. Primary endpoints were episodes of AR, pathology grading of EMBs temporally related to ddcfDNA sampling (0-150 days), and presence of DSAs., Results: There were 471 interpretable samples, in 192 unique patients. Of those, 199 dd-cfDNA tests were paired with EMB ± DSA in 152 patients. Abnormal dd-cfDNA (> 0.2%) was found in 77 samples (median 0.48%, range 0.21%-11%) and led to EMB, where one sample was positive for ACR (grade 2R), 13 for AMR, yielding an NPV of 97% for AMR. After excluding abnormal ddcfDNA testing associated with AR, 65 abnormal dd-cfDNA tests were paired with DSA testing. The NPV of the test for detection of DSAs was 93%., Conclusion: Implementation of noninvasive rejection surveillance with dd-cfDNA in a pediatric cohort demonstrates high NPV for AR and high DSAs, making it an ideal screening tool for long-term monitoring of allograft health in pediatrics., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Pediatric Cardiac Quality of Life Inventory (PCQLI) is a disease-specific pediatric cardiac health-related quality of life (HRQOL) instrument that is reliable, valid, and generalizable. We aim to demonstrate PCQLI responsiveness in children undergoing arrhythmia ablation, heart transplantation, and valve surgery before and after cardiac intervention., Methods: Pediatric cardiac patients 8-18 years of age from 11 centers undergoing arrhythmia ablation, heart transplantation, or valve surgery were enrolled. Patient and parent-proxy PCQLI Total, Disease Impact and Psychosocial Impact subscale scores were assessed pre- and 3-12 months follow-up. Patient clinical status was assessed by a clinician post-procedure and dichotomized into markedly improved/improved and no change/worse/much worse. Paired t-tests examined change over time., Results: We included 195 patient/parent-proxies: 12.6 ± 3.0 years of age; median follow-up time 6.7 (IQR = 5.3-8.2) months; procedural groups - 79 (41%) ablation, 28 (14%) heart transplantation, 88 (45%) valve surgery; clinical status - 164 (84%) markedly improved/improved, 31 (16%) no change/worse/much worse. PCQLI patient and parent-proxies Total scores increased (p ≤ 0.013) in each intervention group. All PCQLI scores were higher (p < 0.001) in the markedly improved/improved group and there were no clinically significant differences in the PCQLI scores in the no difference/worse/much worse group., Conclusion: The PCQLI is responsive in the pediatric cardiac population. Patients with improved clinical status and their parent-proxies reported increased HRQOL after the procedure. Patients with no improvement in clinical status and their parent-proxies reported no change in HRQOL. PCQLI may be used as a patient-reported outcome measure for longitudinal follow-up and interventional trials to assess HRQOL impact from patient and parent-proxy perspectives., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: The aims of the study were to assess the performance of a clinically available cell-free DNA (cfDNA) assay in a large cohort of pediatric and adult heart transplant recipients and to evaluate performance at specific cut points in detection of rejection., Methods: Observational, non-interventional, prospective study enrolled pediatric and adult heart transplant recipients from seven centers. Biopsy-associated plasma samples were used for cfDNA measurements. Pre-determined cut points were tested for analytic performance., Results: A total of 487 samples from 160 subjects were used for the analysis. There were significant differences for df-cfDNA values between rejection [0.21% (IQR 0.12-0.69)] and healthy samples [0.05% (IQR 0.01-0.14), p < .0001]. The pediatric rejection group had a median df-cfDNA value of 0.93% (IQR 0.28-2.84) compared to 0.09% (IQR 0.04-0.23) for healthy samples, p = .005. Overall negative predictive value was 0.94 while it was 0.99 for pediatric patients. Cut points of 0.13% and 0.15% were tested for various types of rejection profiles and were appropriate to rule out rejection., Conclusion: The study suggests that pediatric patients with rejection show higher levels of circulating df-cfDNA compared to adults and supports the specific cut points for clinical use in pediatric and adult patients with overall acceptable performance., (© 2024 Wiley Periodicals LLC.)

Members of the genus Erysipelothrix are emergent pathogens of cultured eels, as well as several characid and cyprinid species. Since 2013, E. rhusiopathiae has been reported from diseased barramundi ( Lates calcarifer ) cultured in North America; we recovered 8 E. rhusiopathiae isolates from diseased fish during different outbreaks from the same farm. The E. rhusiopathiae isolates from barramundi were compared phenotypically and genetically to E. piscisicarius isolates characterized from ornamental fish and E. rhusiopathiae recovered from aquatic and terrestrial animals. All barramundi isolates were PCR-positive for the surface protective antigen type B ( spaB ) gene, and shared ≥ 99.7% sequence similarity among concatenated multilocus sequence analysis gene sequences, indicating a high degree of genetic homogeneity. These isolates were > 99% similar to other spaB- positive isolates from marine invertebrates and marine mammals, consistent with findings for other spa types. The spaA and spaB isolates shared < 98% similarity, as well as < 90% similarity with spaC- positive E. piscisicarius . Similar clonality among the spaB isolates was observed using repetitive element palindromic PCR. In experimental intracoelomic injection challenges conducted to fulfill Koch postulates, 67% of exposed tiger barbs ( Puntigrus tetrazona ) died within 14 d of challenge. Our study supports previous work citing the genetic variability of Erysipelothrix spp. spa types and the emergence of members of the genus Erysipelothrix as nascent fish pathogens., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: There are limited data evaluating the success of a structured transition plan specifically for pediatric heart transplant (HT) recipients following their transfer of care to an adult specialist. We sought to identify risk factors for poor adherence, graft failure, and mortality following the transfer of care to adult HT care teams., Methods: We retrospectively reviewed all patients who underwent transition from the pediatric to adult HT program at our center between January 2011 and June 2021. Demographic characteristics, comorbid conditions, and psychosocial history were collected at the time of HT, the time of transition, and the most recent follow-up. Adverse events including mortality, graft rejection, infection, and renal function were also captured before and after the transition., Results: Seventy-two patients were identified (54.1% male, 54.2% Caucasian). Mean age at the time of transition was 23 years after a median of 11.6 years in the pediatric program. The use of calcineurin inhibitors was associated with reduced mortality (HR .04, 95% CI .0-.6, p = .015), while prior psychiatric hospitalization (HR 45.3, 95% CI, 6.144-333.9, p = .0001) was associated with increased mortality following transition. Medication nonadherence and young age at the time of transition were markers for high-risk individuals prior to the transition of care., Conclusions: Transition of HT recipients from a pediatric program to an adult program occurs during a vulnerable time of emerging adulthood, and we have identified risk factors for mortality following transition. Development of a formalized transition plan with a large multidisciplinary team with focused attention on high-risk patients, including those with psychiatric comorbidities, may favorably influence outcomes., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The Pediatric Heart Transplant Society (PHTS) Registry was founded 30 years ago as a collaborative effort among like-minded providers of this novel life-saving technique for children with end-stage heart failure. In the intervening decades, the data from the Registry have provided invaluable knowledge to the field of pediatric heart transplantation. This report of the PHTS Registry provides a comprehensive look at the data, highlighting both the longevity of the registry and one unique aspect of the PHTS registry, allowing for exploration into children with single ventricle anatomy., Methods: The PHTS database was queried from January 1, 1993 to December 31, 2019 to include pediatric (age < 18 years) patients listed for HT. For our analysis, we primarily analyzed patients by era. The early era was defined as children listed for HT from January 1, 1993 to December 31, 2004; middle era January 1, 2005 to December 31, 2009; and recent era January 1, 2010 to December 31, 2019. Outcomes after listing and transplant, including mortality and morbidities, are presented as unadjusted for risk, but compared across eras., Results: Since 1993, 11 995 children were listed for heart transplant and entered into the PHTS Registry with 9755 listed during the study period. The majority of listings occurred within the most recent era. Waitlist survival improved over the decades as did posttransplant survival. Other notable changes over time include fewer patients experiencing allograft rejection or infection after transplant. Waitlist and posttransplant survival have changed dramatically in patients with single ventricle physiology and significantly differ by stage of single ventricle palliation., Summary: Key points from this PHTS Registry summary and focus on patients with single ventricle congenital heart disease in particular, include the changing landscape of candidates and recipients awaiting heart transplant. There is clear improvement in waitlist and transplant outcomes for children with both cardiomyopathy and congenital heart disease alike., (© 2023 Wiley Periodicals LLC.)

