Children Undergoing Heart Transplantation Research Articles

Pediatric dilated cardiomyopathy: a review of current clinical approaches and pathogenesis.

Pediatric dilated cardiomyopathy (DCM) is a rare, yet life-threatening cardiovascular condition characterized by systolic dysfunction with biventricular dilatation and reduced myocardial contractility. Therapeutic options are limited with nearly 40% of children undergoing heart transplant or death within 2 years of diagnosis. Pediatric patients are currently diagnosed based on correlating the clinical picture with echocardiographic findings. Patient age, etiology of disease, and parameters of cardiac function significantly impact prognosis. Treatments for pediatric DCM aim to ameliorate symptoms, reduce progression of disease, and prevent life-threatening arrhythmias. Many therapeutic agents with known efficacy in adults lack the same evidence in children. Unlike adult DCM, the pathogenesis of pediatric DCM is not well understood as approximately two thirds of cases are classified as idiopathic disease. Children experience unique gene expression changes and molecular pathway activation in response to DCM. Studies have pointed to a significant genetic component in pediatric DCM, with variants in genes related to sarcomere and cytoskeleton structure implicated. In this regard, pediatric DCM can be considered pediatric manifestations of inherited cardiomyopathy syndromes. Yet exciting recent studies in infantile DCM suggest that this subset has a distinct etiology involving defective postnatal cardiac maturation, such as the failure of programmed centrosome breakdown in cardiomyocytes. Improved knowledge of pathogenesis is central to developing child-specific treatment approaches. This review aims to discuss the established biological pathogenesis of pediatric DCM, current clinical guidelines, and promising therapeutic avenues, highlighting differences from adult disease. The overarching goal is to unravel the complexities surrounding this condition to facilitate the advancement of novel therapeutic interventions and improve prognosis and overall quality of life for pediatric patients affected by DCM.

The Effect of Neurodevelopmental Disorders on the Prognosis of Children Undergoing Heart Transplantation: A Retrospective Analysis of the National Inpatient Sample 2011–2019

Background: Many international governing bodies recommend against heart transplantation in patients with severe cognitive-behavioral disabilities, however no clear criteria are offered to define severity. Patients with neurodevelopmental disorders may face systematic discrimination when being evaluated for transplant. We set out to investigate whether children with neurodevelopmental disorders that undergo heart transplantation have poorer in-hospital outcomes compared to neurotypical children. Methods: A retrospective analysis of the National Inpatient Sample database was conducted to identify pediatric patients with neurodevelopmental disorders who underwent heart transplantation from 2011–2019. Baseline characteristics and in-hospital outcomes between patients were compared. Binary logistic regression was used to investigate the association between the documented presence of a neurodevelopmental disorder and in-hospital outcomes in children undergoing heart transplantation. Results: We identified a weighted sample of 3770 pediatric cardiac transplant patients, of whom 245 (6.5%) had a documented diagnosis of neurodevelopmental disorder. There was no significant difference in the odds of major adverse cardiovascular events (all-cause mortality, stroke complications or myocardial infarction), surgical complications, infection, venous thromboembolic events, delirium/restraint use, or cardiac dysrhythmia. Patients with neurodevelopmental disorders had lower overall length of stay (44.0 days interquartile range (IQR): 16.0–90.0 vs. 57.08 days IQR: 22.0–112.0, p < 0.050), and cost of stay ($956,031 IQR: 548,559.0–1,801,412.0 vs. $1,074,793 IQR: 599,089.8–2,129,086.0, p < 0.050). Patients with neurodevelopmental disorders had significantly lower odds of acute transplant complications (adjusted odds ratio (aOR): 0.39, 95% confidence interval (CI): 0.21–0.74, p < 0.050) vascular complications (aOR: 0.36, 95% CI: 0.19–0.66, p < 0.050) and acute kidney injury (AKI) (aOR: 0.52, 95% CI: 0.33–0.83, p < 0.050). Conclusions: These data suggest that patients with neurodevelopmental disorders have overall similar if not potentially improved post-transplant outcomes in the acute setting compared to neurotypical patients, possibly secondary to selection bias in the patient selection process.

