The teammate trial: Study design and rationale tacrolimus and everolimus against tacrolimus and MMF in pediatric heart transplantation using the major adverse transplant event (MATE) score.

BACKGROUND: Currently there are no immunosuppression regimens FDA-approved to prevent rejection in pediatric heart transplantation (HT). In recent years, everolimus (EVL) has emerged as a potential alternative to standard tacrolimus (TAC) as the primary immunosuppressant to prevent rejection that may also reduce the risk of cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD) and cytomegalovirus (CMV) infection. However, the 2 regimens have never been compared head-to-head in a randomized trial. The study design and rationale are reviewed in light of the challenges inherent in rare disease research. METHODS: The TEAMMATE trial (IND 127980) is the first multicenter randomized clinical trial (RCT) in pediatric HT. The primary purpose is to evaluate the safety and efficacy of EVL and low-dose TAC (LD-TAC) compared to standard-dose TAC and mycophenolate mofetil (MMF). Children aged <21 years at HT were randomized (1:1 ratio) at 6 months post-HT to either regimen, and followed for 30 months. Children with recurrent rejection, multi-organ transplant recipients, and those with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 were excluded. The primary efficacy hypothesis is that, compared to TAC/MMF, EVL/LD-TAC is more effective in preventing 3 MATEs: acute cellular rejection (ACR), CKD and CAV. The primary safety hypothesis is that EVL/LD-TAC does not have a higher cumulative burden of 6 MATEs (antibody mediated rejection [AMR], infection, and post-transplant lymphoproliferative disorder [PTLD] in addition to the 3 above). The primary endpoint is the MATE score, a composite, ordinal surrogate endpoint reflecting the frequency and severity of MATEs that is validated against graft loss. The study had a target sample size of 210 patients across 25 sites and is powered to demonstrate superior efficacy of EVL/LD-TAC. Trial enrollment is complete and participant follow-up will be completed in 2023. CONCLUSION: The TEAMMATE trial is the first multicenter RCT in pediatric HT. It is anticipated that the study will provide important information about the safety and efficacy of everolimus vs tacrolimus-based regimens and will provide valuable lessons into the design and conduct of future trials in pediatric HT.

Multi-Disciplinary Management and Surgical Resection of Intracardiac Fibromas Causing Bilateral Ventricular Outflow Tract Obstructions in an Infant.

Cardiac tumors remain rare in children with benign pathologies predominating. Indications for surgical management often result from compromised ventricular chamber size, biventricular outflow tract obstruction, impaired ventricular function, or the presence of medically refractory dysrhythmias. We present a case of a six-month-old infant with two intracardiac fibromas originating in the interventricular septum. The fibromas were causing significant biventricular outflow obstruction. The patient successfully underwent tumor resection on cardiopulmonary bypass The literature on pediatric cardiac tumors is reviewed. Multi-disciplinary medical planning is necessary for successful anesthetic and surgical treatment of this high-risk patient population.

Mechanisms and Insights for the Development of Heart Failure Associated with Cancer Therapy.

Cardiotoxicity is a well-recognized late effect among childhood cancer survivors. With various pediatric cancers becoming increasingly curable, it is imperative to understand the disease burdens that survivors may face in the future. In order to prevent or mitigate cardiovascular complications, we must first understand the mechanistic underpinnings. This review will examine the underlying mechanisms of cardiotoxicity that arise from traditional antineoplastic chemotherapies, radiation therapy, hematopoietic stem cell transplantation, as well as newer cellular therapies and targeted cancer therapies. We will then propose areas for prevention, primarily drawing from the anthracycline-induced cardiotoxicity literature. Finally, we will explore the role of human induced pluripotent stem cell cardiomyocytes and genetics in advancing the field of cardio-oncology.

Neonatal heart transplant outcomes: A single institutional experience.

