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Aims: This review aims to evaluate prospective controlled trials of primary prevention of anthracycline cardiotoxicity in paediatric cancer patients. Methods and Results: Prospective controlled trials in which any cardioprotective agent was compared to no additional therapy or placebo in paediatric cancer patients receiving anthracyclines (PROSPERO: CRD42022367791). Outcomes were assessed using random and fixed-effects meta-analysis models as well as a synthesis without meta-analysis approach. A total of 24 reports of 19 trials were included in our review, 11 trials administered dexrazoxane, two trials administered the angiotensin converting enzyme inhibitor enalapril, one trial administered the beta-blocker carvedilol, one omega-3 fatty acids, one coenzyme Q10, one amifostine, one silymarin and one black seed oil. A total of 1333 paediatric patients receiving anthracyclines were included in meta-analysis of the cardio-protective effect of dexrazoxane in reducing the risk of developing significant systolic dysfunction. A risk ratio of 0.44 (95% CI: 0.33 to 0.61; I2 = 0%) was found, showing that the administration of dexrazoxane was highly effective. Overall, enalapril, carvedilol and dexrazoxane resulted in less left ventricular dysfunction and fewer cardiac biomarker abnormalities compared to placebo. Omega-3 fatty acids, silymarin and black seed oil each demonstrated benefit through less reduction of systolic function and fewer cardiac biomarker abnormalities. Conclusion: Enalapril and dexrazoxane are highly effective in preventing the anthracycline-induced cardiotoxicity in paediatric cancer patients with a highly acceptable safety profile. More randomised-controlled trials are required to reach a conclusion on the efficacy of omega-3 fatty acids, co-enzyme Q10 and amifostine.

The 3D chromatin architecture establishes a complex network of genes and regulatory elements necessary for transcriptomic regulation in development and disease. This network can be modeled by cis-regulatory hubs (CRH) which underscore the local functional interactions between enhancers and promoter regions and differ from other higher order chromatin structures such as topological associated domains (TAD). The Activity-by-contact (ABC) model of enhancer-promoter regulation has been recently used in the identification of these CRHs, but little is known about the role of CTCF on the ABC scores and the consequent impact on CRHs. Here we show that the loss of CTCF leads to a reorganization of the enhancer-promoter interactions resulting in a re-distribution of ABC scores of the putative enhancers in C57/bl6 mouse hearts. The loss of CTCF also leads to a global reduction of the total number of CRHs, and an increase in the size of the CRHs due to increase in the number of elements within each hub. In addition, CTCF loss led to more CRHs that cross TAD boundaries. These results provide another layer of evidence to support the importance of CTCF in the formation of regulatory networks necessary for gene regulation.

Background: Variable penetrance and late-onset phenotypes are key challenges for classifying causal as well as incidental findings in inherited cardiac conditions. Allele frequencies of variants in ancestry-specific populations, along with clinical variant analysis and interpretation, are critical to determine their true significance. Methods: Here, we carefully reviewed and classified variants in genes associated with inherited cardiac conditions based on a population whole-genome sequencing cohort of 4810 Singaporeans representing Southeast Asian ancestries. Results: Eighty-nine (1.85%) individuals carried either pathogenic or likely pathogenic variants across 25 genes. Forty-six (51.7%) had variants in causal genes for familial hyperlipidemia, but there were also recurrent variants in SCN5A and MYBPC3 , causal genes for inherited arrhythmia and cardiomyopathy, which, despite previous reports, we determined to lack criteria for pathogenicity. Conclusions: Our findings highlight the incidence of disease-related variants in inherited cardiac conditions and emphasize the value of large-scale sequencing in specific ancestries. Follow-up detailed phenotyping and analysis of pedigrees are crucial because assigning pathogenicity will significantly affect clinical management for individuals and their family members.

Doxorubicin is an anthracycline widely used for the treatment of various cancers; however, the drug has a common deleterious side effect, namely a dose-dependent cardiotoxicity. Doxorubicin treatment increases the generation of reactive oxygen species, which leads to oxidative stress in the cardiac cells and ultimately DNA damage and cell death. The most common DNA lesion produced by oxidative stress is 7,8-dihydro-8-oxoguanine (8-oxoguanine), and the enzyme responsible for its repair is the 8-oxoguanine DNA glycosylase (OGG1), a base excision repair enzyme. Here, we show that the OGG1 deficiency has no major effect on cardiac function at baseline or with pressure overload; however, we found an exacerbation of cardiac dysfunction as well as a higher mortality in Ogg1 knockout mice treated with doxorubicin. Our transcriptomic analysis also showed a more extensive dysregulation of genes in the hearts of Ogg1 knockout mice with an enrichment of genes involved in inflammation. These results demonstrate that OGG1 attenuates doxorubicin-induced cardiotoxicity and thus plays a role in modulating drug-induced cardiomyopathy.