Objectives: This study investigated the association between early extubation (EE) and the degree of postoperative intensive care unit (ICU) support after the Fontan procedure, specifically evaluating the volume of postoperative intravenous fluid (IVF) and vasoactive-inotropic score (VIS)., Methods: Retrospective analysis of patients who underwent Fontan palliation from 2008 to 2018 at a single center was completed. Patients were initially divided into pre-institutional initiative towards EE (control) and post-initiative (modern) cohorts. Differences between the cohorts were assessed using t-test, Wilcoxon, or chi-Square. Following stratification by early or late extubation, four groups were compared via ANOVA or Kruskal-Wallis Test., Results: There was a significant difference in the rate of EE between the control and modern cohorts (mean 42.6 versus 75.7%, p = 0.01). The modern cohort demonstrated lower median VIS (5 versus 8, p = 0.002), but higher total mean IVF (101±42 versus 82 ±27 cc/kg, p < 0.001) versus control cohort. Late extubated (LE) patients in the modern cohort had the highest VIS and IVF requirements. This group received 67% more IVF (140 ± 53 versus 84 ± 26 cc/kg, p < 0.001) and had a higher median VIS at 24 hours (10 (IQR, 5-10) versus 4 (IQR, 2-7), p < 0.001) versus all other groups. In comparison, all EE patients had a 5-point lower median VIS when compared to LE patients (3 versus 8, p= 0.001)., Conclusions: EE following the Fontan procedure is associated with reduced post-operative VIS. LE patients in the modern cohort received more IVF, potentially identifying a high-risk subgroup of Fontan patients deserving of further investigation.

Purpose: Although waitlist mortality is unacceptably high, nearly half of donor heart offers are rejected by pediatric heart transplant centers. The Advanced Cardiac Therapy Improving Outcome Network (ACTION) and Pediatric Heart Transplant Society (PHTS) convened a multi-institutional donor decision discussion forum (DDDF) aimed at assessing donor acceptance practices and reducing practice variation., Methods: A 1-h-long virtual DDDF for providers across North America, the United Kingdom, and Brazil was held monthly. Each session typically included two case presentations posing a real-world donor decision challenge. Attendees were polled before the presenting center's decision was revealed. Group discussion followed, including a review of relevant literature and PHTS data. Metrics of participation, participant agreement with presenting center decisions, and impact on future decision-making were collected and analyzed., Results: Over 2 years, 41 cases were discussed. Approximately 50 clinicians attended each call. Risk factors influencing decision-making included donor quality (10), size discrepancy (8), and COVID-19 (8). Donor characteristics influenced 63% of decisions, recipient factors 35%. Participants agreed with the decision made by the presenting center only 49% of the time. Post-presentation discussion resulted in 25% of participants changing their original decision. Survey conducted reported that 50% respondents changed their donor acceptance practices., Conclusion: DDDF identified significant variation in pediatric donor decision-making among centers. DDDF may be an effective format to reduce practice variation, provide education to decision-makers, and ultimately increase donor utilization., (© 2023 Wiley Periodicals LLC.)

The Pediatric Heart Network's Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT02741115) demonstrated improvements in some measures of exercise capacity and in the myocardial performance index following 6 months of treatment with udenafil (87.5 mg twice daily). In this post hoc analysis, we evaluate whether subgroups within the population experienced a differential effect on exercise performance in response to treatment. The effect of udenafil on exercise was evaluated within subgroups defined by baseline characteristics, including peak oxygen consumption (VO 2 ), serum brain-type natriuretic peptide level, weight, race, gender, and ventricular morphology. Differences among subgroups were evaluated using ANCOVA modeling with fixed factors for treatment arm and subgroup and the interaction between treatment arm and subgroup. Within-subgroup analyses demonstrated trends toward quantitative improvements in peak VO 2 , work rate at the ventilatory anaerobic threshold (VAT), VO 2 at VAT, and ventilatory efficiency (VE/VCO 2 ) for those randomized to udenafil compared to placebo in nearly all subgroups. There was no identified differential response to udenafil based on baseline peak VO 2 , baseline BNP level, weight, race and ethnicity, gender, or ventricular morphology, although participants in the lowest tertile of baseline peak VO 2 trended toward larger improvements. The absence of a differential response across subgroups in response to treatment with udenafil suggests that the treatment benefit may not be restricted to specific sub-populations. Further work is warranted to confirm the potential benefit of udenafil and to evaluate the long-term tolerability and safety of treatment and to determine the impact of udenafil on the development of other morbidities related to the Fontan circulation.Trial Registration NCT0274115., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Septal reduction therapy via septal myectomy or a modified Konno procedure is the mainstay of therapy for drug-refractory obstructive hypertrophic cardiomyopathy (HCM), although outcomes data on septal myectomy in pediatric patients are limited. We evaluated long-term outcomes following surgery for obstructive HCM in a pediatric cohort., Methods: We retrospectively reviewed patients age ≤18 years with obstructive HCM who underwent a left and/or right ventricular septal myectomy at our institution between 1992 and 2022. Primary endpoints were transplantation-free survival, freedom from HCM-related death, and cumulative probability of HCM-related reintervention. We further evaluated outcomes in patients with and without Noonan syndrome or other RASopathies., Results: Thirty-seven patients (median age, 7.4 years; interquartile range [IQR], 3.4-12.9 years) underwent transaortic septal myectomy. A combined modified Konno procedure was performed in 5 patients (13.9%). Sixteen patients (43.2%) had a RASopathy. A concomitant right ventricular outflow tract resection was performed in 9 patients (24.3%). There was 1 (2.7%) in-hospital death and 4 late deaths at a median follow-up of 10.5 years (IQR, 0.1-29.3). Twenty-year transplant-free survival and freedom from HCM-related death were 80.6% (95% confidence interval [CI], 64.2%-100%) and 87.1% (95% CI, 71.8%-100%), respectively. The 20-year cumulative probability of HCM-related reintervention was 34.2% (95% CI, 12.8%-57.1%). Seven patients required a septal reintervention. There was no difference in any primary endpoints between patients with and without a RASopathy., Conclusions: Surgery for obstructive HCM, including septal myectomy with and without a modified Konno procedure, may be performed with low morbidity and good long-term outcomes in pediatric patients. Recurrent outflow tract obstruction is not uncommon., Competing Interests: The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.