OBJECTIVE: Neonatal orthotopic heart transplantation was introduced in the 1980s as a treatment for complex congenital heart disease. Progress in single-ventricle palliation and biventricular correction has resulted in a decline in neonatal heart transplant volume. However, limited reports on neonatal heart transplants have demonstrated favorable outcomes. We report the long-term outcomes of patients with neonatal heart transplants at our institution spanning nearly 30 years. METHODS: A retrospective analysis of neonatal heart transplants and neonates listed for transplant was performed at Children's Hospital Colorado. Primary outcomes were early and late survival. Secondary outcomes were rejection episodes, retransplantation, and development of cardiac allograft vasculopathy or post-transplant lymphoproliferative disease. RESULTS: A total of 21 neonates underwent orthotopic heart transplantation at our institution. Among these, 10 neonates were transplanted from 1991 to 2000, 8 neonates were transplanted from 2001 to 2010, and 3 neonates were transplanted from 2011 to 2020. The average age of these patients was 17 days, and the average weight was 3.43 kg. Early survival was 95.2%. Survival at 1 and 5 years was 85.7% (confidence interval [CI], 61.9%-95.2%) and 75% (CI, 45.6%-85.5%), respectively. Of eligible patients, the 10-year and 20-year survival was 72.2% (CI, 45.1%-85.3%) and 50% (CI, 25.9%-70.1%), respectively. CONCLUSIONS: Our institution reports favorable outcomes of neonatal heart transplantation. These results should be considered within the context of outcomes for patients awaiting transplant and the limited donor availability. However, the successful nature of these procedures suggest it may be necessary to reevaluate the indications for neonatal heart transplantation, particularly where risk of mortality and morbidity with palliative or corrective surgery is high.

Amniotic fluid microRNA profiles in twin-twin transfusion syndrome with and without severe recipient cardiomyopathy.

BACKGROUND: Twin-twin transfusion syndrome presents many challenges for clinicians, and the optimal means of identifying pregnancies that will benefit most from intervention is controversial. There is currently no clinically available biomarker to detect twin-twin transfusion syndrome or to stratify cases based on the risk factors. microRNAs are small RNAs that regulate gene expression and are biomarkers for various disease processes, including adult and pediatric heart failure. To date, no studies have investigated amniotic fluid microRNAs as biomarkers for disease severity, specifically for severe recipient cardiomyopathy in twin-twin transfusion syndrome cases. OBJECTIVE: This study aimed to assess whether amniotic fluid microRNAs could be useful as biomarkers to identify pregnancies at greatest risk for severe recipient cardiomyopathy associated with twin-twin transfusion syndrome. STUDY DESIGN: Amniotic fluid was collected at the time of amnioreduction or selective fetoscopic laser photocoagulation from monochorionic diamniotic twin pregnancies with twin-twin transfusion syndrome at any stage. Fetal echocardiography was performed on all twins before the procedure, and severe cardiomyopathy was defined as a right ventricular myocardial performance index of the recipient fetus of >4 Z-scores. microRNA was extracted from the amniotic fluid samples and analyzed using an array panel assessing 379 microRNAs (TaqMan Open Array, ThermoFisher). Student t tests were performed to determine significant differences in microRNA expression between pregnancies with severe recipient cardiomyopathy and those with preserved cardiac function. A stringent q value of <.0025 was used to determine differential microRNA expression. Random forest plots identified the top 3 microRNAs that separated the 2 groups, and hierarchical cluster analysis was used to determine if these microRNAs properly segregated the samples according to their clinical groups. RESULTS: A total of 14 amniotic fluid samples from pregnancies with twin-twin transfusion syndrome with severe cardiomyopathy were compared with samples from 12 twin-twin transfusion syndrome control cases with preserved cardiac function. A total of 110 microRNAs were identified in the amniotic fluid samples. Twenty microRNAs were differentially expressed, and the top 3 differentiating microRNAs were hsa-miR-200c-3p, hsa-miR-17-5p, and hsa-miR-539-5p. Hierarchical cluster analysis based on these top 3 microRNAs showed a strong ability to differentiate severe cardiomyopathy cases from controls. The top 3 microRNAs were used to investigate the sensitivity and specificity of these microRNAs to differentiate between the 2 groups with a receiver operating characteristic curve demonstrating sensitivity and specificity of 80.8%. All 20 differentially expressed microRNAs were down-regulated in the group with severe cardiomyopathy. CONCLUSION: Amniotic fluid microRNAs demonstrated differential expression between twin-twin transfusion syndrome recipient fetuses with severe cardiomyopathy and those without and have the potential to be important biomarkers of disease severity in this population.

Serum response factor deletion 5 regulates phospholamban phosphorylation and calcium uptake.