Birth defects contribute to ∼0.3% of global infant mortality in the first month of life, and congenital heart disease (CHD) is the most common birth defect among newborns worldwide. Despite the significant impact on human health, most treatments available for this heterogenous group of disorders are palliative at best. For this reason, the complex process of cardiogenesis, governed by multiple interlinked and dose-dependent pathways, is well investigated. Tissue, animal and, more recently, computerized models of the developing heart have facilitated important discoveries that are helping us to understand the genetic, epigenetic and mechanobiological contributors to CHD aetiology. In this Review, we discuss the strengths and limitations of different models of normal and abnormal cardiogenesis, ranging from single-cell systems and 3D cardiac organoids, to small and large animals and organ-level computational models. These investigative tools have revealed a diversity of pathogenic mechanisms that contribute to CHD, including genetic pathways, epigenetic regulators and shear wall stresses, paving the way for new strategies for screening and non-surgical treatment of CHD. As we discuss in this Review, one of the most-valuable advances in recent years has been the creation of highly personalized platforms with which to study individual diseases in clinically relevant settings.

Tetralogy of Fallot (TOF) is a congenital heart anomaly that causes a drastic reduction in the oxygen level. In this study, we coupled a lumped-parameter model with a patient-specific three-dimensional (3D) model which included a modified Blalock-Taussig (MBT) shunt. By forming a closed loop, we investigated the effects of certain parameters on the flow rates and the pressures at different locations of the developed network. A local sensitivity analysis on an initial zero-dimensional (0D) closed-loop model was conducted. The 0D lumped parameter (LP) model was then refined based on the results of the multiscale 0D-3D model and the local sensitivity analysis was repeated for the refined 0D model. It was shown that the maximum pressure of the pulmonary bed had the highest sensitivity of 94% to the diameter of MBT shunt. We observed that the existence of the flow in the shunt during the diastole caused an elevated wall shear stress (WSS) in the pulmonary artery. In this work, we calculated the flow velocity and pressure field in a 3D patient-specific aorta with an MBT shunt, and then we used the results to increase the accuracy of our LP model to simulate numerous 0D simulations in a significantly shorter time, which is potentially applicable for medical decision-making.

Background: Anthracyclines are widely used to treat childhood cancers; however, they cause cardiotoxicity. To address the paucity of clinical data from Asian populations, this study investigated the epidemiology of pediatric anthracycline-induced cardiotoxicity, during and after chemotherapy, in a multiethnic Asian population.Procedure: This was a single-center, retrospective analysis of 458 anthracycline-treated pediatric oncology patients at KK Women's and Children's Hospital, a tertiary children's hospital in Singapore from 2005 through 2015. We investigated cardiotoxicity (defined as left ventricular fractional shortening Results: Over a follow-up period of almost 4 years, we found that 7% (32/458) of the cohort developed cardiotoxicity, with 37.5% (12/32) of these manifesting as clinical heart failure, whilst the rest were asymptomatic. The cardiotoxic cohort demonstrated a significantly higher mortality rate compared to the non-cardiotoxic group at 46.9 vs. 19.2% (p < 0.001), of whom 3 (9.4%) died from end-stage heart failure. We found that traditional predictors such as female sex, age at diagnosis, and cumulative doxorubicin equivalent dose were not predictors of cardiotoxicity.Conclusion: Our study reaffirms that freedom from symptoms does not ensure normal heart function and suggests that children with abnormal ventricular systolic function have higher mortality risk compared to those with normal systolic function. The findings contribute to improved understanding of the Asian burden to aid development of measures to prevent or reduce the risk of cardiotoxicity.

