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A history of infection has been linked with increased risk of acute myeloid leukaemia (AML) and related myelodysplastic syndromes (MDS). Furthermore, AML and MDS patients suffer frequent infections because of disease-related impaired immunity. However, the role of infections in the development and progression of AML and MDS remains poorly understood. We and others previously demonstrated that the human nucleoside diphosphate kinase (NDPK) NM23-H1 protein promotes AML blast cell survival by inducing secretion of IL-1β from accessory cells. NDPKs are an evolutionary highly conserved protein family and pathogenic bacteria secrete NDPKs that regulate virulence and host-pathogen interactions. Here, we demonstrate the presence of IgM antibodies against a broad range of pathogen NDPKs and more selective IgG antibody activity against pathogen NDPKs in the blood of AML patients and normal donors, demonstrating thatin vivoexposure to NDPKs likely occurs. We also show that pathogen derived NDPK-proteins faithfully mimic the catalytically independent pro-survival activity of NM23-H1 against primary AML cells. Flow cytometry identified that pathogen and human NDPKs selectively bind to monocytes in peripheral blood. We therefore used vitamin D3differentiated monocytes from wild type and genetically modified THP1 cells as a model to demonstrate that NDPK-mediated IL-1β secretion by monocytes is NLRP3-inflammasome and caspase 1 dependent, but independent of TLR4 signaling. Monocyte stimulation by NDPKs also resulted in activation of NF-κB and IRF pathways but did not include the formation of pyroptosomes or result in pyroptotic cell death which are pivotal features of canonical NLRP3 inflammasome activation. In the context of the growing importance of the NLRP3 inflammasome and IL-1β in AML and MDS, our findings now implicate pathogen NDPKs in the pathogenesis of these diseases.Author SummaryAcute myeloid leukaemia (AML) and myelodysplastic syndromes MDS) are related blood cancers that are associated with frequent infections because the cancers suppress normal immunity. These infections are therefore generally considered as medical complications arising as a result of but separate to the cancer. However, we provide evidence here that infections may promote or drive cancer progression. We and others previously demonstrated that a human protein called NM23-H1 promotes the survival of AML cells by eliciting survival signals from other cells. NM23-H1 belongs to a highly conserved family of proteins that also occur in bacteria and fungi that cause infections in AML and MDS patients. Here we demonstrate that these bacterial and fungal proteins recapitulate the pro-survival effect of NM23-H1 on AML cells. We also determine that these effects are mediated via mechanisms already known to be important in the development and progression of AML and MDS. This study is the first to identify NM23-H1 like proteins from pathogenic microorganisms as novel activators of these pathways. These findings have important implications for how we understand infections in AML and MDS patients and suggest that in addition to being the consequence of these diseases, infections may also drive the cancer process.

This document is designed to outline the definition, pathogenesis, diagnostic modalities and therapeutic measures to treat antibody-mediated rejection in children postheart transplant METHODS: Literature review was conducted by a Pediatric Heart Transplant Society (PHTS) working group to identify existing pediatric and adult studies on antibody-mediated rejection (AMR). In addition, the centers participating in PHTS were asked to submit their approach to diagnosis and management of pediatric AMR. This document synthesizes information gathered from both these sources to highlight a practical approach to diagnosing and managing a child with AMR postheart transplant. This document may not represent the practice at all centers in the PHTS and serves as a starting point to understand an approach to this clinical scenario.

We present the case of a 4 year-old boy post heart transplantation who presented with signs and symptoms of critical airway obstruction and was initially diagnosed with infective supraglottitis. Following re-presentation and biopsy, this was confirmed as post-transplant lymphoproliferative disorder (PTLD) in an unusual site; laryngeal PTLD is rare. The patient failed standard therapy and ultimately was successfully treated with EBV-specific cytotoxic T lymphocytes (CTL). This case describes a rare presentation of PTLD which required a novel treatment approach including elective tracheostomy prior to CTL therapy. The treatment was successful and the patient was decannulated prior to discharge following 4 negative biopsies, the most recent 6 months following treatment completion. The case also highlights the importance of extra-vigilance in the post-transplant population and of a collaborative approach between multiple specialties across two separate countries including the transplant center and the referral center.

Dilated cardiomyopathy is an uncommon but serious form of heart muscle disease affecting children and young people. The aetiology and clinical presentation are heterogenous, and a structured approach to identification, classification and management is warranted. Comprehensive initial workup is aimed at identifying potentially reversible causes, as well as identifying children where cardiomyopathy is the initial presenting feature of a multi-systemic condition. Commoner causes of primary myocarditis include infection, and heritable, familial conditions including mitochondrial disease and muscular dystrophies. It may also be secondary to arrhythmias, ischaemia, toxins, nutritional deficiencies or metabolic disturbance. Genetic testing has not yet yielded as illuminating results as in adults, or in children with hypertrophic cardiomyopathy; however, progress in this field is likely to be rapid. Understanding the key underlying pathophysiologic mechanisms, along with extrapolation from adult literature, directs pharmacologic management, which has remained largely unchanged over the past few decades. Novel pharmacologic agents, improvements in mechanical support and innovative surgical techniques, permit cautious optimism for improvement in morbidity, mortality and quality of life. Transplantation remains the gold standard for end-stage disease, with slow but continued prolongation of median survival. Although the overall prognosis remains guarded, the above advances in combination with multi-disciplinary collaboration, are gradually turning the tide in the management of children with this complex condition. In this short review we present a rational approach to diagnosis and management of this complex and challenging illness, and describe recent progress, as well as some cause for optimism.

Background The use of cell-free DNA (cfDNA) as a noninvasive biomarker to detect allograft damage is expanding rapidly. However, quantifying the low fraction of donor-derived cfDNA (ddcfDNA) is challenging and requires a highly sensitive technique. ddcfDNA detection through unique donor single nucleotide polymorphisms (SNPs) is a recent new approach, however there are limited data in pediatric solid organ transplant (SOT) recipients. Methods We developed an assay using a combination of 61 SNPs to quantify the ddcfDNA accurately using a custom R script to model for both the patient and donor genotypes requiring only a single sample from the allograft recipient. Performance of the assay was validated using genomic DNA (gDNA), cfDNA and donor samples where available. Results The R “genotype-free” method gave results comparable to when using the known donor genotype. applicable to both related and unrelated pairs and can reliably measure ddcfDNA (limit of blank, below 0.12%; limit of detection, above 0.25%; limit of quantification 0.5% resulting in 84% accuracy). 159 pediatric SOT recipients (kidney, heart, and lung) were tested without the need for donor genotyping. Serial sampling was obtained from 82 patients. Conclusion We have developed and validated a new assay to measure the fraction of ddcfDNA in the plasma of pediatric SOT recipients. Our method can be applicable in any donor-recipient pair without the need for donor genotyping and can provide results in 48 h at a low cost. Additional prospective studies are required to demonstrate its clinical validity in a large cohort of pediatric SOT recipients.