Impact of the Pediatric ABO Policy Change on Listings, Transplants, and Outcomes for Children Younger Than 2 Years Listed for Heart Transplantation in the United States

We assessed the impact of the liberalized ABO pediatric policy change on candidate characteristics and outcomes for children undergoing heart transplant (HT). Children <2 years undergoing HT with ABO strategy reported at listing and HT from December 2011 to November 2020 to the Scientific Registry of Transplant Recipients database were included. Characteristics at listing, HT, and outcomes during the waitlist and post-transplant were compared before the policy change (December 16, 2011 to July 6, 2016), and after the policy change (July 7, 2016 to November 30, 2020). The percentage of ABO-incompatible (ABOi) listings did not increase immediately after the policy change (P = .93); however, ABOi transplants increased by 18% (P < .0001). At listing, both before and after the policy change, ABOi candidates had higher urgency status, renal dysfunction, lower albumin, and required more cardiac support (intravenous inotropes, mechanical ventilation) than those listed ABO compatible (ABOc). On multivariable analysis, there were no differences in waitlist mortality between children listed as ABOi and ABOc before the policy change (adjusted hazard ratio [aHR] 0.80, 95% confidence interval [CI] 0.61-1.05, P = .10) or after the policy change (aHR 1.2, 95% CI 0.85-1.6, P = .33). Post-transplant graft survival was worse for ABOi transplanted children before the policy change (aHR 1.8, 95% CI 1.1-2.8, P = .014), but not significantly different after the policy change (aHR 0.94, 95% CI 0.61-1.4, P = .76). After the policy change, ABOi listed children had significantly shorter waitlist times (P < .05). The recent pediatric ABO policy change has significantly increased the percentage of ABOi transplantations and decreased waitlist times for children listed ABOi. This change in policy has resulted in broader applicability and actual performance of ABOi transplantation with equal access to ABOi or ABOc organs, and thus eliminated the potential disadvantage of only secondary allocation to ABOi recipients.

A Novel GMP Protocol to Produce High-Quality Treg Cells From the Pediatric Thymic Tissue to Be Employed as Cellular Therapy.

Due to their suppressive capacity, the adoptive transfer of regulatory T cells (Treg) has acquired a growing interest in controlling exacerbated inflammatory responses. Limited Treg recovery and reduced quality remain the main obstacles in most current protocols where differentiated Treg are obtained from adult peripheral blood. An alternate Treg source is umbilical cord blood, a promising source of Treg cells due to the higher frequency of naïve Treg and lower frequency of memory T cells present in the fetus’ blood. However, the Treg number isolated from cord blood remains limiting. Human thymuses routinely discarded during pediatric cardiac surgeries to access the retrosternal operative field has been recently proposed as a novel source of Treg for cellular therapy. This strategy overcomes the main limitations of current Treg sources, allowing the obtention of very high numbers of undifferentiated Treg. We have developed a novel good manufacturing practice (GMP) protocol to obtain large Treg amounts, with very high purity and suppressive capacity, from the pediatric thymus (named hereafter thyTreg). The total amount of thyTreg obtained at the end of the procedure, after a short-term culture of 7 days, reach an average of 1,757 x106 (range 50 x 106 – 13,649 x 106) cells from a single thymus. The thyTreg product obtained with our protocol shows very high viability (mean 93.25%; range 83.35% – 97.97%), very high purity (mean 92.89%; range 70.10% – 98.41% of CD25+FOXP3+ cells), stability under proinflammatory conditions and a very high suppressive capacity (inhibiting in more than 75% the proliferation of activated CD4+ and CD8+ T cells in vitro at a thyTreg:responder cells ratio of 1:1). Our thyTreg product has been approved by the Spanish Drug Agency (AEMPS) to be administered as cell therapy. We are recruiting patients in the first-in-human phase I/II clinical trial worldwide that evaluates the safety, feasibility, and efficacy of autologous thyTreg administration in children undergoing heart transplantation (NCT04924491). The high quality and amount of thyTreg and the differential features of the final product obtained with our protocol allow preparing hundreds of doses from a single thymus with improved therapeutic properties, which can be cryopreserved and could open the possibility of an “off-the-shelf” allogeneic use in another individual.

Risk Factors for Acute Kidney Injury and Chronic Kidney Disease in Pediatric Heart Transplant Population

<h3>Purpose</h3> Children undergoing heart transplantation are at increased risk for the development of both acute kidney injury (AKI) and chronic kidney disease (CKD). The incidence of AKI followed by CKD in the pediatric heart transplant population is known, however, limited pediatric studies have assessed risk factors contributing to post transplantation AKI and the long-term development of CKD. We aimed to assess the incidence of AKI and evaluate risk factors for development of CKD at 1 and 3 years in a large cohort of pediatric heart transplant recipients. <h3>Methods</h3> A retrospective observational study of 122 patients who underwent pediatric heart transplant from infancy to age 18 years was performed with longitudinal follow up three years post transplant from the year 2009 to 2017. AKI was defined as >0.3mg/dl increase from baseline serum creatinine: KDIGO AKI and CKD grading criteria were used. Patients with an initial AKI episode were analysed 90 days from the time of AKI. This eGFR at this 90 day time point was termed as residual renal insufficiency (RRI) if GFR satisfied KDIGO CKD staging 2-5. Of the patients that developed RRI, the CKD incidence and risk factors were analysed 1year and 3 years post transplant. <h3>Results</h3> 60 out of the 122 patients had an overall incidence of AKI of 49%. Out of the AKI patients 45% were male and 33% were female. The mean time to AKI development was 14.8+/- 28 days. 10% of those who had AKI required renal replacement therapy. Of the 60 patients that developed AKI, 28% met our criteria for residual renal insufficiency. In the AKI sub-group, incidence of CKD post heart transplant was 12 % at 1 year and 13% at 3 years. Older age at transplant (<i>p</i>< 0.02) and patients with congenital heart disease (p<0.03) had higher risk of developing AKI. Only 8 out of the 60 patients had full data sets at 3 year follow up. <h3>Conclusion</h3> Estimated creatinine clearance 90 days after AKI may aid in evaluating those children at risk for CKD. Close monitoring of older patients and those with congenital heart disease may potentially decrease progression of AKI to CKD.