Background Anthracycline cardiotoxicity can cause significant long-term morbidity in childhood cancer survivors (CCS), but many CCS do not manifest clinical symptoms until adulthood. The aims of this study were to characterize the dynamic myocardial response to exercise of CCS at long-term follow-up by combining semisupine bicycle exercise stress echocardiography with myocardial imaging techniques and to establish whether semisupine bicycle exercise stress echocardiography could identify CCS with abnormal exercise response. Methods This was a single-center prospective cross-sectional study. One hundred CCS and 51 control subjects underwent semisupine bicycle exercise stress echocardiography. Color Doppler tissue imaging peak systolic (s′) and diastolic (e′) velocities, myocardial acceleration during isovolumic contraction, and longitudinal strain were measured at rest and at incremental heart rates in the left ventricular (LV) lateral wall, basal septum, and right ventricle. The relationship with increasing heart rate was evaluated for each parameter by plotting the values against heart rate at each stage of exercise. Kernel density estimate was used to establish the normality of the individual CCS exercise responses. Results At rest, no significant differences were found for LV lateral wall, right ventricular (RV), and basal septal systolic and diastolic velocities between CCS and control subjects. Only septal e′ was lower in CCS. LV longitudinal strain was similar between groups, while RV longitudinal strain was lower in CCS. At peak exercise, LV lateral wall, RV, and septal s′ were not different between groups, while e′ were significantly lower in CCS. LV lateral wall and septal isovolumic acceleration were also reduced in CCS. LV longitudinal strain was different between groups, while RV longitudinal strain was similar. The dynamic response of Doppler tissue imaging velocities, isovolumic acceleration, and strain was similar between CCS and control subjects. Kernel density estimate analysis confirmed that most CCS responses were within the normal range. Conclusions At 10-year follow-up, anthracycline-treated CCS with normal baseline ejection fractions have LV and RV systolic and diastolic myocardial exercise response comparable with that of control subjects. Minor differences were observed between CCS and control subjects at rest and at peak exercise, but the dynamic response is within the normal range.

Anthracycline-induced cardiotoxicity (AC) is a major cause of morbidity in childhood cancer survivors. Doxorubicin cardiotoxicity however, is consistently observed to develop chronically over time. We sought to develop a mouse model of pediatric AC to test our hypothesis for an epigenetic mechanism, which may be operating to explain delayed-onset AC. Three week-old male and female C57Bl/6J mice were administered 5 weekly injections with doxorubicin (1mg/kg) (n=24) or saline (n=8). The dosage used was intended to closely mimic the clinical scenario. Half of the doxorubicin-treated (DOX) mice (n=12) and all controls (n=8) were sacrificed 1 week after the last injection; the rest of DOX mice (n=12) were given 4 weeks of drug-free holiday before sacrifice. Echocardiographic measurements were obtained before the first injection, 1 week after the final injection, and before sacrifice. Gene expression profiles were assessed by RNA-sequencing, reduced representation bisulphite sequencing (RRBS), and by ATAC-seq. These analyses were performed on purified pools of isolated cardiac myocytes, procured using a published Langendorff-free method. There was no death in the cohort. LV chamber dimension and wall thickness as well as fractional shortening did not differ between DOX and controls, implying the lack of obvious functional insufficiency from this dose. Similarly, DOX mice did not differ in body weight, heart weights (HW), and HW-to-tibia length ratios compared with controls. Cardiomyocyte dimensions and myocardial interstitial fibrosis were the same between groups. Despite the lack of echo and histological changes in DOX mice, RNA-seq analysis revealed profound and significant differentially expressed genes between the DOX mice and controls. Importantly, a significant proportion of downregulated and upregulated genes persisted, despite the period of drug-free holiday. Moreover, despite being taken off DOX, cardiomyocytes appeared to display new gene expression changes taking place even 4 weeks after stopping DOX. Detailed results of RNA-sequencing, RRBS and ATAC-Seq will be presented during the meeting. These results suggest that cardiomyocytes display DOX-related epigenetic alterations, which may implicate the basis for delayed-onset AC.

Congenital heart disease (CHD) is the most common birth defect among newborns worldwide and contributes to significant infant morbidity and mortality. Owing to major advances in medical and surgical management, as well as improved prenatal diagnosis, the outcomes for these children with CHD have improved tremendously so much so that there are now more adults living with CHD than children. Advances in genomic technologies have discovered the genetic causes of a significant fraction of CHD, while at the same time pointing to remarkable complexity in CHD genetics. For this reason, the complex process of cardiogenesis, which is governed by multiple interlinked and dose-dependent pathways, is a well investigated process. In addition to the sequence of the genome, the contribution of epigenetics to cardiogenesis is increasingly recognized. Significant progress has been made dissecting the epigenome of the heart and identified associations with cardiovascular diseases. The role of epigenetic regulation in cardiac development/cardiogenesis, using tissue and animal models, has been well reviewed. Here, we curate the current literature based on studies in humans, which have revealed associated and/or causative epigenetic factors implicated in CHD. We sought to summarize the current knowledge on the functional role of epigenetics in cardiogenesis as well as in distinct CHDs, with an aim to provide scientists and clinicians an overview of the abnormal cardiogenic pathways affected by epigenetic mechanisms, for a better understanding of their impact on the developing fetal heart, particularly for readers interested in CHD research.