The number of potential pediatric heart transplant recipients continues to exceed the number of donors, and consequently the waitlist mortality remains significant. Despite this, around 40% of all donated organs are not used and are discarded. This document (62 authors from 53 institutions in 17 countries) evaluates factors responsible for discarding donor hearts and makes recommendations regarding donor heart acceptance. The aim of this statement is to ensure that no usable donor heart is discarded, waitlist mortality is reduced, and post-transplant survival is not adversely impacted.

Background Anti-human leukocyte antigen (HLA)-antibody production represents a major barrier to heart transplantation, limiting recipient compatibility with potential donors and increasing the risk of complications with poor waiting-list outcomes. Currently there is no consensus to when desensitization should take place, and through what mechanism, meaning that sensitized patients must wait for a compatible donor for many months, if not years. We aimed to determine if intraoperative immunoadsorption could provide a potential desensitization methodology. Methods Anti-HLA antibody-containing whole blood was added to a Cardiopulmonary bypass (CPB) circuit set up to mimic a 20 kg patient undergoing heart transplantation. Plasma was separated and diverted to a standalone, secondary immunoadsorption system, with antibody-depleted plasma returned to the CPB circuit. Samples for anti-HLA antibody definition were taken at baseline, when combined with the CPB prime (on bypass), and then every 20 min for the duration of treatment (total 180 min). Results A reduction in individual allele median fluorescence intensity (MFI) to below clinically relevant levels (4000 was demonstrated. Reduction occurred in all cases within 120 min, demonstrating efficacy in a time period usual for heart transplantation. Flowcytometric crossmatching of suitable pseudo-donor lymphocytes demonstrated a change from T cell and B cell positive channel shifts to negative, demonstrating a reduction in binding capacity. Conclusions Intraoperative immunoadsorption in an ex vivo setting demonstrates clinically relevant reductions in anti-HLA antibodies within the normal timeframe for heart transplantation. This method represents a potential desensitization technique that could enable sensitized children to accept a donor organ earlier, even in the presence of donor-specific anti-HLA antibodies.

Limited availability of suitable donor hearts remains a challenge to pediatric heart transplantation, contributing to waitlist mortality. Controlled donation after circulatory death (DCD) has demonstrated success in adults. Early series of pediatric DCD heart transplantation using cold storage alone reported significant early mortality. We report a collaboration between 2 centers in the United Kingdom, combining expertise in adult DCD organ retrieval and pediatric transplantation.This retrospective series comprises 6 children (4 male, all20 kg) undergoing DCD heart transplantation at Great Ormond Street Hospital between 1 February and 30 September 2020, following retrieval with direct procurement and perfusion using portable normothermic machine perfusion by the Royal Papworth Hospital service. Baseline characteristics and 1-year follow-up were compared to 9 children who underwent donation after brain death (DBD) transplants contemporaneously.Mean DCD donor age was 24.67 years and mean DCD recipient age was 13.83 years. Mean functional warm ischemic time was 28.5 minutes and ex-situ heart perfusion time was 280 minutes. Median ICU and hospital stay were 9 and 17 days, respectively. All children survived to 1-year post-transplant. Survival and ICU and hospital stay were similar between the DCD and DBD cohorts. Performing DCD transplants resulted in a 66.7% increase in transplants for children20 kg at GOSH during the study.This series demonstrates that DCD heart transplant can be performed safely with excellent short-term survival in children. Although the cohort is small, there was no significant difference in major outcomes compared to a DBD cohort.

ObjectiveWe provide succinct, evidence-based and/or consensus-based best practice guidance for the cardiac care of children living with Duchenne muscular dystrophy (DMD) as well as recommendations for screening and management of female carriers of mutations in theDMD-gene.MethodsInitiated by an expert working group of UK-based cardiologists, neuromuscular clinicians and DMD-patient representatives, draft guidelines were created based on published evidence, current practice and expert opinion. After wider consultation with UK-cardiologists, consensus was reached on these best-practice recommendations for cardiac care in DMD.ResultsThe resulting recommendations are presented in the form of a succinct care pathway flow chart with brief justification. The guidance signposts evidence on which they are based and acknowledges where there have been differences in opinion. Guidelines for cardiac care of patients with more advanced cardiac dystrophinopathy at any age have also been considered, based on the previous published work of Quinlivanet aland are presented here in a similar format. The recommendations have been endorsed by the British Cardiovascular Society.ConclusionThese guidelines provide succinct, reasoned recommendations for all those managing paediatric patients with early or advanced stages of cardiomyopathy as well as females with cardiac dystrophinopathy. The hope is that this will result in more uniform delivery of high standards of care for children with cardiac dystrophinopathy, so improving heart health into adulthood through timely earlier interventions across the UK.

BACKGROUND Learning networks have emerged in medicine as a novel organizational structure that contains elements of quality improvement, education, and research with the goal of effecting rapid improvements in clinical care. In this article, the concept of a learning network is defined and highlighted in the field of pediatric heart failure and transplantation. METHODS Learning networks are defined, with particular attention paid to the recent creation of the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) for children with heart failure and those being supported with ventricular assist devices (VAD). RESULTS The mission, goals, and organizational structure of ACTION are described, and recent initiatives promoted by ACTION are highlighted, such as stroke reduction initiatives, practice harmonization protocols, and use of ACTION data to support the recent US Food and Drug Administration approval of newer VAD for pediatric patients. CONCLUSIONS The learning network, exemplified by ACTION, is distinguished from traditional clinical research collaboratives by contributions in research, quality improvement, patient-reported outcomes, and education, and serves as an effective vehicle to drive clinical improvement in the care of children with advanced heart failure.

We report a patient with congenital heart disease and end stage heart failure after interventions for congenital heart disease resulting in aortic regurgitation that could not be treated with mechanical support to bridge to transplantation. We used a Melody valve (Medtronic Inc, Minneapolis, MN) in aortic position to achieve aortic competence to allow use of a left ventricular assist device to bridge the patient successfully to cardiac transplantation.

Background: Sensitised patients undergoing Human Leukocyte Antigen-incompatible transplantation are at increased risk of hyperacute rejection and may be predisposed to antibody-mediated rejection, chronic lung allograft dysfunction and higher mortality. Case: We present a case of primary lung transplantation in the setting of late identification of donor specific antibodies treated with intraoperative target plasma exchange. The patient was treated with fresh human plasma to a final volume of 1.5 times the patient’s systemic circulation. From a pre-transplant mean fluorescence intensity of 5002, donor-specific antibodies were undetectable following plasma exchange on single antigen bead assay. Conclusions: This method represents a potential desensitisation technique for use in the intraoperative period.