Background: Patients after Fontan palliation represent a growing pediatric population requiring heart transplant (HTx) and often have lymphopenia (L) and/or hypogammaglobinemia that may be exacerbated by protein-losing enteropathy (PLE, P). The post-HTx effects of this altered immune phenotype are not well studied., Methods: In this study of the Pediatric Heart Transplant Society Registry, 106 Fontan patients who underwent HTx between 2005 and 2018 were analyzed. The impact of lymphopenia and PLE on graft survival, infection, rejection, and malignancy was analyzed at 1 and 5 years post-HTx., Results: The following combinations of lymphopenia and PLE were noted: +L+P, n = 37; +L-P, n = 23; -L+P, n = 10; and -L-P, n = 36. Graft survival between the groups was similar within the first year after transplant (+L+P: 86%, +L-P: 86%, -L+P: 87%, -L-P: 89%, p = .9). Freedom from first infection post-HTx was greatest among -L-P patients compared to patients with either PLE, lymphopenia, or both; with a 22.1% infection incidence in the -L-P group and 41.4% in all others. These patients had a significantly lower infection rate in the first year after HTx (+L+P: 1.03, +L-P: 1, -L+P: 1.3, -L-P: 0.3 infections/year, p < .001) and were similar to a non-single ventricle CHD control group (0.4 infections/year). Neither freedom from rejection nor freedom from malignancy 1 and 5 years post-HTx, differed among the groups., Conclusions: Fontan patients with altered immunophenotype, with lymphopenia and/or PLE, are at increased risk of infection post-HTx, although have similar early survival and freedom from rejection and malignancy. These data may encourage alternative immunosuppression strategies and enhanced monitoring for this growing subset of patients., (© 2022 Wiley Periodicals LLC.)

Objectives: Allogeneic valve transplantation is an emerging therapy that delivers a living valve from a donor heart. We reviewed the national discard rate of pediatric and young adult (aged 25 years or younger) donor grafts to estimate the number of hearts potentially available to source valve allotransplantation., Methods: We queried the United Network for Organ Sharing database to identify pediatric and young adult heart donors from 1987 to 2022. Donor heart discard was defined as nontransplantation of the allograft., Results: Of 72,460 pediatric/young adult heart donations, 41,065 (56.7%) were transplanted and 31,395 (43.3%) were unutilized. The average annual number of discarded hearts in era 1 (1987-2000), era 2 (2000-2010), and era 3 (2010-2022) was 791 (42.8%), 1035 (46.3%), and 843 (41.2%), respectively. From 2017 to 2021, the average annual number of discards by age was: 39 (31.8%) neonates/infants, 78 (38.0%) toddlers, 41 (49.4%) young children, 240 (38.0%) adolescents, and 498 (40.1%) young adults. High-volume procurement regions had the greatest proportion of nonutilization, with the national average discard rate ranging from 39% to 49%. The most frequently documented reasons for nonallocation were distribution to the heart valve industry (26.5%), presumably due to suboptimal graft function, poor organ function (22.7%), and logistical challenges (10.8%)., Conclusions: With ∼900 pediatric/young adult donor hearts discarded annually, unutilized grafts represent a potential source of valves for allogeneic valve transplant to supplement current conduit and valve replacement surgery. The limited availability of neonatal and infant hearts may limit this technique in the youngest patients, for whom cryopreserved homografts or xenografts will likely remain the primary valve substitute., (© 2023 The Author(s).)

Patients with hypoplastic left heart syndrome who have been palliated with the Fontan procedure are at risk for adverse neurodevelopmental outcomes, lower quality of life, and reduced employability. We describe the methods (including quality assurance and quality control protocols) and challenges of a multi-center observational ancillary study, SVRIII (Single Ventricle Reconstruction Trial) Brain Connectome. Our original goal was to obtain advanced neuroimaging (Diffusion Tensor Imaging and Resting-BOLD) in 140 SVR III participants and 100 healthy controls for brain connectome analyses. Linear regression and mediation statistical methods will be used to analyze associations of brain connectome measures with neurocognitive measures and clinical risk factors. Initial recruitment challenges occurred that were related to difficulties with: (1) coordinating brain MRI for participants already undergoing extensive testing in the parent study, and (2) recruiting healthy control subjects. The COVID-19 pandemic negatively affected enrollment late in the study. Enrollment challenges were addressed by: (1) adding additional study sites, (2) increasing the frequency of meetings with site coordinators, and (3) developing additional healthy control recruitment strategies, including using research registries and advertising the study to community-based groups. Technical challenges that emerged early in the study were related to the acquisition, harmonization, and transfer of neuroimages. These hurdles were successfully overcome with protocol modifications and frequent site visits that involved human and synthetic phantoms.

Lactococcus petauri is an important emergent bacterial pathogen of salmonids in the USA. The purpose of this study was to evaluate the protection conferred to rainbow trout ( Oncorhynchus mykiss ) against L. petauri by formalin-killed vaccines in immersion and injectable forms, as well as the enhanced protection afforded by booster vaccination. In the first challenge, fish were immunized via intracoelomic injection (IC) or immersion (Imm) routes alone. Approximately 418 degree days (Temperature in degree Celsius × days post-immunization) (dd) Imm, or 622 dd IC post-vaccination, fish were challenged via IC with wild-type L. petauri. In the second experiment, initial Imm vaccination was followed by booster vaccination via Imm or IC routes 273 dd post-immunization along with appropriate PBS controls. The various vaccination protocol efficacies were evaluated by challenging fish with L. petauri by cohabitation with diseased fish 399 dd post-booster administration. A relative percent survival (RPS) of 89.5% and 28% was recorded in the IC and Imm single immunization treatments, respectively. In the second study, an RPS of 97.5%, 10.2%, 2.6% and -10.1% plus approximately 0%, 50%, 20%, and 30% bacterial persistence was recorded in the Imm immunized + IC boosted, Imm immunized + mock IC boosted, Imm immunized + Imm boosted, and Imm immunized + mock Imm boosted treatments, respectively. Only the Imm immunized + IC injection boosted treatments provided significant protection when compared to unvaccinated and challenged treatments ( p < 0.05). In conclusion, although both Imm and IC vaccines appear safe for trout, the inactivated Imm vaccines seem to provide only mild and temporary protection against lactococcosis; whereas IC immunized trout develop a significantly stronger protective response in both challenges.