Pediatric Heart Transplant: Initial Experience in a Tertiary Center in Brazil.

IntroductionPediatric heart transplantation is the definitive therapy for children with end-stage heart failure. This paper describes our initial experience in pediatric heart transplantation in a tertiary center in BrazilMethodsThis is a historical prospective descriptive cohort study based on a review of the medical records of children undergoing heart transplantation at Hospital de Base and Hospital da Criança e Maternidade de São José do Rio Preto. Variables were displayed as frequency, mean, or median. Statistical analysis and Kaplan-Meier actuarial curve were obtained with the aid of Microsoft® Excel® 2019 and STATSDirect version 3.3.5.ResultsBetween January 2010 and December 2020, ten children underwent bicaval orthotopic heart transplantation, 30% of which were under one year of age. Nine patients had end-stage heart failure (International Society for Heart and Lung Transplantation-Heart Failure D) and 50% of the recipients were transplanted under conditions of progressive clinical deterioration (Interagency Registry for Mechanically Assisted Circulatory Support ≤ 2). Forty percent of the recipients had a panel-reactive antibody > 20% on virtual crossmatch. In the postoperative period, 80% of patients required high dose of inotropic support (vasoactive-inotropic score > 10) for > 48 hours. The death-free survival rate at 131 months was 77.1±14.4%. Most patients (88.9%) in late follow-up had an episode of active cytomegalovirus infection. Cellular rejection, with or without clinical repercussion, was present in 44.4% of the patients.ConclusionPediatric heart transplantation produces acceptable and feasible outcomes as definitive therapy for children with end-stage heart failure.

Sex disparities in the current era of pediatric heart transplantation in the United States

While sex-related differences in transplant outcomes have been well characterized amongst adults, there are no sex-specific pediatric heart transplant studies over the last decade and none evaluating waitlist outcomes. In a contemporary cohort of children undergoing heart transplantation in the United States, this analysis was performed to determine if there were sex disparities in waitlist and/or post-transplant outcomes. Retrospective review of Scientific Registry of Transplant Recipients database from December 16, 2011 to February 28, 2019 to compare male and female children after listing and after transplant. Demographic, clinical characteristics and outcomes were compared unadjusted and after 1:1 propensity matching for selected covariates. Of 4089 patients, 2299 (56%) were males. At listing, males were more likely to be older, have congenital heart disease (58% vs 48%), renal dysfunction (49% vs 44%) and implantable cardioverter defibrillator (9% vs 7%). At transplant, males were more likely to have renal (42 % vs 35%) and liver dysfunction (13% vs 10%), PRA >10% (29% vs 22%) and ischemic time >3.5 hours (p < 0.05 for all). There were no significant sex differences found in unadjusted rates of transplant or mortality. After propensity matching, females had increased waitlist mortality (HR 1.3, 95%CI 1.04-1.5; p =0.019) compared to males. There were no significant differences in post-transplant morbidity or mortality (HR 1.2, 95% CI 0.93-1.5; p=0.18) between groups. In a contemporary pediatric cohort, females have inferior heart transplant waitlist survival compared to propensity-matched males despite lower acuity of illness at listing and similar rates of transplantation. There were no sex-disparities noted in post-transplant outcomes.