Intramyocardial hematoma is a rare condition and is an incomplete form of myocardial rupture, which may occur after myocardial infarction, cardiac surgery, trauma, percutaneous coronary intervention, or spontaneously. We describe a case of a 16-year-old girl with intramyocardial hematoma mimicking an intracavitary thrombus following repair of Ebstein anomaly. The intramyocardial hematoma was incorrectly diagnosed on echocardiography as a right ventricular thrombus, and the true nature of the lesion was only realized during repeat surgical intervention for severe tricuspid regurgitation. The hematoma was managed conservatively and spontaneously resolved.

Background Endovascular stenting has emerged as a treatment option for children with coarctation of the aortic (CoA), but the impact on left ventricular (LV) function has been poorly documented. The aim of this study was to characterize the LV myocardial and hemodynamic response to exercise in young patients who underwent endovascular stenting for CoA during childhood using semisupine bicycle exercise stress echocardiography. Methods This was a single-center prospective cross-sectional study including 30 patients with CoA and 30 age- and gender-matched control subjects who underwent semisupine bicycle exercise stress echocardiography. Color Doppler tissue imaging peak systolic (s′) and early diastolic (e′) velocities in the LV lateral wall and basal septum, LV myocardial acceleration during isovolumic acceleration were measured at rest and with incremental heart rate (HR). The relationship with increasing HR was evaluated for each parameter by plotting the values at each stage of exercise versus HR. Results At rest, HR was similar between the two groups. LV ejection fraction and fractional shortening were within the normal range in the CoA group. LV lateral wall and basal septal s′ and e′ velocities did not differ between the two groups, but isovolumic acceleration values were significantly lower in the CoA group. At peak exercise, HR was similar between the groups, but all Doppler tissue imaging parameters were lower in patients than in control subjects. When assessing the increase of each parameter versus HR, the increase in slope was significantly lower in patients than in control subjects for LV lateral wall Doppler tissue imaging s′ and e′ velocities, and septal e′ velocity, but not for septal s′. The relationship of isovolumic acceleration with HR was significantly reduced in the CoA group. Conclusion The results of this study demonstrate reduced systolic and diastolic myocardial reserve in patients with CoA compared with control subjects. An abnormal myocardial contractile response to exercise was also found, as shown by an abnormal LV force-frequency relationship in patients with stented CoA. The prognostic clinical implications require further study.

Background Pediatric dilated cardiomyopathy (DCM) is associated with death or transplantation and is typically considered a homogeneous process affecting global left ventricular (LV) function. However, assessment of regional abnormalities that contribute to pumping inefficiencies is lacking. The aim of this study was to define regional strain patterns of mechanical inefficiency in the broader context of LV discoordination (dysfunction and timing abnormalities) and to evaluate their associations with LV function and clinical outcomes. Methods Multiplanar apical LV echocardiographic images from patients with pediatric DCM ( n = 56) and control subjects ( n = 20) were analyzed by two-dimensional longitudinal speckle-tracking strain analysis to identify segmental strain patterns and global contraction groups. Clinical outcome (death or transplantation vs transplantation-free survival) and echocardiographic data were evaluated. Outcome groups were compared using the Fisher exact test, the χ 2 test, or analysis of variance (with P values ≤ .05 considered to indicate statistical significance). Results Of 56 patients with DCM, 29 (52%) progressed to death or transplantation. Five segmental strain patterns were observed that were used to define seven contraction groups by regional contractility and/or timing discoordination. The group(s) with the most discoordination had the most LV dysfunction ( P = .0004) and a trend toward the highest frequency of death or transplantation ( P = .069). Interreader reproducibility of segmental strain patterns agreed in 165 or 180 (92%) segments tested (κ = 0.90). Control subjects had normal strain patterns. Conclusions A heterogeneous mixture of abnormalities in the regional wall mechanics that lead to inefficient pump mechanics through functional and timing abnormalities were seen in this cohort and were categorized into natural subgroups. More severe LV discoordination was associated with increased LV dysfunction and a trend toward death or transplantation.