Objectives: Donor-specific cell-free DNA shows promise as a noninvasive marker for allograft rejection, but as yet has not been validated in both adult and pediatric recipients. The study objective was to validate donor fraction cell-free DNA as a noninvasive test to assess for risk of acute cellular rejection and antibody-mediated rejection after heart transplantation in pediatric and adult recipients., Methods: Pediatric and adult heart transplant recipients were enrolled from 7 participating sites and followed for 12 months or more with plasma samples collected immediately before all endomyocardial biopsies. Donor fraction cell-free DNA was extracted, and quantitative genotyping was performed. Blinded donor fraction cell-free DNA and clinical data were analyzed and compared with a previously determined threshold of 0.14%. Sensitivity, specificity, negative predictive value, positive predictive value, and receiver operating characteristic curves were calculated., Results: A total of 987 samples from 144 subjects were collected. After applying predefined clinical and technical exclusions, 745 samples from 130 subjects produced 54 rejection samples associated with the composite outcome of acute cellular rejection grade 2R or greater and pathologic antibody-mediated rejection 2 or greater and 323 healthy samples. For all participants, donor fraction cell-free DNA at a threshold of 0.14% had a sensitivity of 67%, a specificity of 79%, a positive predictive value of 34%, and a negative predictive value of 94% with an area under the curve of 0.78 for detecting rejection. When analyzed independently, these results held true for both pediatric and adult cohorts at the same threshold of 0.14% (negative predictive value 92% and 95%, respectively)., Conclusions: Donor fraction cell-free DNA at a threshold of 0.14% can be used to assess for risk of rejection after heart transplantation in both pediatric and adult patients with excellent negative predictive value., (Copyright © 2022 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

This manuscript outlines a clinical approach to vasoplegia incorporating the current state of knowledge regarding vasoplegia in pediatric patients immediately post-transplant and to identify modifiable factors both pre- and post-transplant that may reduce post-operative morbidity, end-organ dysfunction, and mortality. Centers participating in the Pediatric Heart Transplant Society (PHTS) were asked to provide their internal protocols and rationale for vasoplegia management, and applicable adult and pediatric data were reviewed. The authors synthesized the above protocols and literature into the following description of clinical approaches to vasoplegia highlighting areas of both broad consensus and of significant practice variation., (© 2022 Wiley Periodicals LLC.)

Background: Clinical rejection (CR) defined as decision to treat clinically suspected rejection with change in immunotherapy based on clinical presentation with or without diagnostic biopsy findings is an important part of care in heart transplantation. We sought to assess the utility of donor fraction cell-free DNA (DF cfDNA) in CR and the utility of serial DF cfDNA in CR patients in predicting outcomes of clinical interest., Methods: Patients with heart transplantation were enrolled in two sequential, multi-center, prospective observational studies. Blood samples were collected for surveillance or clinical events. Clinicians were blinded to the results of DF cfDNA., Results: A total of 835 samples from 269 subjects (57% pediatric) were included for this analysis, including 28 samples associated with CR were analyzed. Median DF cfDNA was 0.43 (IQR 0.15, 1.36)% for CR and 0.10 (IQR 0.07, 0.16)% for healthy controls (p < .0001). At cutoff value of 0.13%, the area under curve (AUC) was 0.82, sensitivity of 0.86, specificity of 0.67, and negative predictive value of 0.99. There was serial decline in DF cfDNA post-therapy, however, those with cardiovascular events (cardiac arrest, need for mechanical support or death) showed significantly higher levels of DF cfDNA on Day 0 (2.11 vs 0.31%) and Day 14 (0.51 vs 0.22%) compared to those who did not have such an event (p < .0001)., Conclusion: DF cfDNA has excellent agreement with clinical rejection and, importantly, serial measurement of DF cfDNA predict clinically significant outcomes post treatment for rejection in these patients., (© 2022 Wiley Periodicals LLC.)

Background: Surgical repair for patients with congenital heart disease (CHD) often incorporates homograft tissue or other foreign material that can lead to allosensitization. We sought to identify the relationship between pre-sensitization prior to heart transplant and exposure to homograft tissue in CHD patients., Methods: Retrospective chart review of all CHD patients who underwent heart transplant at a major pediatric transplant center between 1/1/2011-3/31/18. Operative records determined use of homograft tissue or foreign material. Panel reactive antibody (PRA) and Luminex TM single-antigen bead (SAB) testing results were reviewed. Statistical analysis determined odds of pre-sensitization in patients exposed to homograft tissue., Results: Fifty-six CHD patients underwent transplant during the review period. Thirteen patients (23%) were pre-sensitized by PRA>10%. By SAB testing, 33 patients (59%) developed any anti-HLA antibody >0 MFI, 30 patients (54%) >2000 MFI, and 19 patients (34%) >6000 MFI. Patients with homografts were more likely to be pre-sensitized by PRA (OR = 7.31, p = .007), and to have developed any anti-HLA antibody at various levels, >0 (OR = 4.52, p = .034), >2000 (OR = 8.59, p = .003), and >6000 (OR = 8.50, p = .004). Of patients with homografts, those pre-sensitized by PRA had longer exposure times (9.80 vs 4.96 years, p = .025). There was no difference in exposure time with relation to pre-sensitization by SAB testing., Conclusions: Previous exposure to homograft tissue appears to increase the odds of pre-sensitization by either the PRA or SAB testing. Longer exposure time to homograft tissue prior to transplant is associated with increased pre-sensitization at transplant as determined by PRA, though not by SAB testing., (© 2021 Wiley Periodicals LLC.)