Zapalenie mięśnia sercowego u dzieci i młodzieży — przegląd piśmiennictwa

Myocarditis is defined by the World Health Organization as an inflammatory disease involving cardiomyocytes, interstitial tissue, vessels and occasionally the pericardium. In this article, literature from the past 5 years regarding epidemiology, diagnostic tests, treatment and prognosis in myocarditis in young children and adolescents was analyzed. For this purpose the Pubmed database was screened using the key words “myocarditis” and “children”, yielding 117 articles. This list of was narrowed down to those in which the study group consisted of at least 5 people and included information about: symptoms and signs, abnormalities in additional tests, etiology, treatment, length of hospitalization and mortality. Finally, the review included 17 studies, describing 1891 children with a diagnosis of myocarditis. The analysis shows that myocarditis is a rare disease. Two peaks of the disease are observed: the first in newborns and infants, the second one in adolescents. Age less than 2 years is a predictor of severe prognosis. In reported cases the most common symptoms were: fatigue, chest pain, palpitations or irregular heart rhythm. Tachycardia, tachypnoe, hypotension and hepatomegaly dominated among findings in physical examination. The interview, the result of physical examination and additional tests (troponin levels, electrocardiogram, echocardiogram) are helpful in making a diagnosis. Cardiac magnetic resonance imaging is used to confirm the diagnosis. In the analyzed group, 65–90% of children were treated in the Intensive Care Unit. Extracorporeal membrane oxygenation was used in 168 cases, a ventricular assist device was implanted in 35 children and 38 children underwent heart transplantation. The mortality rate in myocarditis remains high (25–35% in analyzed studies). Up to 25% of children may develop chronic heart failure. Due to the unpredictable course of this disease, patients in the acute period of the disease should be hospitalized, and after being discharge from the hospital undergo further cardiological check-up.

Single nuclei sequencing reveals novel insights into cardiac cell signatures in human pediatric dilated cardiopathy

Abstract The mechanism underlying dilated cardiomyopathy (DCM) in children without a known genetic disorder are unclear. In contrast to adult DCM patients, there is an unmet need for therapeutic options that improve survival in pediatric DCM. Therefore, we performed single nuclei RNA sequencing (snRNA-seq) from heart tissue obtained from children undergoing heart transplantation due to severe heart failure. We processed heart tissue from 6 children with DCM (EF: 18.67±2.11%) of an age of 0.5, 0.75, 5, 6, 12 and 13 years (y). After snRNA-seq, unsupervised clustering was performed identifying 8 major cell types, including cardiomyocytes (CM), fibroblasts (FB), endothelial cells, leukocytes, pericytes, smooth muscle cells, neuronal-like cells and an endothelial-fibroblast-like cluster. Relative numbers of FB clusters correlated with increasing age of the children which was clinically validated by measuring late enhancement (LE) with cardiac magnetic resonance imaging in 68 pediatric DCM patients. The mean age of patients with LE was 5.86±0.53y vs. 2.36±0.53y in patients without LE (p&amp;lt;0.05). Further analysis of unique highly expressed genes (DEGs) between the 3 age groups identified a profound alteration of gene expression in FB clusters. FBs of explants of &amp;lt;1y old patients showed high expression of anti-fibrotic, development and remodeling associated genes. In contrast, FBs of 12–13y old children highly expressed pro-fibrotic and FB activation associated genes as transforming growth factor beta binding protein (6.63 fold), cytochrome P450 1B1 (3.79 fold), and periostin (7.67 fold) (all p&amp;lt;0.05). Moreover, we observed a switch in collagen expression patterns and in thrombospondin isoforms (from THBS1 to THBS4). Furthermore, our analysis revealed most profound transcriptional changes in CMs. We identified a cluster of CMs with a pro-regenerative profile in &amp;lt;1y old patients, which could not be detected during adolescence. This CM cluster showed high expression of genes associated with proliferation (e.g. cyclin D2), glycolytic metabolism and anti-oxidant markers. Increased cyclin D2 was confirmed by immunostaining (1.43 fold higher in &amp;lt;1y vs. 12–13y). Since all of these gene expression patterns might be affected by the underlying disease of the pediatric heart recipients, we explored their expression in FBs and CMs of postnatal vs. adult mice. Importantly, we could recapitulate the vast majority of the findings from humans in the mice experiments. Together, these data demonstrate an age-dependent decrease in CM numbers concomitant with increased FBs in pediatric DCM. FBs of &amp;lt;1y old pediatric patients revealed a distinct collagen expression profile and showed lower levels of pro-fibrotic genes. CMs of &amp;lt;1y old donors where characterized with a regeneration enabling gene expression profile, which include pro-proliferative genes. The expression patterns of the CMs indicates, that regeneration might also occur in humans during the firs year of life. Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): Dr. Rolf M. Schwiete Stiftung, DZHK

Transplantation for congenital heart disease is associated with an increased risk of Epstein-Barr virus–related post-transplant lymphoproliferative disorder in children