Studies have suggested the effect of blood flow forces in pathogenesis and progression of some congenital heart malformations. It is therefore of interest to study the fluid mechanic environment of the malformed prenatal heart, such as the tetralogy of Fallot (TOF), especially when little is known about fetal TOF. In this study, we performed patient-specific ultrasound-based flow simulations of three TOF and seven normal human fetal hearts. TOF right ventricles (RVs) had smaller end-diastolic volumes (EDVs) but similar stroke volumes (SVs), whereas TOF left ventricles (LVs) had similar EDVs but slightly increased SVs compared with normal ventricles. Simulations showed that TOF ventricles had elevated systolic intraventricular pressure gradient (IVPG) and required additional energy for ejection but IVPG elevations were considered to be mild relative to arterial pressure. TOF RVs and LVs had similar pressures because of equalization via ventricular septal defect (VSD). Furthermore, relative to normal, TOF RVs had increased diastolic wall shear stresses (WSS) but TOF LVs were not. This was caused by high tricuspid inflow that exceeded RV SV, leading to right-to-left shunting and chaotic flow with enhanced vorticity interaction with the wall to elevate WSS. Two of the three TOF RVs but none of the LVs had increased thickness. As pressure elevations were mild, we hypothesized that pressure and WSS elevation could play a role in the RV thickening, among other causative factors. Finally, the endocardium surrounding the VSD consistently experienced high WSS because of RV-to-LV flow shunt and high flow rate through the over-riding aorta. NEW & NOTEWORTHY Blood flow forces are thought to cause congenital heart malformations and influence disease progression. We performed novel investigations of intracardiac fluid mechanics of tetralogy of Fallot (TOF) human fetal hearts and found essential differences from normal hearts. The TOF right ventricle (RV) and left ventricle had similar and elevated pressure but only the TOF RV had elevated wall shear stress because of elevated tricuspid inflow, and this may contribute to the observed RV thickening. TOF hearts also expended more energy for ejection.

There is increasing evidence that de novo anti-HLA antibodies, more specifically de novo donor-specific antibodies (DSA) following solid organ transplantation may be associated with negative outcomes including rejection in the first year and graft loss. Limited data are available in pediatric heart transplant recipients. We sought to prospectively determine the incidence, class and early impact of de novo anti-HLA antibodies in a cohort of pediatric heart transplant recipients. Serial panel reactive antibody testing posttransplant was performed in 25 patients (14 males) transplanted between January 2008 and June 2010. Five patients were sensitized pretransplant; all patients had negative direct crossmatch. Seventy-two percent developed de novo anti-HLA antibodies at a median of 2.6 weeks (IQR 1.2 weeks to 6.2 months) posttransplant; 67% of these were DSA. The majority of recipients in our cohort developed de novo anti-HLA antibodies within the first year posttransplant, with two-thirds being donor-specific. Acute cellular rejection, though frequent, was not different in patients with antibody development regardless of class or specificity, and there was no antibody-mediated rejection, graft loss or early cardiac allograft vasculopathy.

Infants listed for heart transplantation experience high waitlist and early post-transplant mortality, and thus, optimal allocation of scarce donor organs is required. Unfortunately, the creation and validation of multivariable regression models to identify risk factors and generate individual-level predictions are challenging. We sought to explore the use of data mining methods to generate a prediction model. CART analysis was used to create a model which, at the time of listing, would predict which infants listed for heart transplantation would survive at least 3 months post-transplantation. A total of 48 infants were included; 13 died while waiting, and six died within 3 months of heart transplant. CART analysis identified RRT, blood urea nitrogen, and hematocrit as terminal nodes with alanine transaminase as an intermediate node predicting death. No patients listed on RRT (n = 10) survived and only three of 12 (25%) patients listed on ECLS survived >3 months post-transplant. CART analysis overall accuracy was 83%, with sensitivity of 95% and specificity 76%. This study shows that CART analysis can be used to generate accurate prediction models in small patient populations. Model validation will be necessary before incorporation into decision-making algorithms used to determine transplant candidacy.