Background: Reports focused on adult heart transplant (HTx) recipients with COVID-19 suggest an increased risk of severe disease, however; it is unclear if this holds true for pediatric HTx patients, given the typically milder course of illness in children in general with COVID-19. We sought to rapidly implement a system for multi-center data collection on pediatric HTx candidates and recipients, with the aim of describing the patient population and infection related outcomes., Methods: The Pediatric Heart Transplant Society (PHTS) is a multi-center collaboration that seeks to improve the outcomes of children who are listed and undergo HTx. The society consists of pediatric HTx centers in North America (n = 53), UK (n = 2), and Brazil (n = 1). In response to the pandemic, PHTS developed a web-based platform to collect COVID-19 specific data on pediatric HTx candidates and recipients. Non-PHTS centers were also invited to submit data. Data fields included pre-and post-HTx patient characteristics, presumed versus documented infection, need for hospitalization (including ICU and ventilator use), treatments administered, and 30-day outcome (resolution, death, sequelae, and or unresolved) RESULTS: Data collection was initiated on 4/30/20. As of 03/15/21 there were 225 patients [19 pre-HTx and 206 post-HTx, median age 14 years (IQR 7, 18)] reported from 41 centers. Hospitalization occurred in 42% (n = 8) of the pre-HTx and 21% (n=43) of the post-HTx patients. Among the patients listed for HTx, 21% (n = 4) required ICU and 10.5% (n = 2) were mechanically ventilated. Among post-HTx patients, 7% (n = 14) required ICU and 1% (n = 3) were mechanically ventilated. At 30 days, the majority of patients had resolution of symptoms (94.7% pre-HTx, 95.6% post-HTx). One death was reported in a post-HTx patient prior to 30 days from onset of COVID-19 illness., Conclusions: These data demonstrate the ability to rapidly adapt the PHTS data collection infrastructure in response to a novel infection and represent the first known multi-center report of characteristics and early outcomes for patients listed and following pediatric HTx with COVID-19. Hospitalization appears to be more common for both candidates and recipients due to COVID-19 than for the general pediatric population though stays were short and mortality minimal., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Cell-free DNA is an emerging biomarker. While donor fraction may detect graft events in heart transplant recipients, the prognostic value of total nuclear cell-free DNA (ncfDNA) itself is largely unexplored., Objective: Explore the relationship between ncfDNA and clinical events in heart transplant recipients., Methods: We conducted a multi-center prospective study to investigate the value of cell-free DNA in non-invasive monitoring following heart transplantation. Over 4000 blood samples were collected from 388 heart transplant patients. Total ncfDNA and donor fraction were quantified. Generalized linear models with maximum likelihood estimation for repeated measures with subjects as clusters were used to explore the relationship of ncfDNA and major adverse events. Receiver operating characteristic curves were used to help choose cutpoints., Results: A ncfDNA threshold (50 ng/ml) was identified that was associated with increased risk of major adverse events. NcfDNA was elevated in patients who suffered cardiac arrest, required mechanical circulatory support or died post heart transplantation as well as in patients undergoing treatment for infection., Conclusions: Elevated ncfDNA correlates with risk for major adverse events in adult and pediatric heart transplant recipients and may indicate a need for enhanced surveillance after transplant., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: To describe the clinical and hemodynamic characteristics of Fontan failure in children listed for heart transplant., Methods: In a nested study of the Pediatric Heart Transplant Society, 16 centers contributed information on Fontan patients listed for heart transplant between 2005and 2013. Patients were classified into four mutually exclusive phenotypes: Fontan with abnormal lymphatics (FAL), Fontan with reduced systolic function (FRF), Fontan with preserved systolic function (FPF), and Fontan with "normal" hearts (FNH). Primary outcome was waitlist and post-transplant mortality., Results: 177 children listed for transplant were followed over a median 13 (IQR 4-31) months, 84 (47%) were FAL, 57 (32%) FRF, 22 (12%) FNH, and 14 (8%) FPF. Hemodynamic characteristics differed between the 4 groups: Fontan pressure (FP) was most elevated with FPF (median 22, IQR 18-23, mmHg) and lowest with FAL (16, 14-20, mmHg); cardiac index (CI) was lowest with FRF (2.8, 2.3-3.4, L/min/m 2 ). In the entire cohort, 66% had FP >15 mmHg, 21% had FP >20 mmHg, and 10% had CI <2.2 L/min/m 2 . FRF had the highest risk of waitlist mortality (21%) and FNH had the highest risk of post-transplant mortality (36%)., Conclusions: Elevated Fontan pressure is more common than low cardiac output in pediatric failing Fontan patients listed for transplant. Subtle hemodynamic differences exist between the various phenotypes of pediatric Fontan failure. Waitlist and post-transplant mortality risks differ by phenotype., Competing Interests: Disclosure Statement This study complies with the Declaration of Helsinki and the research was approved by Stanford University Institutional Review Board. Participating centers contributed supplemental data to the Pediatric Heart Transplant Society under Institutional Review Board approval or waiver of consent where applicable., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Hypertension is a known complication of pediatric heart transplantation. We sought to identify factors associated with anti-hypertensive use in pediatric heart transplant recipients immediately post-transplant and oral anti-hypertensive use at discharge and 1-year post-transplant. Retrospective chart review was conducted of patients ≤18 years who underwent heart transplantation at two major heart transplant centers between August 1, 2009 and December 31, 2017 with ≥1-year follow-up. Exclusion criteria included re-transplant, multi-organ recipients, survival <1 year, and comorbidities associated with hypertension. Anti-hypertensive use was recorded during initial ICU stay, at discharge, and 1-year post-transplant. Univariate and multivariate analyses determined associations of demographic and diagnostic factors and need for anti-hypertensives. There were 188 patients that met inclusion criteria. Anti-hypertensive infusions were required in the ICU post-transplant in 46 patients (24.5%) for a median of 3 days (1-21 days). Oral anti-hypertensives were required in 58 patients (30.9%) at discharge and 1-year post-transplant. Anti-hypertensive infusion in the ICU post-transplant was associated with donor-to-recipient weight ratio. Oral anti-hypertensive use at discharge was associated with weight ratio and pretransplant VAD use, and at 1-year, post-transplant was associated with age at transplant, steroid use at discharge, and oral anti-hypertensive use at discharge. Hypertension is common immediately following and 1-year post-transplant. Weight ratio was the only independent predictor of anti-hypertensive use in the early post-transplant period, whereas VAD use was also associated with anti-hypertensive use at discharge. Anti-hypertensive use 1-year post-transplant was not associated with those factors, but rather with age at transplant and steroid use., (© 2020 Wiley Periodicals LLC.)

Despite improvements in operative and perioperative care, the risk of significant morbidity and mortality for children undergoing Fontan procedures persists. Previous investigations have identified peri-Fontan characteristics that may predict early adverse events. The purpose of this study was to identify characteristics from throughout a patient's lifespan, including all perioperative stages, that might predict early Fontan failure-defined as death, Fontan takedown, or listing for cardiac transplantation before hospital discharge or within 30 postoperative days. A single-center retrospective study of all patients undergoing a Fontan procedure was performed. Patient and intervention-related characteristics were examined from birth through Fontan. Data were described using standard summary statistics. Univariable, logistic regression was used to examine associations with early Fontan failure. In total, 191 patients met inclusion criteria. The incidence of early Fontan failure was 4% (n = 8: 6 deaths, 2 Fontan takedowns). Neonatal balloon atrial septostomy was the only patient characteristic significantly associated with Fontan failure. Patients who underwent balloon septostomy had 8.5 times higher odds of Fontan failure (confidence interval (CI) 2.6-28.1, P < 0.001) than those who did not. Children who require balloon septostomy as neonates remain at higher risk of Fontan takedown, listing for heart transplantation, or death in the early post-Fontan period., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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.