Children undergoing heart transplant are at higher risk of developing post-transplant lymphoproliferative disorder (PTLD) than other solid organ recipients. The factors driving that risk are unclear. This study investigated risk factors for PTLD in children transplanted at 1 of 2 United Kingdom pediatric cardiac transplantation centers. All children (<18 years, n = 200) transplanted at our institution over a 16-year period were analyzed. Freedom from PTLD was assessed using the Kaplan-Meier method and Cox proportional regression. PTLD occurred in 17 of 71 children transplanted for congenital heart disease (CHD) and 18 of 129 transplanted for acquired cardiomyopathy (ACM). The cumulative incidence of all PTLD was 21.1% at 5 years after transplant. Median time from transplant to PTLD was 2.9 years (interquartile range: 0.9-4.6). Negative Epstein-Barr virus (EBV) serostatus pre-transplant (adjusted hazard ratio [HR]: 2.7, 95% CI: 1.3-5.6, p = 0.01) and underlying CHD (adjusted HR: 3.2, 95% CI: 1.4-7.4, p = 0.007) were independently associated with higher risk of PTLD. Age at thymectomy was significantly different between children with CHD and ACM (0.4 vs 5.5 years, p < 0.01). Median CD4+ and CD8+ T lymphocyte counts at 2years after transplant were significantly lower in children transplanted for CHD vs ACM (CD4+: 391/µl vs 644/µl, p = 0.01; CD8+: 382/µl vs 500/µl, p = 0.01). At 5years after transplant, those differences persisted among patients who developed PTLD (CD4+, 430/µl vs 963/µl, p < 0.01 and CD8+, 367/µl vs 765/µl, p < 0.01). Underlying CHD is an independent risk factor for PTLD and is associated with a younger age at thymectomy. A persistent association with altered T lymphocyte subsets may contribute to the impaired response to primary EBV infection and increase the risk of PTLD.

Acute kidney injury and chronic kidney disease after combined heart-liver transplant in patients with congenital heart disease: A retrospective case series.

Although it is known that children undergoing heart transplantation are at increased risk for both AKI and CKD, renal function following CHLT remains understudied. All pediatric CHLT patients from 2006 to 2019 were included. The prevalence of AKI in the first 7 post-operative days, renal recovery at 30 post-operative days, and CKD were ascertained. AKI was defined as an increase in creatinine greater than 1.5 times baseline, and CKD, as an eCrCl less than 90mL/min/1.73m2 . The need for RRT was also analyzed. 10 patients were included, with an average age of 20years and an average listing time of 130days. Preoperatively, the median eCrCl was 91.12mL/min/m2 (IQR 70.51, 127.75min/mL/m2 ). 5 (50%) patients had CKD, with 4 at stage 2 and 1 at stage 3. AKI occurred post-operatively in 3 of 9 (33%) patients: 2 at stage 1 and 1 at stage 2. 2 (67%) resolved by 7days. Of the 5 patients who reached their 1-year follow-up, 1 (20%) had stage 3 CKD. Among 2 patients, neither had CKD at 5years. One patient required RRT 2weeks after CHLT. Despite an increased prevalence of preoperative CKD, patients undergoing CHLT have a lower AKI prevalence than those receiving an isolated heart or liver transplant. Of those with AKI, early renal recovery is common, although at 1year CKD remains present in 20%. Among long-term survivors, normal renal function is achievable.

Heart Retransplantation for Coronary Allograft Vasculopathy in Children: 25 Years of Single-Center Experience

BackgroundPediatric end-stage heart disease is surgically managed by heart transplantation. A major complication of primary transplantation (PTx) is coronary allograft vasculopathy (CAV), a form of accelerated atherosclerosis. Retransplantation (RTx) has been the management of CAV; however, there is limited comprehensive literature on this subject. Here we report 25 years of single-center experience in managing CAV with RTx and place it in the context of recent studies. MethodsA retrospective cohort study was undertaken on patients who underwent PTx <18 years old and subsequent RTx due to CAV at the Heart Institute (InCor) University of São Paulo Medical School between 1992 and 2018. The maintenance immunosuppression protocol was double immunosuppression. For both PTx and RTx, quantitative and qualitative analyses were conducted for transplantation indication, donor/recipient demographics, post-transplant survival, rejection, infection, and immunosuppression. ResultsBetween 1992 and 2018, 200 children underwent heart transplantation. Ten re-transplantations were performed, for which 7 (70%) were for CAV. Ages at RTx ranged from 11.5 to 29.3 years (19.1 ± 5.68 years; median 18.2 years). The mean time between PTx and RTx was 12.9 ± 3.4 years (median 13.4 years). The Kaplan-Meier survival rate at 1 month, 3 years, and 5 years was 85.7%, 71.5%, and 47.6%, respectively. ConclusionCardiac RTx can be a management option for CAV in patients who have undergone PTx in childhood with double immunosuppression therapy.

Changes in Pediatric Heart Transplant Hospitalization Costs Over Time.