BACKGROUND Intraoperative anti-A/B immunoadsorption (ABO-IA) was recently introduced for ABO-incompatible heart transplantation. Here we report the first case series of patients transplanted with ABO-IA, and compare outcomes with those undergoing plasma exchange facilitated ABO-incompatible heart transplantation (ABO-PE). METHODS Data were retrospectively analysed on all ABO-incompatible heart transplants undertaken at a single centre between January 1, 2000 and June 1, 2020. Data included all routine laboratory tests, demographics and pre-operative characteristics, intraoperative details and post-operative outcomes. Primary outcome measures were volume of blood product transfusions, maximum post-transplant isohaemagglutinin titres, occurrence of rejection and graft survival. Secondary outcome measures were length of intensive care and hospital stay. Demographic and survival data were also obtained for ABO-compatible transplants during the same time period for comparison. RESULTS Thirty-seven patients underwent ABO-incompatible heart transplantation, with 27 (73%) using ABO-PE and 10 (27%) using ABO-IA. ABO-IA patients were significantly older than ABO-PE patients (p < 0.001) and the total volume of blood products transfused during the hospital admission was significantly lower (164 [126-212] ml/kg vs 323 [268-379] ml/kg, p < 0.001). No significant differences were noted between methods in either pre or post-transplant maximum isohaemagglutinin titres, incidence of rejection, length of intensive care or total hospital stay. Survival comparison showed no significant difference between antibody reduction methods, or indeed ABO-compatible transplants (p = 0.6). CONCLUSIONS This novel technique appears to allow a significantly older population than typical to undergo ABO-incompatible heart transplantation, as well as significantly reducing blood product utilization. Furthermore, intraoperative anti-A/B immunoadsorption does not demonstrate increased early post-transplant isohaemagglutinin accumulation or rates of rejection compared to ABO-PE. Early survival is equivalent between ABO-IA, ABO-PE and ABO-compatible heart transplantation.

When faced with patients with deteriorating cardiac disease, nephrologists tend to accept that heart disease is unmodifiable, accepting mediocrity and opting for stabilization. Likewise cardiac patients with persistent renal failure are presented with a poor renal prognosis and prepared for renal transplantation. We present three dialysis dependent children with moderate-to-severe cardiac failure in whom home hemodialysis normalized the cardiac function and restored renal function. These cases highlight the medical benefits of home hemodialysis in severe cardio-renal cases but not without acknowledgement of the resource, commitment, and safety challenges that accompanies them.

We describe a case of an 82-year-old man who developed an anterior ST-elevation myocardial infarction (STEMI) and left ventricular thrombus while an inpatient following a diagnosis of severe COVID-19 infection (SARS-CoV-2). His D-dimer was significantly elevated at 12,525 ng/mL (normal range

Coronary allograft vasculopathy (CAV) is a leading cause of mortality after heart transplantation (HT) in children. Variation in CAV screening practices may impact detection rates and patient outcomes.Among 50 Pediatric Heart Transplant Society (PHTS) sites from 2001 to 2016, coronary evaluations were classified as angiography or non-invasive testing, and angiograms were designated as routine or symptom based. CAV detection rates stratified by routine vs symptom-based angiograms were calculated. Freedom from CAV and mortality after CAV diagnosis, stratified by study indication, were calculated.A total of 3,442 children had 13,768 coronary evaluations; of these, 97% (n = 13,012) were for routine surveillance, and only 3% (n = 333) were for cause. Over the study period, CAV was detected in 472 patients (14%). Whereas 58% (n = 29) of PHTS sites evaluate by angiography alone, 42% reported supplementing with a non-invasive test, although only 423 non-invasive studies were reported. Angiographic detection of CAV was higher for symptom-based testing than for routine testing (29% vs 4%, p0.0001), although routine testing identified a majority of cases (88%; n = 414). The 10-year freedom from CAV was 77% overall. Once CAV is detected, 5-year graft survival was 58%, with lower survival for patients diagnosed after symptoms angiogram than after routine angiogram (30% vs 62%; p0.0001).Development of a robust model for CAV risk should allow low-risk patients to undergo less frequent invasive angiography without adverse impact on CAV detection rates or outcomes.

Heart transplantation (HTx) is a treatment option for end-stage heart failure in children. HTx is limited by the availability and acceptability of donor hearts. Refusal of donor hearts has been reported to be common with reasons for refusal including preexisting donor characteristics. This review will focus on the impact of donor characteristics and comorbidities on outcomes following pediatric HTx. A literature review was performed to identify articles on donor characteristics and comorbidities and pediatric HTx outcomes. There are many donor characteristics to consider when accepting a donor heart. Weight-based matching is the most common form of matching in pediatric HTx with a donor-recipient weight ratio between 0.7 and 3 having limited impact on outcomes. From an age perspective, donors

International audience; BACKGROUND: Our purpose was to determine the complication rate from intravascular ultrasound (IVUS) in a large, multicenter cohort of pediatric heart transplant (PHT) patients. METHODS: We retrospectively reviewed all PHT who underwent IVUS at 5 institutions (2006-2014). Rates of major and minor complications were calculated. All adverse events (AE) were graded from 1 to 5 using a previously published AE severity scale. RESULTS: There were 1380 catheterizations in 505 patients and 32 AE (2.3%); 9 major (0.6%) and 23 AE (1.7%). The major AE attributed to IVUS were all coronary artery vasospasm (7). Major and minor AE rates directly related to IVUS were 0.5% and 0.7%, respectively. Minor AE possibly attributable to IVUS included excessive fluoroscopy (3) and transient ST segment changes (7). Of AE related to IVUS, only 3 were of moderate severity. The rest were ≤ minor in severity. There were no reports of coronary artery dissection or death. CONCLUSION: Most AE during routine PHT coronary evaluation with IVUS were minor and not directly related to the use of IVUS. The number of coronary related AE was similar to a registry-based report of coronary angiography alone. Efforts to minimize IVUS-related complications should be focused on preventing coronary artery vasospasm.