Background: Endomyocardial biopsy (EMB) is the current standard for rejection surveillance in heart transplant recipients. The quantification of donor-specific cell-free DNA (cfDNA) may be an appropriate biomarker for non-invasive rejection surveillance. A multicenter prospective blinded study (DNA-Based Transplant Rejection Test, DTRT) investigated the value of donor fraction (DF), defined as the ratio of cfDNA specific to the transplanted organ to the total amount of cfDNA present in a blood sample., Methods: A total of 241 heart transplant patients were recruited from 7 centers. Age at transplant ranged from 8 days to 73 years, with 146 subjects <18 years and 95 ≥18 years. All the patients were followed for at least 1 year, with blood samples drawn at routine and for-cause biopsies. A total of 624 biopsy-paired samples were included for analysis through a commercially available cfDNA assay (myTAI HEART , TAI Diagnostics Inc.). A blinded analysis of repeated measures compared the outcomes using receiver operating characteristic (ROC) curves. All primary clinical end-points were monitored at 100%. All analysis and conclusions were reviewed by both an independent external oversight committee and the National Institutes of Health-mandated DTRT steering committee., Results: DF in acute cellular rejection (ACR) 1R/2R (n = 15) was higher than ACR 0R (n = 42) (p = 0.02); DF in antibody-mediated rejection pAMR1 (n = 8) and pAMR2 (n = 12) (p = 0.05) were higher than pAMR0 (n = 466) (p = 0.04 and p = 0.05 respectively). An optimal DF threshold was determined by the use of an ROC analysis, which ruled out the presence of either ACR or antibody-mediated rejection., Conclusions: The cell-free DNA DF holds promise as a non-invasive diagnostic test to rule out acute rejection in both adult and pediatric heart transplant populations., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Relative contraindications to adenosine use have included heart transplant and dipyridamole. We previously demonstrated the safety and efficacy of adenosine-induced atrioventricular (AV) block in healthy young heart transplant recipients while suspending dipyridamole therapy (dual antiplatelet agent). This prospective follow-up study evaluated the safety and efficacy of adenosine use in the same cohort of heart transplant recipients while on dipyridamole., Methods: Adenosine was incrementally dosed until AV block occurred (maximum 200 mcg/kg up to 12 mg). The primary outcome was clinically significant asystole (≥12 seconds). Secondary outcomes included maximal adenosine dose, AV block duration, dysrhythmias, and clinical symptoms. Outcomes were compared to the parent study., Results: Thirty of 39 eligible patients (5-24 years) were tested. No patient (0%, CI 0%-8%) experienced clinically significant asystole. AV block occurred in 29/30 patients (97%, CI 86%-100%). The median dose causing AV block was 50mcg/kg (vs 100 mcg/kg off dipyridamole; P = .011). Seventeen patients (57%, CI 39%-72%) required less adenosine to achieve AV block on dipyridamole; six (20%) required more. AV block occurred at doses ≥25 mcg/kg in all patients. In pairwise comparison to prior testing off dipyridamole, no significant change occurred in AV block duration, frequency of cardiac ectopy, or incidence of reported symptoms. No atrial fibrillation/flutter occurred., Conclusions: AV block often occurs at twofold lower adenosine doses in healthy young heart transplant recipients taking oral dipyridamole, compared with previous testing of this cohort off dipyridamole. Results suggest that initial dosing of 25 mcg/kg (maximum 0.8 mg) with stepwise escalation poses low risk of prolonged asystole on dipyridamole., (© 2020 Wiley Periodicals, Inc.)

Background: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking., Methods: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide., Results: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (-0.2%) in the placebo group ( P =0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus -9±193 [-0.9%] mL/min, P =0.012), ventilatory equivalents of carbon dioxide (-0.8 versus -0.06, P =0.014), and work rate (+3.8 versus +0.34 W, P =0.021). There was no difference in change of myocardial performance index, the natural log of the reactive hyperemia index, or serum brain-type natriuretic peptide level., Conclusions: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02741115.

Rejection with severe hemodynamic compromise is a significant source of morbidity and mortality for pediatric heart transplant patients. Traditionally, treatment for these patients includes inotropes and escalation to extracorporeal membrane oxygenation (ECMO) when necessary. There is increasing interest in using percutaneous ventricular assistive devices in the pediatric population as a less invasive alternative to ECMO. We report the largest case series to date of biventricular support using percutaneous Impella devices. Retrospective case series was performed by chart review. Hemodynamics, left ventricular ejection fraction (LVEF), and indices of end organ function were collected before and after Impella placement. A 14-year-old male, 18-year-old male, and 19-year-old female, all status post heart transplant, presented with severely decreased biventricular function due to presumed clinical rejection, requiring maximal inotropic support without improvement. In all the three cases, simultaneous Impella CP and RP devices were placed percutaneously. Prior to implantation, LVEFs were 40%, 23%, and 25%, respectively. Hemodynamics measured invasively prior to device placement showed elevated filling pressures. Adverse events while on support included bleeding, hemolysis, and right femoral arterial dissection during implantation. All patients were successfully weaned from the devices and survived to discharge. The average time of right-sided support and total support was 11 days and 13 days, respectively. After device removal, right-sided pressures and echocardiographic measurements showed improvement in all patients. Bilateral Impella configuration (BiPella) is a viable option for temporary mechanical circulatory support in pediatric patients with significant graft dysfunction., (© 2019 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Background: The Single Ventricle Reconstruction Trial randomised neonates with hypoplastic left heart syndrome to a shunt strategy but otherwise retained standard of care. We aimed to describe centre-level practice variation at Fontan completion., Methods: Centre-level data are reported as median or median frequency across all centres and range of medians or frequencies across centres. Classification and regression tree analysis assessed the association of centre-level factors with length of stay and percentage of patients with prolonged pleural effusion (>7 days)., Results: The median Fontan age (14 centres, 320 patients) was 3.1 years (range from 1.7 to 3.9), and the weight-for-age z-score was -0.56 (-1.35 + 0.44). Extra-cardiac Fontans were performed in 79% (4-100%) of patients at the 13 centres performing this procedure; lateral tunnels were performed in 32% (3-100%) at the 11 centres performing it. Deep hypothermic circulatory arrest (nine centres) ranged from 6 to 100%. Major complications occurred in 17% (7-33%). The length of stay was 9.5 days (9-12); 15% (6-33%) had prolonged pleural effusion. Centres with fewer patients (<6%) with prolonged pleural effusion and fewer (<41%) complications had a shorter length of stay (<10 days; sensitivity 1.0; specificity 0.71; area under the curve 0.96). Avoiding deep hypothermic circulatory arrest and higher weight-for-age z-score were associated with a lower percentage of patients with prolonged effusions (<9.5%; sensitivity 1.0; specificity = 0.86; area under the curve 0.98)., Conclusions: Fontan perioperative practices varied widely among study centres. Strategies to decrease the duration of pleural effusion and minimise complications may decrease the length of stay. Further research regarding deep hypothermic circulatory arrest is needed to understand its association with prolonged pleural effusion.