Despite significant changes in the past decade for children undergoing heart transplantation, including the evolution of mechanical circulatory support and increasing patient complexity, costs and resource utilization have not been reassessed. We sought to use a novel linkage of clinical-registry and administrative data to examine changes in hospitalization costs over time in this population. We identified all pediatric heart transplant recipients in a unique linked Pediatric Health Information System/Scientific Registry of Transplant Recipients data set (2002-2016). Hospital costs were estimated from charges using cost-to-charge ratios, inflated to 2016 dollars. Severity-adjusted costs were calculated using generalized linear mixed-effects models. Costs were compared across 3 eras (era 1, 2002-2006; era 2, 2007-2011; and era 3, 2012-2016). A total of 2896 pediatric heart transplant recipients were included: era 1, 649 (22.4%); era 2, 1028 (35.5%); and era 3, 1219 (42.1%). Extracorporeal membrane oxygenation support at transplant decreased over time, concurrent with an increase in ventricular assist device-supported patients. Between era 1 and era 2, there was an increase in pretransplant hospitalization costs (US $343 692 vs US $435 554; P < 0.001). However, between era 2 and era 3, there was a decline in total (US $906 454 vs US $767 221; P < 0.001), pretransplant (US $435 554 vs US $353 364; P < 0.001), and posttransplant (US $586 133 vs US $508 719; P = 0.002) hospitalization costs. Concurrent with the increase in utilization of ventricular assist device support, there has been an increase in pretransplant costs associated with pediatric heart transplantation. However, in the most recent era, costs have declined. These findings suggest the evolution of more cost-effective management strategies, which may be related to shifts in the approach to pediatric mechanical circulatory support.

Post-transplant lymphoproliferative disease is associated with early sternotomy and left ventricular hypoplasia during infancy: a population-based retrospective review.

Heart transplantation has been an option for children in Sweden since 1989. As our unit faced an increased rate of post-transplant lymphoproliferative disorder, the objective of the study was to identify possible risk factors. This is a retrospective study of all children aged 0-18 years who underwent heart transplantation in Gothenburg from 1989 to 2014. A total of 71 children underwent heart transplantation. The overall incidence of post-transplant lymphoproliferative disorder was 14% (10/71); however, 17% (6/36) of those undergoing transplantation after 2007 developed lymphoma, compared with only 10% (4/35) of transplantation cases before 2007 (p=0.85). The mean age at transplantation was 9 years (0-17). The mean post-transplant follow-up time was 5.5 years (0.5-21.9) in the group that developed post-transplant lymphoproliferative disorder, compared with 10.2 years (0.02-25.2) in those who did not. In our study group, risk factors for post-transplant lymphoproliferative disorder were surgically palliated CHD (p=0.0005), sternotomy during infancy (p⩽0.0001), hypoplastic left ventricle (p=0.0001), number of surgical events (p=0.0022), mismatch concerning Epstein-Barr virus infection - that is, a positive donor-negative recipient (p⩽0.0001) - and immunosuppressive treatment with tacrolimus compared with ciclosporine (p=0.028). Discussion This study has three major findings. First, post-transplant lymphoproliferative disorder only developed in subjects born with CHD. Second, the vast majority (9/10) of the subjects developing the disorder had undergone sternotomy as infants. Third, the number of surgical events correlated with a higher risk for developing post-transplant lymphoproliferative disorder.

Era effect on survival following paediatric heart transplantation.

Paediatric heart transplantation is performed to salvage children with end-stage heart failure from various underlying pathologies. Despite several developments in all management aspects of transplantation candidates, the effect of those advances on outcomes has not been consistent. We report our institutional experience with focus on examining era effect on early and late survival. Between 1988 and 2015, 320 children underwent heart transplantation. Competing risk analysis modelled events after transplantation (retransplantation, death without retransplantation). Multivariable parametric risk hazard analysis examined the risk factors affecting survival. Patients were divided to three groups based on underlying pathology: congenital group (n = 132, 41%), acquired group (n = 153, 48%) and retransplant group (n = 35, 11%). Competing risk analysis showed that at 10 years following transplantation, 11% of patients had undergone retransplantation, 39% had died without retransplantation and 44% were alive without retransplantation. Ten-year survival was 61, 51 and 45% for acquired, congenital and retransplant groups, respectively. Overall, survival following heart transplantation for the late era (2005-15) was 63% compared with 49% for the early era (1988-2004) at 10 years (P = 0.022). Compared with early era, 1-year survival in the late era was 84 vs 79% {odds ratio (OR): 0.72 [95% confidence interval (CI) 0.3-1.8], P = 0.470} for congenital, 98 vs 86% [OR: 0.14 (95% CI 0.03-0.68), P = 0.006] for acquired and 73 vs 88% [OR: 2.6 (95% CI 0.4-1.9), P = 0.282] for retransplant. The effect of late era on survival was not significant for congenital [hazard ratio (HR) 0.6 (95% CI 0.2-1.4), P = 0.206] or retransplant patients [HR: 1.7 (95% CI 0.5-5.5), P = 0.400], but showed improvement trend for acquired patients [HR: 0.53 (95% CI 0.3-1.0), P = 0.052]. The era effect on early survival following heart transplantation is related to underlying pathology; there is a significant improvement in early survival in children with acquired pathology, whereas there is no significant change in early survival in children with congenital pathology or failed prior transplantation. This suggests a potential area for improvement that might include pretransplant stabilization and management of immunosuppression. On the other hand, era effect on late survival is not significant. This demonstrates that advances in the care of paediatric heart transplantation patients have not affected ongoing problems that diminish late survival.