Unlike adult patients, the utility of cardiopulmonary exercise testing (CPET) in children as a prognostic tool is unclear. We sought to examine the associations of CPET with outcomes in children with dilated cardiomyopathy (DCM).This was a single-center, retrospective review of children with DCM who underwent CPET. The primary endpoint for this study was a time-dependent composite outcome of hospitalization for management of decompensated heart failure, initiation of mechanical circulatory support, heart transplant, or death.We examined 52 children with DCM who underwent CPET at median age 12.6 years (interquartile range [IQR], 9.9-14.6 years). At first CPET, the median peak heart rate was 80% (IQR, 70-88%) of predicted, median peak oxygen consumption 62% (IQR, 45-77%) of predicted, and median minute ventilation/carbon dioxide production slope 34.9 (IQR, 27.9-39.4). Eighteen (35%) patients reached the composite outcome during follow-up. Univariable factors associated with the composite outcome included: lower peak heart rate predicted, lower blood pressure response, lower peak oxygen consumption predicted, and higher minute ventilation/carbon dioxide production slope. The association between exercise performance and composite outcome was linear; thus, no reliable cutoff point could be identified. Serial CPET had been performed in 30 patients; clinically, those with deterioration of exercise capacity had poorer outcomes.Cardiopulmonary exercise testing is feasible in children with DCM and is useful to predict outcomes. The finding of lower exercise capacity and lower blood pressure response should prompt closer follow-up. In those with serial testing, a decline in exercise capacity may be a marker of clinical deterioration.

Progressive heart failure leading to transplantation or death is common in pediatric dilated cardiomyopathy (DCM), and treatment options are limited. Select children with DCM have improved after cardiac resynchronization therapy (CRT), but predicting response is challenging. Nonetheless, considering the frequency of death or transplantation in this population, identifying any candidate would be valuable. Classic-pattern dyssynchrony (CPD) identifies mechanical dyssynchrony patterns consistent with underlying electrical activation delays and strongly predicts CRT response in adult DCM but has not been evaluated in pediatric DCM. The aim of this study was to test the hypothesis that CPD is present in a subgroup of patients with pediatric DCM and is associated with activation delays.Fifty-nine subjects with pediatric DCM (left ventricular end-diastolic diameter Z score2 and left ventricular ejection fraction40%) who underwent echocardiography with a functional protocol with apical images optimized for two-dimensional speckle-tracking strain analysis (EchoPAC) were retrospectively analyzed for CPD. Electrocardiograms were evaluated for activation delays (prolonged QRS duration and strict criteria for left bundle branch block [LBBB]). Forty control subjects with no cardiac disease and good imaging widows were also analyzed.The mean age was 5.4 years (range, 1 day to 20 years); idiopathic DCM was most common (57%). Severe cardiomyopathy was present in 75% (end-diastolic diameter Z score4.6 and left ventricular ejection fraction32%). CPD was identified in seven subjects (12%), and prolonged QRS durations were present in 13 (22%), but only two subjects met strict criteria for LBBB. Six of seven subjects in the CPD group had prolonged QRS durations, and two of seven had LBBB. No control subjects had CPD. The CPD analysis was highly feasible and reproducible.In this severely affected cohort, the small CPD subgroup is potentially important because their progressive disease may respond to CRT. CPD is associated with activation delays, although not necessarily strict LBBB. This has important potential implications for prospective evaluation of CRT in this disease.

Hepatoblastoma is a highly malignant embryonal liver tumor that occurs almost exclusively in infants and toddlers. Trisomy 18 is the second most common autosomal trisomy after trisomy 21 and is generally considered a lethal disorder. Ten cases of hepatoblastoma in children with trisomy 18 have been published to date. Here, we report on two female patients with trisomy 18 and pretreatment extent of disease (PRETEXT) stage 1 hepatoblastoma, which support the presence of a nonrandom association between hepatoblastoma and trisomy 18. Both patients underwent primary surgical resection without any neoadjuvant or adjuvant chemotherapy. The histologies returned as pure fetal epithelial type, and combined fetal and embryonal epithelial type. There was no evidence of recurrence on serial abdominal ultrasound and serum alpha-fetoprotein levels on follow-up. Conclusion: Primary surgical resection is a treatment approach that can be considered in children with trisomy 18 and PRETEXT stage 1 tumor. However, in view of the overall prognosis for trisomy 18, the decision on the optimal treatment is a delicate one and has to be individualized in the context of the best interests of the child.