Corticosteroids (CSs) have prolonged survival and respiratory function in boys with Duchenne muscular dystrophy (DMD) when compared with CSs-naïve boys.The differential impact of frequently used CSs and their regimens on long-term (5 years) cardiorespiratory progression in children with DMD is unknown.This was a retrospective longitudinal study including children with DMD followed at Dubowitz Neuromuscular Centre, Great Ormond Street Hospital London, England, from May 2000 to June 2017. Patients enrolled in any interventional clinical trials were excluded. We collected patients' anthropometrics and respiratory (FVC, FVC % predicted and absolute FVC, and noninvasive ventilation requirement [NIV]) and cardiac (left ventricular shortening function [LVFS%]) function. CSs-naïve patients had never received CSs. Patients who were treated with CSs took either deflazacort or prednisolone, daily or intermittently (10 days on/10 days off) for1 month. Average longitudinal models were fitted for yearly respiratory (FVC % predicted) and cardiac (LVFS%) progression. A time-to-event analysis to FVC % predicted 50%, NIV start, and cardiomyopathy (LVFS% 28%) was performed in CS-treated (daily and intermittent) vs CS-naïve patients.There were 270 patients, with a mean age at baseline of 6.2 ± 2.3 years. The median follow-up time was 5.6 ± 3.5 years. At baseline, 263 patients were ambulant. Sixty-six patients were treated with CSs daily, 182 patients underwent CSs intermittent60% treatment, and 22 were CS-naïve patients. Yearly FVC % predicted declined similarly from 9 years (5.9% and 6.9% per year, respectively; P = .27) in the CSs-daily and CSs-intermittent groups. The CSs-daily group declined from a higher FVC % predicted than the CSs-intermittent group (P .05), and both reached FVC % predicted 50% and NIV requirement at a similar age,2 years later than the CS-naïve group. LVFS% declined by 0.53% per year in the CSs-treated group irrespective of the CSs regimen, significantly slower (P .01) than the CSs-naïve group progressing by 1.17% per year. The age at cardiomyopathy was 16.6 years in the CSs-treated group (P .05) irrespective of regimen and 13.9 years in the CSs-naïve group.CSs irrespective of the regimen significantly improved respiratory function and delayed NIV requirement and cardiomyopathy.

Background There is inadequate power to perform a valid clinical trial in pediatric heart transplantation (HT) using a conventional end-point, because the disease is rare and hard end-points, such as death or graft loss, are infrequent. We sought to develop and validate a surrogate end-point involving the cumulative burden of post-transplant complications to predict death/graft loss to power a randomized clinical trial of maintenance immunosuppression in pediatric HT. Methods Pediatric Heart Transplant Study (PHTS) data were used to identify all children who underwent an isolated orthotopic HT between 2005 and 2014 who survived to 6 months post-HT. A time-varying Cox model was used to develop and evaluate a surrogate end-point comprised of 6 major adverse transplant events (MATEs) (acute cellular rejection [ACR], antibody-mediated rejection [AMR], infection, cardiac allograft vasculopathy [CAV], post-transplant lymphoproliferative disease [PTLD] and chronic kidney disease [CKD]) occurring between 6 and 36 months, where individual events were defined according to international guidelines. Two thirds of the study cohort was used for score development, and one third of the cohort was used to test the score. Results Among 2,118 children, 6.4% underwent graft loss between 6 and 36 months post-HT, whereas 39% developed CKD, 34% ACR, 34% infection, 9% AMR, 4% CAV and 2% PTLD. The best predictive score involved a simple MATE score sum, yielding a concordance probability estimate (CPE) statistic of 0.74. Whereas the power to detect non-inferiority (NI), assuming the NI hazard ratio of 1.45 in graft survival was 10% (assuming 200 subjects and 6% graft loss rate), the power to detect NI assuming a 2-point non-inferiority margin was >85% using the MATE score. Conclusion The MATE score reflects the cumulative burden of MATEs and has acceptable prediction characteristics for death/graft loss post-HT. The MATE score may be useful as a surrogate end-point to power a clinical trial in pediatric HT.

Restrictive cardiomyopathy (RCM) is a rare form of heart muscle disease accounting for just 2 to 5% of paediatric cardiomyopathies. It is characterised by increased myocardial stiffness and restrictive filling pattern in to the left ventricle. Idiopathic RCM with no obvious identifiable cause is the most common form of the disease. RCM can also be a secondary manifestation of miscellaneous systemic conditions. Typical examples include infiltrative and storage disorders, systemic inflammatory diseases, tumors and drug toxicity. RCM-specific mutations have been identified in several genes encoding sarcomeric proteins. Patients with RCM have heart failure symptoms related to diastolic dysfunction. Unfortunately, there is no curative treatment for RCM and the prognosis is generally very poor. Cardiac transplantation is the only effective treatment. High risk of sudden cardiac death justifies early listing especially in symptomatic children. When making the diagnosis of RCM, it is crucial to rule out constrictive pericarditis which presents with a similar clinical and haemodynamic picture. Unlike RCM it can often be cured surgically.

Heart transplantation improves the prognosis and quality of life in children with end-stage cardiac disease. With advances in surgical technique, post-operative care and immunosuppression the survival has considerably increased and can reach in most cases 15–20 years. The commonest indication for heart transplantation in childhood is cardiomyopathy, followed by complex congenital heart disorders. Prognosis following heart transplantation is largely determined by complications resulting from rejection or complications from medications. Primary graft failure, acute rejection, coronary allograft vasculopathy, infections and development of malignancy are the main causes of death. Despite decreasing incidence of graft rejection following improved immunosuppressive protocols, coronary allograft vasculopathy remains the main long term cause of death after transplant and has limited treatment options. Although most organs arise following neurological determination of death, donation after circulatory determination of death is now possible but is not routinely utilised for heart transplantation. The demand for hearts outstrips the number of available organs and nearly a third of those listed will die waiting. Alternative strategies are required to support children in heart failure in addition to improvement in public awareness so that donor availability can increase. This article briefly reviews the current criteria for transplantation, the important aspects of surgical and medical care of the paediatric heart transplant recipient and the prognosis.

Purpose Currently there are no-FDA approved immunosuppressants specific to pediatric heart transplantation (HT). In recent years, everolimus (EVL) has emerged as an alternative to tacrolimus (TAC) as a primary immunosuppressant to prevent rejection that may also prevent kidney and coronary disease. However, the two regimens have never been evaluated systematically. Methods The TEAMMATE Trial (IND 127980) is designed to evaluate the safety and efficacy of EVL and low-dose (LD-TAC) compared to standard-therapy TAC and mycophenolate mofetil (MMF). The study design and rationale are reviewed in light of challenges inherent in rare disease research. Results The TEAMMATE trial is the first multicenter randomized clinical trial (RCT) in pediatric HT. The primary purpose is to evaluate the risk-benefit profile of the two regimens to prevent major adverse transplant events (MATE), and to support FDA approval of 1 or both regimens for pediatric HT. Children Conclusion The TEAMMATE trial is the first RCT in pediatric HT. It is anticipated that the study will provide important information about the safety and effectiveness of EVL and TAC and provide valuable lessons into the design and conduct of future trials in pediatric HT.