Background: Evolution of right ventricular (RV) systolic function after pediatric heart transplantation (HT) has not been well described., Methods: We analyzed echocardiograms performed over the first year after HT among children and young adults who remained rejection-free. Ninety-six patients (median age 7.1 [0.1-24.4] years at HT) were included: 22 infants (≤1 year) and 74 noninfants (>1 year). Two-dimensional tricuspid annular plane systolic excursion (TAPSE), tissue Doppler-derived tricuspid annular systolic velocity (S'), fractional area change (FAC), myocardial performance index (MPI), and two-dimensional speckle-tracking-derived RV global longitudinal (GLS) and free wall strain (FWS) were assessed., Results: All measures of RV function were impaired immediately after HT and significantly improved over the first year: TAPSE z-score (-8.15 ± 1.88 to -3.94 ± 1.65, P < .0001), S' z-score (-4.30 ± 1.36 to -2.28 ± 1.33, P < .0001), FAC (24.37% ± 7.71% to 42.02% ± 7.09%, P < .0001), MPI (0.96 ± 0.47 to 0.41 ± 0.22, P < .0001), GLS (-10.37% ± 3.86% to -21.05% ± 3.41%, P < .0001), and FWS (-11.2% ± 4.08% to -23.66% ± 4.13%, P < .0001). By 1 year post-HT, TAPSE, S', GLS, and FWS, remained abnormal, whereas FAC and MPI nearly normalized. Patients transplanted during infancy demonstrated better recovery of RV systolic function., Conclusions: Although RV systolic function improved over the first year after HT in children and young adults without rejection, measures that assess longitudinal contractility remained abnormal at 1 year post-HT. These findings contribute to our understanding of RV myocardial contractility after HT in children and young adults and improve our ability to assess function quantitatively in this population., (Copyright © 2019 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

RV systolic function is important early after HT; however, it has not been critically assessed in children using quantitative measures. The aim of this study was to describe the most validated and commonly used quantitative echocardiographic measures of RV systolic function early after pediatric HT and to assess associations with qualitative function evaluation and clinical factors. RV systolic function was quantified on the first post-HT echocardiogram >24 hours after cardiopulmonary bypass using two-dimensional TAPSE, Tricuspid annular S', FAC, and MPI. In 145 patients (median age 7.6 years), quantitative RV systolic function was markedly abnormal: mean TAPSE z-score -8.43 ± 1.89; S' z-score -4.36 ± 1.22; FAC 24.4 ± 8.34%; and MPI 0.86 ± 0.51. Few patients had normal quantitative function: TAPSE (0%), S' (1.2%), FAC (9.4%), and MPI (28.4%). In contrast, 48.3% were observed as normal by qualitative assessment. Most clinical factors, including diagnosis, pulmonary vascular resistance, posttransplant hemodynamics, inotropic support, and rejection, were not associated with RV function. In this large pediatric HT population, TAPSE, S', FAC, and MPI were strikingly abnormal early post-HT despite reassuring qualitative assessment and no significant association with clinical factors. This suggests that the accepted normal values of these quantitative measures may not apply in the early post-HT period to accurately grade RV systolic function, and there may be utility in adapting a concept of normal reference values after pediatric HT., (© 2018 Wiley Periodicals, Inc.)

Climate change increases local climatic variation and unpredictability, which can alter ecological interactions and trigger wildlife disease outbreaks. Here we describe an unprecedented multi-species outbreak of wild fish disease driven by a climate perturbation. The 2015-16 El Niño generated a +2.5 °C sea surface temperature anomaly in the Galapagos Islands lasting six months. This coincided with a novel ulcerative skin disease affecting 18 teleost species from 13 different families. Disease signs included scale loss and hemorrhagic ulcerated patches of skin, fin deterioration, lethargy, and erratic behavior. A bacterial culture isolated from skin lesions of two of the affected fish species was identified by sequencing of the 16S rRNA gene as a Rahnella spp. Disease prevalence rates were linearly correlated with density in three fish species. In January 2016, disease prevalence reached 51.1% in the ring-tailed damselfish Stegastes beebei (n = 570) and 18.7% in the king angelfish Holacanthus passer (n = 318), corresponding to 78% and 86% decreases in their populations relative to a 4.5-year baseline, respectively. We hypothesize that this outbreak was precipitated by the persistent warm temperatures and lack of planktonic productivity that characterize extreme El Niño events, which are predicted to increase in frequency with global warming.

Influenza is a cause of significant morbidity and mortality worldwide. Myocarditis is a rare complication of the virus and can vary widely in severity. The published cases of influenza B myocarditis in children tend to be severe with a high mortality rate. Current standard treatment of viral myocarditis is supportive care, although immunomodulatory therapies, such as steroids and intravenous immunoglobulin, are often used. T cells have been implicated in causing significant myocyte damage in myocarditis by leading to the downstream production of antibodies against viral and myocyte antigens; this has created a theoretical basis for the use of antithymocyte globulin to target T cells in these patients. We present a case of acute fulminant influenza B myocarditis in a pediatric patient that required mechanical circulatory support and improved only after treatment with antithymocyte globulin., 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.)

Transcatheter stent implantation for SVC obstruction following OHT has been well described, particularly in pediatric patients. This study describes a large single-center pediatric heart transplant experience that investigates the risk factors for SVC stenosis requiring stent implantation and its associated outcomes. All pediatric OHTs between January 1, 2000, and December 12, 2016, were examined for risk factors. Twelve of 349 (3.4%) OHTs required SVC stent implantation. Patients who required stents were younger (2.5 years vs 10.0 years, P = 0.0097), weighed less (8.6 kg vs 26.0 kg, P = 0.0024), and were more likely to have had CHD (83% vs 32%, P = 0.001) or previous SCPA (58% vs 18%, P = 0.002). Bicaval anastomosis was not associated with subsequent SVC stent implantation. Symptoms included SVC syndrome and chylous effusions. All 12 patients had evidence of significant SVC obstruction by both echocardiographic Doppler interrogation and transcatheter angiography. There were no acute procedural complications; however, reinterventions were common (four of 12 patients) and occurred at a mean of 5.7 ± 3.6 months poststent implantation. In conclusion, transcatheter SVC stent implantation is safe and effective after OHT. There were significant associations between SVC stent implantation and younger age, smaller weight, CHD, and history of SCPA, but not with bicaval anastomosis or donor-recipient weight ratio., (© 2018 Wiley Periodicals, Inc.)

Speckle tracking echocardiography (STE)-derived strain indices are believed to detect early cardiac dysfunction in survivors of childhood cancer and have potential to identify patients who may benefit from early heart failure treatment. However, effects of heart failure treatment on STE-derived strain measurements in this population are unknown. The aim of this study was to assess STE-derived strain measurements in survivors of childhood cancer treated with angiotensin converting enzyme inhibition or receptor blockade (ACEi/ARB). Two-dimensional speckle tracking analysis was retrospectively performed on echocardiograms from childhood cancer survivors before and during therapy with ACEi/ARB. Global left ventricular longitudinal and circumferential strain (GLS and GCS) and strain rates (LSR and CSR) were assessed and correlated with conventional echocardiographic measures of function. In 22 childhood cancer survivors (median age: 14.8, range 6.4-21.6 years), mean GLS (- 13.83 ± 0.74% to - 15.94 ± 0.74%, p = 0.002), GCS (- 18.79 ± 1.21% to - 20.74 ± 0.84%, p = 0.027), LSR (- 0.78 ± 0.04 to - 0.88 ± 0.04 s -1 , p = 0.022), and CSR (- 1.08 ± 0.07 to - 1.21 ± 0.06 s -1 , p = 0.027) improved on therapy. Improvement in GLS was maintained for greater than 1 year on ACEi/ARB (p = 0.02). Measures of strain and strain rate correlated with standard echocardiographic measures of function and were reproducible. These findings support the use of ACEi/ARB to treat post-chemotherapy-related cardiovascular changes in childhood cancer survivors, provide proof-of-concept that STE-derived strain and strain rate may be used to reliably monitor cardiac function during therapy, and support continued investigation into the clinical benefit of strain measurements in this population.