Pediatric heart transplantation has now been established as standard of care for infants and children with end-stage heart disease. Initial experience with transplantation of the heart in children was met with high mortality owing primarily to the lack of effective immunosuppressive medications. However, interest in pediatric heart transplantation had its resurgence in the late 1970s and early 1980s with the discovery and introduction of cyclosporine-based immunosuppression regimens. Outcomes have consistently improved with improved selection of candidates and donors, enhanced preservation of the donor heart, refinements in surgical technique, the development of endomyocardial biopsy for surveillance of rejection, and the histopathologic standardization of rejection. The last 10 years have shown exponential growth in knowledge affecting the clinical course and outcomes of these patients, contributing to the length of patient survival and improved quality of life. Significant limitations still exist including the need for lifelong immunosuppressive medications and toxicities associated with these drugs, the development of post-transplant lymphoproliferative disease, and chronic rejection or allograft vasculopathy. In this review, we will summarize some of the many lessons learned over the last 10 years, highlight recent advances in our knowledge, and describe some of the key issues and future trends of pediatric heart transplantation.

Dilated cardiomyopathy (DCM) carries poor prognosis in children, often needing heart transplant. Regional differences in left ventricular (LV) function suggest inhomogeneous expression of contractility related proteins. However, associations between myocardial performance and histological / molecular findings are poorly defined. We sought to investigate associations of regional myocardial performance with histological and molecular changes in hearts explanted from children with DCM, undergoing transplantation. Clinical and echo features (including tissue Doppler and strain) were correlated with histological and molecular findings in hearts explanted from 9 children [median age 2.8 years (range 4.4 months-17 years); 6 had LVAD]. Interstitial fibrosis, myocyte volume, and expression of proteins (western blot) implicated in fibrosis and function ( p38 , ERK , phospho- JNK , phospho- GSK , SMA , myosin heavy chain, cadherin, ILK , sarcoplasmic reticulum Ca 2+ -ATPase [SERCA2a], phospho- CamKII , phospholamban [PLN], and phospho-PLN) were correlated with speckle tracking strain from 11 regions per patient (basal and mid regions of anterior septum, anterior, lateral, posterior and inferior LV segments, and right ventricular [RV] free wall). On average, no significant difference was noted for the percentage of fibrosis and myocyte volume between the various LV segments, and between RV and LV. LV dimension, systolic and diastolic function were not related to interstitial fibrosis, myocyte volume or molecular signaling. Tricuspid annular plane systolic excursion was related to myocyte volume (r=0.89; p p p =0.05). Global longitudinal strain was related to expression of ILK and SERCA2a (ILK, r=0.78, p =0.02; SERCA2a, r=0.71, p =0.04). This study demonstrated association of regional cardiac function in children with DCM with expression of calcium-cycling and contractile proteins, as well as interstitial fibrosis. These findings have implications for diagnosis and therapeutic targets in pediatric DCM.

BACKGROUND It is unclear whether the myocardium undergoes accelerated fibrotic remodeling in children after heart transplantation (HTx). METHODS In this prospective study, cardiac magnetic resonance (CMR) studies in 17 patients 1.3 years (median, range 0.03-12.6 years) after HTx (mean age, 9.8 ± 6.2 years; 8 girls) were compared to CMR studies in 9 healthy controls (mean age, 12.4 ± 2.4 years; 4 girls). T1 measurements were performed at a midventricular short axis slice before (ie, native T1 times) and after the application of 0.2 mmol/kg gadopentetate dimeglumine in the interventricular septum, left ventricular (LV) free wall and encompassing the entire LV myocardium. The tissue-blood partition coefficient (TBPC), reflecting the degree of diffuse myocardial fibrosis, was calculated as a function of the ratio of T1 change of myocardium compared to blood. Native T1 times and TBPC were correlated with echocardiographic parameters of diastolic function. RESULTS Native T1 times were significantly higher in HTx patients compared to controls in all regions assessed (LV free wall 973 ± 42 vs 923 ± 12 ms; P < 0.005; interventricular septum 1003 ± 31 vs 974 ± 21 ms, P < 0.05; entire LV myocardium 987 ± 33 vs 951 ± 16 ms; P < 0.005) and correlated with LV E/e' as an echocardiographic marker of diastolic dysfunction (r = 0.54, P < 0.05). The TBPC was elevated in the LV free wall (0.45 ± 0.06 vs 0.40 ± 0.03, P < 0.005) and the entire LV myocardium (0.47 ± 0.06 vs 0.43 ± 0.03, P < 0.05). CONCLUSIONS Evidence of diffuse myocardial fibrosis and is already present in children after HTx. It appears to be associated with diastolic dysfunction.