Purpose Donor-derived cell-free cell free DNA (ddcfDNA) is a noninvasive biomarker undergoing investigation in adult heart and lung allograft recipients. Elevated ddcfDNA levels have been correlated with active rejection, most robustly for antibody-mediated rejection (ABMR). However, complex methodology limits clinical implementation of this promising biomarker. There are no data in the paediatric population. Methods Blood from 96 heart and 19 lung pediatric transplant recipients were taken at various time points, e.g. as a baseline, before/after biopsies and the clinical status was recorded. Donor allograft biopsies were available from 7 heart patients. A multiplex PCR assay consisting of a panel of 61 highly heterogeneous single nucleotide polymorphic markers (SNPs), HLA exon 3 and X/Y-markers was designed and validated by using genomic DNA (gDNA). This assay was then used to look for evidence of the donor's unique genotype in the recipient's cell free DNA (cfDNA). A statistical model using R was developed to perform donor genotype-free analysis which was validated against the known donor genotype from donor allograft biopsies. Total cell free DNA concentration was also measured. Results The ddcfDNA assay showed a limit of blank (LoB) of 0.12% (based on SNPs homozygous for the same allele from each genomic contribution) and a limit of detection/quantification (LoD/LoQ) of 0.28%. The accuracy of the genotype free analysis was greatest for donor fractions above 0.5%. For patients without clinical evidence of allograft damage a stable low baseline of ddcfDNA was observed. A single heart patient in this series died approximately 2 years post-transplantation. The assay demonstrated a stable baseline initially but increased to 2.03% five weeks prior to death and further increased to 12.16% one week prior to death due to poor function and cardiac allograft rejection. Conclusion We present the first study in pediatric heart and lung transplantation validating the performance of a SNP-based PCR assay, rather than a whole genome assay, to detect recipient ddcfDNA fraction. This offers the potential for a rapid and cheaper noninvasive biomarker for monitoring allograft damage.

Purpose There remains a significant shortage of organs for children listed for heart transplant. This may be ameliorated by controlled donation after circulatory death (DCD), which has proven success in adults. However, there are numerous challenges in retrieval, assessment and transportation of DCD hearts. We report a unique collaboration between 2 centres, combining expertise in DCD organ retrieval and paediatric transplantation. Methods All families of children over 20 kg listed for heart transplantation were approached for DCD listing; all consented (n = 20). DCD hearts were procured by direct retrieval and perfusion, and then mounted, perfused and assessed on an ex-situ cardiac perfusion machine (Organ Care System (OCS), TransMedics, Inc., Andover, MA), before transfer to the implanting unit. Results Between 1 Feb and 30 Jun 2020, 5 children received a DCD heart (aged 12 to 16 years; two female). Two had previous cardiac surgery, and none had transpulmonary gradient > 8 mmHg. Donor median age was 19.5 years (15-43); three were male. Donor heart mean functional warm ischaemic time was 25 minutes (22 - 28). Mean travel distance was 150 miles (40 - 220) and mean ex-situ perfusion time was 266 minutes (192 - 325). Initial arterial lactate on the OCS was 8.8 mmol/l (4.7-11.7) and venous 8.0 mmol/l (4.7 - 10.1); these fell to 4.7 mmol/l (2.2 - 7.4) and 4.4 mmol/L (2 - 7.1) respectively during transport. No recipients required post-operative mechanical support. Median ITU stay was 8 days (7 - 11) and total hospital stay was 16 days (12 - 21). Pre-discharge echocardiography showed good biventricular function in all recipients except one with mild left and moderate right ventricular dysfunction; all now have excellent graft function. In the same period, 6 DBD transplants were performed in those listed for DCD; although not reaching statistical significance, ventilation, inotrope use, ITU and hospital stay were all shorter in the DCD group. Conclusion The use of previously unavailable DCD hearts has increased transplant activity by 83% in children > 20 kg in this early series. By combining the expertise of one unit in organ retrieval using novel technologies with another in paediatric transplantation, all patients had excellent short-term outcomes. Development of the DCD program to include the use of smaller organs is now a priority for both units.

Chronic allograft vasculopathy (CAV) limits the lifespan of pediatric heart transplant recipients. We investigated blood markers of inflammation, endothelial dysfunction, and damage to both the native and transplanted vasculature in children after heart transplantation. Serum samples were taken from pediatric heart transplant recipients for markers of inflammation and endothelial activation. The systemic vasculature was investigated using brachial artery flow-mediated dilatation and carotid artery intima-medial hyperplasia. CAV was investigated using intravascular ultrasound. Mean intima-media thickness (mIMT)0.5 mm was used to define significant CAV. Forty-eight children (25 male) aged 8-18 years were enrolled in the study. Patients were a median (interquartile range) 4.1 (2.2-8.7) years after transplant. Patients had increased levels of circulating IL6 (3.86 [2.84-4.95] vs. 1.66 [1.22-2.63] p0.0001), vascular cell adhesion molecule 1 (539 [451-621] vs. 402 [342-487] p0.001), intracellular adhesion molecule 1 305 (247-346) vs. 256 (224-294) p = 0.002 and thrombomodulin (7.1 [5.5-8.1] vs. 3.57 [3.03-4.71] p0.0001) and decreased levels of tumor necrosis factor-α, E selectin, and P selectin, compared with controls. The systemic vasculature was unaffected. Patients with severe CAV had raised serum von Willebrand factor and decreased serum thrombomodulin. Posttransplant thrombomodulin levels are elevated after transplant but significantly lower in those with mIMT0.5 mm. This suggests that subclinical inflammation is present and that natural anticoagulant/thrombomodulin activity is important after transplant.

Objective To describe the presenting clinical features, treatment and outcome in children with eosinophilic granulomatosis with polyangiitis (EGPA) and to define factors that predicted mortality. Methods A retrospective case notes review of patients fulfilling the Chapel Hill Consensus Conference definition and/or ACR criteria for EGPA seen at Great Ormond Street Hospital, London. Demographics, clinical features, histopathology, treatment and outcomes were recorded. Descriptive statistics were expressed as median and range. Fisher's exact test was used for group comparisons. The Paediatric Vasculitis Activity Score and Paediatric Vasculitis Damage Index (PVDI) were calculated. Results Thirteen children (38% female) aged at diagnosis 14.1 (4-15.6) years were identified. The median time to diagnosis was 2 (0-7.3) years. History of asthma was documented in 76%. The most common presenting features were pulmonary (69%), skin (61%), gastrointestinal (46%), cardiac involvement (46%), paranasal sinus abnormality (38%), arthritis/arthralgia (38%) and neurological involvement (15%). Paediatric Vasculitis Activity Score at presentation was 8/63 (2-25/63); ANCA was negative in all 10/13 patients tested. Treatment included corticosteroids in all, combined with CYC in 38% or AZA in 23%. PVDI at 12 (3-48) months follow-up was 3/72 (0-13/72). Relapses were recorded in 46%. Mortality was 15%; cardiomyopathy and PVDI scores ⩾5 significantly associated with mortality risk (P = 0.012). Conclusion EGPA in the paediatric population is a rare and potentially life-threatening vasculitis. Increased awareness is essential to secure a timely diagnosis and to promptly initiate treatment since our data emphasize a high mortality, particularly in those with cardiac involvement and significant accrued damage.