Background: Pediatric ventricular assist device (VAD) use has evolved dramatically over the last 2 decades., Objectives: This study sought to describe the evolution of VAD support to heart transplantation (HTx) in children in a large international multicenter cohort., Methods: Using data from the Pediatric Heart Transplant Study, comparisons were made between children (<18 years) supported to HTx (January 1, 1993 to December 31, 2015) with VAD or extracorporeal membrane oxygenation (ECMO) to VAD support., Results: Of 7,135 listed patients, 5,145 underwent HTx; 995 (19.3%) were supported by a VAD (113 with congenital heart disease [CHD]). Patients with a VAD as their first device (n = 821) were older, larger, and more likely to have cardiomyopathy (80%) than patients transitioned from ECMO to VAD (n = 164). In the VAD-only cohort, 79% underwent HTx and 14% died, compared with 69% and 24% in the ECMO-to-VAD cohort, respectively. Patients with cardiomyopathy achieved HTx 84% of the time, with a 9% waitlist mortality rate compared with 55% and 36%, respectively, for CHD. Among VAD-treated patients, 79% were age >10 years in the earliest era, a percentage decreasing to 34% more recently, though neonates still represent <1%. Overall, survival at 2 and 20 years showed no difference between VAD and no support (2 years: 75% vs. 80%; 20 years: 55% vs. 54%). Post-HTx outcomes were better for durable versus temporary VADs (p < 0.01) and for continuous versus pulsatile VADs (p < 0.01) from 2005 onward; timing of VAD had no impact on post-HTx survival (p = 0.65)., Conclusions: For one-quarter of a century, major advances have occurred in mechanical support technology for children, thereby expanding the capability to bridge to HTx without compromising post-HTx outcomes. Significant challenges remain, especially for neonates and patients with CHD, but ongoing innovation portends improved methods of support during the next decade., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Heart failure results in significant morbidity and mortality in young children with hypoplastic left heart syndrome (HLHS) after the Norwood procedure., Methods: We studied subjects enrolled in the prospective Single Ventricle Reconstruction (SVR) Trial who survived to hospital discharge after a Norwood operation and were followed up to age 6 years. The primary outcome was heart failure, defined as heart transplant listing after Norwood hospitalization, death attributable to heart failure, or symptomatic heart failure (New York Heart Association [NYHA] Class IV). Multivariate modeling was undertaken using Cox regression methodology to determine variables associated with heart failure., Results: Of the 461 subjects discharged home following a Norwood procedure, 66 (14.3%) met the criteria for heart failure. Among these, 15 died from heart failure, 39 were listed for transplant (22 had a transplant, 12 died after listing, and 5 were alive and not yet transplanted), and 12 had NYHA Class IV heart failure but were never listed. The median age at heart failure identification was 1.28 (interquartile range 0.30 to 4.69) years. Factors associated with early heart failure included post-Norwood lower fractional area change, need for extracorporeal membrane oxygenation, non-Hispanic ethnicity, Norwood perfusion type, and total support time (p < 0.05)., Conclusions: By 6 years of age, heart failure developed in nearly 15% of children after the Norwood procedure. Although transplant listing was common, many patients died from heart failure before receiving a transplant or without being listed. Shunt type did not impact the risk of developing heart failure., (Copyright © 2018 International Society for Heart and Lung Transplantation. All rights reserved.)

The Fontan operation creates a circulation characterized by elevated central venous pressure and low cardiac output. Over time, these characteristics result in a predictable and persistent decline in exercise performance that is associated with an increase in morbidity and mortality. A medical therapy that targets the abnormalities of the Fontan circulation might, therefore, be associated with improved outcomes. Udenafil, a phosphodiesterase type 5 inhibitor, has undergone phase I/II testing in adolescents who have had the Fontan operation and has been shown to be safe and well tolerated in the short term. However, there are no data regarding the long-term efficacy of udenafil in this population. The Fontan Udenafil Exercise Longitudinal (FUEL) Trial is a randomized, double-blind, placebo-controlled phase III clinical trial being conducted by the Pediatric Heart Network in collaboration with Mezzion Pharma Co, Ltd. This trial is designed to test the hypothesis that treatment with udenafil will lead to an improvement in exercise capacity in adolescents who have undergone the Fontan operation. A safety extension trial, the FUEL Open-Label Extension Trial (FUEL OLE), offers the opportunity for all FUEL subjects to obtain open-label udenafil for an additional 12 months following completion of FUEL, and evaluates the long-term safety and tolerability of this medication. This manuscript describes the rationale and study design for FUEL and FUEL OLE. Together, these trials provide an opportunity to better understand the role of medical management in the care of those who have undergone the Fontan operation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Infections are frequent in pediatric ventricular assist device (VAD) patients. In this study we aimed to describe infections in durable VAD patients reported to Pedimacs., Methods: Durable VAD data from the Pedimacs registry (September 19, 2012 to December 31, 2015) were analyzed. Infections were described with standard descriptive statistics, Kaplan-Meier analysis and competing outcomes analysis., Results: There were 248 implants in 222 patients, with a mean age and a median follow-up of 11 ± 6.4 years and 2.4 patient-months (<1 day to 2.6 years), respectively. Device types were pulsatile flow (PF) in 91 (41%) patients and continuous flow (CF) in 131 (59%) patients. PF patients were younger (4 ± 4 vs 14 ± 4 years; p < 0.0001) and were more likely to have congenital heart disease (25% vs 12%; p = 0.03), prior surgery (53% vs 26%; p < 0.0001) and prior extracorporeal membrane oxygenation (24% vs 7%; p = 0.0003). Infection accounted for 17% (96 of 564) of the reported adverse events (AEs). A non-device infection was most common (51%), followed by sepsis (24%), external pump component infection (20%) and internal pump component infection (5%). Most infections were bacterial (73%) and required intravenous therapy only (77%). The risk of infection in the constant phase was higher in patients with a history of prior infection and in patients with a history of a non-infectious major AEs. Survival was lower after infection only in CF patients (p = 0.008)., Conclusions: Infection was the most common AE after pediatric VAD implantation. Non-device infections were most common. The best predictor of a future infection was a past infection. CF patients have higher risk of death after an infection., (Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

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.