Recovery From Acute Kidney Injury and CKD Following Heart Transplantation in Children, Adolescents, and Young Adults: A Retrospective Cohort Study.

Acute kidney injury (AKI) is common in children following surgery for congenital heart disease and has been associated with poor long-term kidney outcomes. Children undergoing heart transplantation may be at increased risk for the development of both AKI and chronic kidney disease (CKD). This study examines AKI rates in children, adolescents, and young adults after heart transplantation and analyzes the relationship between AKI and CKD in this population. Retrospective cohort study. 88 young patients who underwent heart transplantation at Lucile Packard Children'sHospital, Stanford, CA, September 1, 2007, to November 30,2013. The primary independent variable was AKI within the first 7 postoperative days, ascertained according to the KDIGO (Kidney Disease: Improving Global Outcomes) creatinine criteria (increase in serum creatinine≥ 1.5 times baseline within 7 days). Recovery from AKI at 3 months, ascertained as serum creatinine level< 1.5 times baseline; and development of CKD at 6 and 12 months, ascertained as estimated glomerular filtration rate< 60mL/min/1.73m(2) for more than 3 months. 63 (72%) patients developed AKI; 57% had moderate (stage 2 or severe stage 3) disease. Recoveryoccurred in 39 of 63 (62%), 50% for stage 2 or 3 versus 78% for stage 1 (P=0.04). At 6 and 12 months, 3 of 82 (4%) and 4 of 76 (5%) developed CKD, respectively. At both time points, CKD was more common in those without recovery (3/22 [14%] vs 0/38 (0%); P=0.04, and 3/17 (18%) vs (0/34) 0%; P=0.03, respectively). Retrospective design, small sample size, and single-center nature of the study. AKI is common after heart transplantation in children, adolescents, and young adults. Nonrecovery from AKI is more common in patients with more severe AKI and is associated with the development of CKD during the first year.

Heart Transplantation in Children after a Fontan Procedure: Better than People Think.

Previous studies have reported that children with a prior Fontan procedure have decreased survival after heart transplantation. We examined 273 primary pediatric heart transplants. Since 1988, 33 (12.1%) of 273 children <18 years old undergoing primary heart transplantation had a Fontan procedure 3.7 ± 4.3 years before transplantation. Compared with 240 (87.9%) non-Fontan primary transplants, the Fontan patients were older (8.8 ± 5.2 vs 6.6 ± 5.9 years; P = .023), but were similar in presensitization and pre-transplant clinical status. More Fontan patients had prior operations (100% vs 51.7%; P < .0001) and needed pulmonary artery reconstruction (100% vs 21.7%; P < .0001). Thirteen (39%) had protein-losing enteropathy. Donor ischemic times (213 ± 73 vs 177 ± 57 minutes; P = .0013) and cardiopulmonary bypass times (199 ± 86 vs 125 ± 53 minutes; P < .0001) were greater in the Fontan group, as were durations of ventilator support (4.4 ± 6.0 vs 2.5 ± 4.3 days; P = .035) and hospital stay (18.6 ± 16.1 vs 14.7 ± 13.1 days; P = NS). The Fontan group had one 30-day mortality. One-year actuarial survival (84.8% vs 86.9%, Fontan vs non-Fontan) and 5-year actuarial survival (70.8% vs 70.3%, Fontan vs non-Fontan) were similar, as was rejection incidence at 1 year (2.0 ± 2.0 vs 1.7 ± 1.9 episodes/patient; P = .3972). Five Fontan patients (18.5%) required retransplantation 4.9 ± 3.6 years post-transplant, compared with 22 non-Fontan patients (9.2%) retransplanted 5.2 ± 3.4 years post-transplant. Contrary to prior reports, we did not identify any early or mid-term disadvantage for children undergoing heart transplantation after a previous Fontan procedure, despite more complex transplant operations. We contend that carefully selected children with a failing Fontan circulation can do as well as other children with heart transplantation.