Aims Our original study, the first national prospective study of new-onset heart failure from heart muscle disease in children, showed overall 1-year survival of 82%, and event (death or transplantation)-free survival of 66%. This study aimed to evaluate 5 + year outcomes of this important cohort. Methods and results All centres in the UK and Ireland with 1-year event-free survivors participated (n = 14). Anonymised data based on last hospital attendance and echocardiograms were reviewed. The investigator was blinded to outcome at the time of echo review. Of sixty-nine 1-year event-free survivors, data were obtained on 64, with three lost to follow-up and two moved abroad. There were three deaths at 2.2, 3.3 and 9.0 years after presentation and one transplant, at 5.2 years. Overall/event-free survival was 77%/62% at 5 years and 73%/59% at 10 years, respectively. Overall and event-free survival conditional on 1-year survival was 94% at 5 years, and 89% at 10 years. For the 60 event-free survivors, median (range) follow-up duration was 9.04 (5.0–10.33) years for those still under review (n = 45), or time to discharge 5.25 (0.67–10.0) years (n = 15). Fifty-eight were in New York Heart Association (NYHA) Class 1, and two in Class 2. Forty-one out of sixty had normal echocardiograms at last follow-up. Predictors of better longer-term outcome were the same as for the original 1-year follow-up study, namely, younger age and higher fractional shortening measurement at presentation. Conclusions Children who survive the first year following their first presentation with significant heart failure from heart muscle disease have a good longer-term outcome although there remains a small attrition rate.

Background Cytomegalovirus (CMV) infection is implicated in endothelial dysfunction and graft damage after pediatric heart transplantation. CMV-specific immune responses are thought to be necessary for CMV viral control but there is little data in pediatric heart transplantation. Methods We studied 28 consecutive pediatric heart transplant recipients for 1 year posttransplant. CMV T-cell expressing IFN-γ, TNF-α, and IL-2 in response to ex vivo stimulation with CMV lysates or peptides were measured. Circulating cytokines were measured in plasma. Generalized Additive Models were applied to the data to model changes of cell population dynamics over time. Results CMV-specific T cell-mediated responses were impaired in the first 8 weeks posttransplant. During this period, 25% of patients had CMV viremia, of which those with VLs of 10 000 or more CMV deoxyribonucleic acid copies/mL were given ganciclovir. In this group, the frequency of CD4+ and CD8+ T cells producing IFN-γ and the CD8+CD57+ granzyme B+ T-cell population increased at 12 to 24 weeks and remained elevated for the duration of the study. Conclusions We have shown that CMV viremia is associated with CMV-specific immune responses and increased CD8+CD57+ granzyme B+ cells at 1 year posttransplant; however, early responses were not predictive of impending CMV viremia. It remains to be seen if the early CMV immune response detected is associated with endothelial and allograft damage, in light of previous studies demonstrating increased vasculopathy in pediatric patients with CMV viremia.

Elevated plasma levels of the nucleoside diphosphate kinase (NDPK) NM23-H1 are associated with poorer prognosis in acute myeloid leukemia (AML). We previously demonstrated that leukemic blasts release NM23-H1, which binds to more differentiated myeloid cells inducing their secretion of inflammatory cytokines, including IL-1β, that promote survival and proliferation of leukemic blasts1. Both AML and myelodysplastic syndrome (MDS) patients are prone to infections due to impaired hematopoiesis that is worsened by treatment. NDPKs are highly evolutionarily conserved raising the possibility that bacterial/fungal NDPKs could mediate the same survival effect on malignant AML/MDS blasts and exacerbate disease progression. To test this, we generated recombinant NDPKs (rNDPKs) from bacteria and fungi associated with common infections in these patients (E. coli, S. aureus, S. pneumoniae, K. pneumoniae, C. albicans). Cytokine production and survival responses of primary AMLs to these proteins were indistinguishable from their response to rNM23-H1. This activity was independent of NDPK enzyme activity since mutant rNM23-H1 and bacterial and fungal rNDPKs with impaired oligomerization, kinase or exonuclease activity elicited the same cytokine and survival response. Toll like receptors (TLRs) are the major family of human DAMP/PAMP receptors and IL-1β secretion is closely associated with TLR-4 mediated activation of the NLRP3 inflammasome in monocytes. We therefore postulated that NM23-H1 and pathogen derived NDPKs act as novel damage- and pathogen- associated molecular pattern (DAMP, PAMP) molecules. We confirmed that fluorescently labelled rNM23-H1 and S. pneumoniae rNDPK bound selectively to monocytes in peripheral blood. Using in vitro generated monocytes (vitamin D3 differentiated THP-1 cells) we demonstrated that both wild type and mutant rNM23-H1 and bacterial/fungal rNDPKs induced activation of caspase-1 and cleavage of pro-IL-1β into its active form. Secretion of IL-1β was inhibited by antagonists/inhibitors of TLR4, NLRP3 and caspase-1 indicating the involvement of the TLR4-NLRP3 inflammasome axis is mediating the NDPK response. Unlike the canonical NLRP3-inflammasome pathway that leads to monocyte cell death by pyroptosis, rNM23-H1 and rNDPKs did not lead to cell death indicating that rNDPKs are responsible for the activation of the alternative inflammasome. In our earlier studies, and those of others, we demonstrated that not all AML primary samples responsed to NM23-H1 in vitro. We have observed that non responders to NM23-H1 also do not respond to pathogen derived rNDPKs. In contrast, we have observed uniform responses in terms of cytokine release in all normal peripheral blood. We hence hypothesized that the non-rNDPK-responding AML samples may reflect the absence of monocytes in culture. To test this, we generated conditioned media using normal donor leukocytes, in presence or absence of a TLR-4 antagonist to inhibit the IL-1β production. The conditioned media was then used to culture primary AML samples, in parallel with rNDPK in unconditioned media. All the samples analyzed showed increased survival in rNDPK conditioned media even whilst some did not respond to rNDPK in unconditioned media. In summary, our data demonstrate for the first time that NM23-H1 and bacterial/fungal NDPKs are novel DAMPs/PAMPS that signal via TLR4 in monocytes. We further demonstrate that this interaction results in activation of the alternative NLRP3 inflammasome and subsequent cleavage and secretion of IL-1β without death by pyroptosis. Our data showing that bacterial/fungal NDPKs can promote survival of AML blasts indicates that rather than just being a consequence of AML associated immunosuppression, infections may drive the progression and AML. These findings have important implications in the clinical management of AML and its precursor myelodysplastic syndromes (MDS). Lilly AJ, et al.Cancer Res. 2011;71(3):1177-86.Gaidt MM, et al. Immunity. 2016;44(4):833-46 Disclosures Drayson: Abingdon Health: Consultancy, Equity Ownership.