Introduction: There are limited data on myocardial systolic & diastolic response to exercise in pediatric cancer survivors treated with anthracycline. We used exercise echocardiography to evaluate ventricular systolic and diastolic reserve in these patients. Methods: 50 children (age 14.4±2.4 years) who had received anthracycline treatment with median dose 178mg/m 2 (range 60-450) underwent stepwise exercise echocardiography at 9.3±2.9 years after end of therapy, and compared with 50 normal controls. All subjects had normal resting LVEF. Peak systolic (s’) & early diastolic (e’) myocardial velocities in the LV & RV lateral wall, & basal septum were measured at rest & during exercise using color TDI. Measurements of myocardial isovolumic acceleration (IVA) at incremental heart rates (HR) were used to study force-frequency relationships (FFR). Results: At rest, LV systolic parameters were preserved in patients; septal e’ was significantly lower compared to controls (10.4±1.9cm/s vs 11.4±1.9cm/s; p =0.009). At peak exercise, LV & RV lateral wall, & basal septal e’ velocities were lower in patients (17.4±3.8cm/s vs 19.6±3.1cm/s, p =0.002; 21.5±1.6cm/s vs 22.3±1.9cm/s, p =0.02; & 16.3±2.4cm/s vs 18.7±2.7cm/s, p p p p =0.001]. During exercise, peak contractile force developed by patients was significantly lower (LV IVA 5.12±1.85m/s 2 vs 6.75±3.28m/s 2 ; p =0.004). FFR analysis showed reduced rate-contractility trajectory in patients [+0.202 (0.008) vs +0.217 (0.008) natural log m/s 2 per 10 bpm; p =0.001]. Conclusions: Long-term survivors of anthracycline-treated pediatric cancer have reduced systolic & diastolic myocardial reserve in response to exercise.

A case of traumatic haemopericardium, sustained after blunt thoracic trauma, is described in a paediatric patient that was successfully drained by needle pericardiocentesis under 2D-echocardiographic guidance, via an intercostal approach, in the Children's Intensive Care Unit. The patient was haemodynamically unstable with obvious signs of cardiac tamponade. Drainage of the haemopericardium resulted in immediate improvement in haemodynamics. There was no re-accumulation of the haemopericardium. There were no complications as a result of the pericardiocentesis. No further surgical intervention was required.

Purpose There is increasing evidence that the de novo development of anti-HLA antibodies (Abs) following solid organ transplantation may be associated with negative outcomes including rejection in the first year and graft loss; especially de novo donor-specific antibodies (DSAs). Little data is available in paediatric heart transplant (HTx) recipients. We sought to prospectively determine the incidence, class and early impact of de novo anti-HLA Abs in a cohort of pediatric HTx recipients. Methods and Materials Following informed consent, serial panel reactive antibody (PRA) testing post-HTx (weeks 1, 2, & 4, and months 6 & 12) was done in 25 patients (14 males) transplanted between Mar 2008 & Mar 2010. Development of DSAs was correlated with rejection, allograft vasculopathy (AV) and survival. Results Median age at HTx was 8 yrs (1.5 mos – 16.3 yrs) with mean follow-up time of 15 mos (1.5 – 31 mos). 4 patients were highly sensitized pre-HTx (cPRA > 10%); 2 to Class II and 2 to both Class I & II. 4 patients had a positive crossmatch (XM), 1 T cell, 3 B cell. 18 (72%) patients developed de novo anti-HLA Abs at a median of 6 wks (IQR: 10 days – 1.7 yrs) post-HTx: anti-Class I in 6 (33%), anti-Class II in 1 (6%), and Both in 11 (61%). De novo DSAs occurred in 12/25 (48%) at a median of 2 mos (IQR: 1 month – 1.6 years) post-HTx: anti-Class I in 5 (42%), anti-Class II in 5 (42%), and Both in 2 (16%). 14 (56%) patients had evidence of acute cellular rejection (ACR) ≥ ISHLT 2 R on biopsy; 6 with multiple episodes. A positive T cell crossmatch (p Conclusions The majority of pediatric HTx recipients develop de novo anti-HLA antibodies within the first 2 years post-HTx with half being donor-specific. Anti-Class I antibodies were associated with cellular rejection but not mortality. Further study is required to determine the long term impact on graft and patient survival.