Pediatric End-Stage Failing Hearts Demonstrate Increased Cardiac Stem Cells

We sought to determine the location, expression, and characterization of cardiac stem cells (CSCs) in children with end-stage heart failure (ESHF). We hypothesized ESHF myocardium would contain an increased number of CSCs relative to age-matched healthy myocardium, and ESHF-derived CSCs would have diminished functional capacity as evidenced by reduced telomere length. Tissue samples were obtained from the explanted hearts of children undergoing heart transplantation with ESHF, defined as New York Heart Association class III or IV and ejection fraction less than 0.20, and from age-matched congenital heart disease patients with normal myocardium. The expression profile of cardiac-specific stem cell markers was determined using quantitative real time polymerase chain reaction and immunofluorescence. Cardiac stem cell growth reserve was assessed with telomere length. There were 15 ESHF and 15 age-matched congenital heart disease patients. End-stage heart failure myocardium demonstrated increased expression of c-kit(+) and islet-1(+) CSCs by 2.0- and 2.5-fold, respectively, compared with myocardium from congenital heart disease patients. There was no difference in expression of c-kit(+) CSCs with advancing age from infants to children in ESHF myocardium. The c-kit(+) CSCs isolated from ESHF patients demonstrated significantly reduced telomere length, suggesting a diminished functional capability in these cells (8.1 ± 0.6 kbp versus 6.3 ± 0.3 kbp; p=0.015). End-stage heart failure myocardium demonstrated an age-independent increase in CSCs relative to healthy myocardium; however, these CSCs from ESHF patients may have diminished proliferative ability and reduced functionality as an autologous cell therapy candidate. Further investigation is necessary to determine the role of ESHF-derived CSCs within the myocardium.

Surgical strategies to facilitate heart transplantation in children after failed univentricular palliations: the role of advanced intraoperative surgical preparation

Heart transplantation in children after univentricular palliation is a technical challenge. As the national referral centre for heart transplantation in children, we review national trends in transplantation and describe technical innovations used in the current era. Children undergoing heart transplantation were separated into patients with (i) structural congenital heart disease (sCHD; subdivided into univentricular and biventricular) and (ii) cardiomyopathy (CM). The operation notes and surgeons' diagrams were reviewed with particular attention to surgical innovations introduced after 2000. Between January 1988 and December 2012, 111 primary transplantations were performed: 50 for sCHD (30 univentricular and 20 biventricular) and 61 for CM. Thirty-day mortality for univentricular patients compared to those with CM was significantly higher before 2000 (21 vs 0%, 3/14 vs 0/20, P = 0.023) and not different after 2000 (8 vs 6%, 3/38 vs 1/16, P = 0.852). At the same time, the percentage of patients with univentricular physiology increased from 47% (14 of 30 patients) to 80% (16 of 20 patients) versus those with biventricular physiology. After 2000, 12 of 16 patients (75%) with univentricular sCHD required reconstruction of the great vessels. Of these, 8 (50%) patients had reached the stage of Fontan, 5 had reached bidirectional cavopulmonary shunt, 2 had reached Kawashima procedure and 1 had only a Blalock-Taussig shunt. The following techniques were employed in 12 transplantations: aortic arch replacement (n = 3), hilum-to-hilum pulmonary artery (PA) reconstruction (n = 5), PA patch reconstruction (n = 5), reconstruction of the PA bifurcation using donor bifurcation (n = 2) and left superior vena cava (SVC) to donor SVC reconstruction (n = 3). In the current era, the majority of children undergoing heart transplantation for sCHD have had univentricular palliation. These patients pose challenges because of prior surgeries and complex anatomy, but the techniques described here in may enable improved outcome.

Pediatric ventricular assist device use as a bridge to transplantation does not affect long-term quality of life

The present study sought to determine the long-term quality of life (QOL) of children who required long-term ventricular assist device (VAD) support as a bridge to transplantation (BTT) compared with children who underwent heart transplantation without VAD support. Currently, 20% of children undergoing heart transplantation have required a VAD as a BTT. Few data have been published assessing how children requiring a VAD as a BTT will fair in terms of their long-term QOL. The present study used a cross-sectional design, using the Core and Cardiac modules of the Pediatric Quality of Life Inventory survey. In a secondary analysis, the factors associated with worse QOL outcomes among the VAD patients were also investigated. At follow-up (median, 4.2 years), between the 21 children who required a VAD as a BTT and 42 who went straight to transplantation, no significant differences were found in the QOL as measured using the Psychosocial Health Summary Score, Physical Health Summary Score, or Total Score in the survey's Core Module, nor were any differences found in the outcomes assessed using the survey's Cardiac Module. Of the patients who required a VAD, only the presence of a neurologic complication was associated with worse QOL, which was demonstrated by decreased Physical Health Summary and Cardiac Communication scores. Over the long term, surviving children who required a long-term VAD as a BTT experience a similar QOL as those who went straight to transplantation.