Some studies have shown that pre-transplant cytomegalovirus (CMV) serostatus is associated with heart transplant patient survival while others have not. We analyzed the relationship between pre-transplant donor/recipient CMV serostatus and long-term mortality in a retrospective cohort of heart transplant recipients at our center.Adult (Age17 years) heart recipients transplanted between July 1985-December 2015 were analyzed. Variables included age, sex, pre-transplant donor (D)/recipient (R) serostatus [D-/R-, D-/R+, D+/R+, D+/R-], CMV infection within 2 years of transplant and transplant eras divided by changes in CMV prevention strategies: Era 1 (Pre-ganciclovir, July 1985-April 1998), Era 2 (Oral ganciclovir, May 1998-December 2004), Era 3 (Valganciclovir, January 2005-December 2015). Survival analysis and Cox regression were performed at 10 years.A total of 620 heart transplants were included in our analysis; 20% were CMV mismatched pre-transplant. Thirty-eight percent of patients were infected with CMV within the first two post-transplant years. Survival analysis showed D/R CMV serostatus did not significantly impact survival of heart recipients at 10 years (P = 0.11). Survival was significantly different across eras for D-/R+, D+/R+, and D+/R+ (P = 0.043) but not D-/R- patients (P = 0.8). Cox regression revealed that patients transplanted in the valganciclovir era have an estimated 29% reduced risk of death (P = 0.047) compared to patients transplanted in the pre-ganciclovir era after controlling for age at transplantation, D/R CMV serostatus and CMV infection.Our review of the impact of CMV managed differently across eras suggests in heart transplantation there is no influence of D/R CMV serostatus on 10 year survival.

Background Coronary allograft vasculopathy (CAV) is the leading cause of death after pediatric heart transplantation from 1 year postoperation. Anecdotal evidence suggests a difference in the severity of disease between UK and North America. We performed a comparative study using intravascular ultrasound (IVUS). Methods Consecutive IVUS procedures from a single year were included from each center. Using standardized techniques, measurement of the vessel area, lumen area, and maximal intimamedial thickening (IMT) were performed with calculation of intimal index (II) for each slice. Mean II, mean IMT, and absolute maximum IMT were calculated along the left coronary artery for each patient. Transplant demographics and treatment details were included in the analysis. Results One hundred four patients were included between the 2 centers. Interobserver variability for IVUS analysis was excellent. Patients were aged mean 14.2 (SD 3.3) years at the time of the study and 9.2 (SD 6.0) years earlier post-transplant procedure. UK patients were older, at transplant for a shorter time, and demonstrated more severe CAV. Multiple regression analysis demonstrated the detrimental effect of donor age and time from transplant on CAV severity and benefits of sirolimus use. Conclusions The data show more severe CAV in the UK cohort despite significantly shorter time post-transplant. Donor age and time post-transplant were associated with more severe CAV and sirolimus use was associated with a reduction in IMT. This study demonstrates a marked difference in the prevalence of CAV in children between UK and North America. The causes are likely to be multifactorial; however, younger donors and recipients have significantly less disease.

Enzyme replacement therapy (ERT) for infantile-onset Pompe disease has been commercially available for almost 10 years. We report the experience of its use in a cohort treated at three specialist lysosomal treatment centres in the UK.A retrospective case-note review was performed, with additional data being gathered from two national audits on all such patients treated with ERT. The impact on the outcome of various characteristics, measured just prior to the initiation of ERT (baseline), was evaluated using logistic regression.Thirty-three patients were identified; 13/29 (45%) were cross-reactive immunological material (CRIM) negative, and nine were immunomodulated. At baseline assessment, 79% were in heart failure, 66% had failure to thrive and 70% had radiological signs of focal pulmonary collapse. The overall survival rate was 60%, ventilation-free survival was 40% and 30% of patients were ambulatory. Median follow-up of survivors was 4 years, 1.5 months (range 6 months to 13.5 years). As with previous studies, the CRIM status impacted on all outcome measures. However, in this cohort, baseline failure to thrive was related to death and lack of ambulation, and left ventricular dilatation was a risk factor for non-ventilator-free survival.The outcome of treated patients remains heterogeneous despite attempts at immunomodulation. Failure to thrive at baseline and left ventricular dilation appear to be associated with poorer outcomes.

Duchenne Mmuscular Ddystrophy (DMD) related cardiomyopathy is associated with significant perioperative mortality. Cardiac MRI (CMR) has not previously been systematically evaluated as pre-operative assessment tool for heart function in DMD. Our aim was to establish whether CMR versus echocardiography contributes to pre-operative DMD assessment.Case records were retrospectively reviewed of 35 consecutive DMD boys who underwent evaluation for surgical procedures between 2010 and 2013.Echocardiography revealed a median left ventricular (LV) shortening fraction (SF) of 29/% (range: 7-44). 37% of boys (13/35) had abnormal SF25%, 66% (23/35) showed hypokinesia and 26% (9/35) had LV dilatation. CMR revealed a median left ventricular ejection fraction (LVEF) of 52% (range: 27-67%). 57% of boys (20/35) had abnormal LVEF55%, 71% (25/35) had hypokinesia, and 82% late gadolinium enhancement. Extensive versus minimal late gadolinium enhancement was associated with reduced left ventricular ejection fraction (48% vs 58%; p = 0.003) suggesting more severe cardiomyopathy. Although echocardiography shortening fraction correlated with CMR ejection fraction (rs = 0.67; p0.001), three-quarter of echocardiography studies had suboptimal scanning windows and in 26% measurements significantly over- or underestimated left-ventricular function compared to CMR.Our findings clearly demonstrate the added value of CMR versus echocardiography in assessing DMD-cardiomyopathy. Particularly when echocardiographic scanning windows are suboptimal, CMR should be considered to allow accurate pre-operative cardiac assessment.

Background No data are available for the outcome of children undergoing cardiac transplantation with shared care programs in different countries. We sought to investigate the outcome of a shared care transplant program between 2 countries given the complex immunologic, cardiac, and psychologic needs of these young people. Methods We investigated the results of a shared care program for children who underwent cardiac transplantation between our center in the Republic of Ireland and 2 centers in the United Kingdom over 2 decades. Results Between 1990 and 2013, 22 patients underwent 23 cardiac transplants. The median age at transplant was 3.2 years (range, 0.3–13.3 years), median age at listing was 30 months (range, 0.1–13.3 years), and the median waiting list time was 2.8 months (range, 0.3–14 months). The median time to return to the referral center from the time of transplant was 3 weeks (range, 2–8 weeks). The referral center treated 4 of 5 late rejection episodes. Angiography was undertaken in the transplant center at annual or biannual review. Outcomes for rejection, coronary vasculopathy, and survival were comparable between the referral and transplant centers. Conclusions This report of shared care for pediatric transplant patients between 2 sovereign nations demonstrates good results, with comparable outcomes to the specialist transplant center. These data may encourage liberalization of follow-up in other centers.

Clinical practice variations are a barrier to the study of pediatric heart transplants and coordination of multicenter RCTs in this patient population. We surveyed centers to describe practice patterns, understand areas of variation, and willingness to modify protocol. Pediatric heart transplant centers were identified, and one survey was completed per center. Simple descriptive statistics were used. The response rate was 77% (40 responses from 52 contacted centers, 37 with complete responses). Median center volume of respondents was eight transplants/year (IQR 3-19). Most centers reported tacrolimus (36/38, 95%) and mycophenolate mofetil (36/38, 95%) as maintenance immunosuppression. Other immunosuppression agents reported were cyclosporine (7/38, 18%), everolimus or sirolimus (3/38, 8%), and azathioprine (2/38, 5%). Overall, respondents answered similarly for questions regarding clinical practices including induction therapy, maintenance immunosuppression, and rejection treatment threshold (>85% agreement for all). Additionally, willingness to change clinical practices was over 70% for all practices surveyed (35 total respondents), and 97% of centers (36/37) were willing to participate in a RCT of maintenance immunosuppression. In conclusion, we found many similar clinical practice protocols. Most centers are willing to collaborate on a common protocol in order to participate in a RCT and support a trial investigating maintenance immunosuppression.

Objective Understanding the clinical course and time-frame for recovery is helpful to guide management and counselling following a diagnosis of Dilated Cardiomyopathy (DCM). We aimed to document outcomes and time to recovery for a cohort of patients with a dilated cardiomyopathy phenotype. Methods An observational cohort methodology was used to collect retrospective data from the departmental database for those identified with DCM. Data relating to mode of presentation, echocardiographic parameters, clinical management and outcome were collated and analysed. Predictors and time-scale for recovery were investigated and reported. Results 209 new referrals were included within the time frame. 82 children median age 1.0 years (IQR 3.4) required intensive care (ICU) and their survival without death or transplant was 51% to one year and 45% to five years. 127 children presented to the pediatric heart failure clinic. Excluding 58 with neuromuscular disease, median age was 4.1 years (IQR 11.3) & survival without death or transplant 85% to 1 year and 50% to 5 years. NT-proBNP normalized in survivors before echocardiographic parameters. Predictors of recovery included younger age, female sex and smaller left ventricular end diastolic Z score on echocardiogram at presentation. Conclusion Transplant-free survival to one year is significantly better for patients presenting to clinic, but longer-term survival is better amongst those presenting to ICU due to a late attrition in those with less severe heart failure at presentation. Falling NT-proBNP is the earliest marker of recovery. Recovery of cardiac function remains possible up to three years from presentation.

Intravascular ultrasound (IVUS) has been routinely used in some centers to investigate cardiac allograft vasculopathy in pediatric heart transplant recipients. We present an alternative method using more sophisticated imaging software. This study presents a comparison of this method with an established standard method. All patients who had IVUS performed in 2014 were retrospectively evaluated. The standard technique consisted of analysis of 10 operator-selected segments along the vessel. Each study was re-evaluated using a longitudinal technique, taken at every third cardiac cycle, along the entire vessel. Semiautomatic edge detection software was used to detect vessel imaging planes. Measurements included outer and inner diameter, total and luminal area, maximal intimal thickness (MIT), and intimal index. Each IVUS was graded for severity using the Stanford classification. All results were given as mean ± standard deviation (SD). Groups were compared using Student t test. A P value .05 was considered significant. There were 59 IVUS studies performed on 58 patients. There was no statistically significant difference between outer diameter, inner diameter, or total area. In the longitudinal group, there was a significantly smaller luminal area, higher MIT, and higher intimal index. Using the longitudinal technique, there was an increase in Stanford classification in 20 patients. The longitudinal technique appeared more sensitive in assessing the degree of cardiac allograft vasculopathy and may play a role in the increase in the degree of thickening seen. It may offer an alternative way of grading severity of cardiac allograft vasculopathy in pediatric heart transplant recipients.

Background Permanent pacemaker (PPM) placement in adults following orthotopic heart transplantation (OHT) has been well documented. However, studies concerning the need for PPM implantation in pediatric heart transplant recipients are less common. Methods Institutional transplant and pacing databases as well as patient medical records were reviewed for all pediatric patients undergoing OHT (n = 314; all with bicaval connection) at our institution between January 2000 and March 2018. Results A total of 16 patients (5.1%) were implanted with a pacemaker after transplantation. Donor age was the only significant risk factor for post-transplant PPM implantation, with a median age of 28.5 years (7.0-49.0) in the pacing group vs 15.5 years (0.4-56.0) in the non-pacing group (P = 0.009). Indication for pacemaker insertion was more often complete heart block (CHB) (12/16, 75%) than sinus node dysfunction (SND) (4/16, 25%). There was no significant difference in mortality between recipients who received a PPM and those who did not (log-rank test; P = 0.345). Conclusions Increasing donor age is associated with increased PPM placement following pediatric heart transplantation. Interestingly, a high proportion of CHB patients recovered sinus rhythm, and long-term outcomes for paced patients are similar to other heart transplant recipients.

Background Recent reports suggest worse outcomes in pediatric orthotopic heart transplantation (OHT) for congenital heart disease (CHD) and restrictive cardiomyopathy (RCM). We examined early outcomes in these diverse groups of patients in comparison with patients with dilatated cardiomyopathy (DCM). Methods From 2000 to 2011, 209 patients were included: 50 with CHD, 23 with RCM, and 136 with DCM. Early survival was studied, as was the occurrence of acute rejection, donor-specific antibodies (DSAs) and nondonor-specific antibodies (NSDAs), incidence of pulmonary hypertension (PHT), right ventricular failure (RVF), and the need for mechanical circulatory support (MCS). Results The incidence of preoperative PHT was greatest in the RCM group (χ 2 p = 0.0006); the requirement for mechanical support before OHT was greatest in patients with DCM. Thirty-day survival was 92.0%, 97.1%, and 100% for patients with CHD, DCM, and RCM respectively. The incidence of RVF was highest for patients with RCM (43.5%; versus CHD, 26.0%; versus DCM, 14.7%). One-year survival estimates for patients with CHD, DCM, and RCM were 92.0%, 97.8%, and 82.6%, respectively (log-rank p = 0.165). Multivariable analysis revealed 4 significant risk factors for mortality: age, incidence of acute rejection, preoperative PHT, and the presence of NDSAs. The occurrence of DSAs was similar, although there was a significantly higher incidence of NDSAs in the CHD and RCM groups (36.0% and 30.4%, respectively, versus 14.0% in the DCM group; χ 2 p = 0.0024). Conclusions Equivalent outcomes are achievable in pediatric OHT despite marked heterogeneity in anatomic and physiologic complexity in recipients. Physiologic factors such as PHT are likely to be more important than anatomic complexities in determining survival. The potential relevance of NDSAs warrants further investigation.