AIMS: Pediatric dilated cardiomyopathy (pDCM) is characterized by unique age-dependent molecular mechanisms that include myocellular responses to therapy. We previously showed that pDCM, but not adult DCM patients respond to phosphodiesterase 3 inhibitors (PDE3i) by increasing levels of the second messenger cAMP and consequent phosphorylation of phospholamban (PLN). However, the molecular mechanisms involved in the differential pediatric and adult response to PDE3i are not clear. METHODS AND RESULTS: Quantification of serum response factor (SRF) isoforms from the left ventricle of explanted hearts showed that PDE3i treatment affects expression of SRF isoforms in pDCM hearts. An SRF isoform lacking exon 5 (SRFdel5) was highly expressed in the hearts of pediatric, but not adult DCM patients treated with PDE3i. To determine the functional consequence of expression of SRFdel5, we overexpressed full length SRF or SRFdel5 in cultured cardiomyocytes with and without adrenergic stimulation. Compared to a control adenovirus, expression of SRFdel5 increased phosphorylation of PLN, negatively affected expression of the phosphatase that promotes dephosphorylation of PLN (PP2Cε), and promoted faster calcium reuptake, whereas expression of full length SRF attenuated calcium reuptake through blunted phosphorylation of PLN. CONCLUSIONS: Taken together, these data indicate that expression of SRFdel5 in pDCM hearts in response to PDE3i contributes to improved function through regulating PLN phosphorylation and thereby calcium reuptake.

Circulating cyclic adenosine monophosphate concentrations in milrinone treated paediatric patients after congenital heart surgery.

BACKGROUND: Milrinone is a phosphodiesterase type 3 inhibitor that results in a positive inotropic effect in the heart through an increase in cyclic adenosine monophosphate. The purpose of this study was to evaluate circulating cyclic adenosine monophosphate and milrinone concentrations in milrinone treated paediatric patients undergoing congenital heart surgery. METHODS: Single-centre prospective observational pilot study from January 2015 to December 2017 including children aged birth to 18 years. Milrinone and circulating cyclic adenosine monophosphate concentrations were measured at four time points through the first post-operative day and compared between patients with and without low cardiac output syndrome, defined using clinical and laboratory criteria. RESULTS: Fifty patients were included. Nine (18%) developed low cardiac output syndrome. For all patients, 22% had single ventricle heart disease. The density and distribution of cyclic adenosine monophosphate concentrations varied between those with and without low cardiac output syndrome but were not significantly different. Milrinone concentrations increased in all patients. Paired t-tests demonstrated an increase in circulating cyclic adenosine monophosphate concentrations during the post-operative period among patients without low cardiac output syndrome. CONCLUSIONS: In this prospective observational study, circulating cyclic adenosine monophosphate concentrations increased in those without low cardiac output syndrome during the first 24 post-operative hours and milrinone concentrations increased in all patients. Further study of the utility of cyclic adenosine monophosphate concentrations in milrinone treated patients is necessary.

Elamipretide Improves Mitochondrial Function in the Failing Human Heart.

Negative alterations of mitochondria are known to occur in heart failure (HF). This study investigated the novel mitochondrial-targeted therapeutic agent elamipretide on mitochondrial and supercomplex function in failing human hearts ex vivo. Freshly explanted failing and nonfailing ventricular tissue from children and adults was treated with elamipretide. Mitochondrial oxygen flux, complex (C) I and CIV activities, and in-gel activity of supercomplex assembly were measured. Mitochondrial function was impaired in the failing human heart, and mitochondrial oxygen flux, CI and CIV activities, and supercomplex-associated CIV activity significantly improved in response to elamipretide treatment. Elamipretide significantly improved failing human mitochondrial function.

Elevated serum vascular endothelial growth factor and development of cardiac allograft vasculopathy in children.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a leading cause of retransplantation and death in pediatric heart transplant recipients. Our aim was to evaluate the association between serum vascular endothelial growth factor-A (VEGF) and CAV development in the pediatric heart transplant population. METHODS: In this retrospective study performed at a university hospital, VEGF concentrations were measured by enzyme-linked immunosorbent assay in banked serum from pediatric heart transplant recipients undergoing routine cardiac catheterization. In subjects with CAV (n = 29), samples were obtained at 2 time-points: before CAV diagnosis (pre-CAV) and at the time of initial CAV diagnosis (CAV). In subjects without CAV (no-CAV, n = 16), only 1 time-point was used. VEGF concentrations (n = 74) were assayed in duplicate. RESULTS: Serum VEGF is elevated in pediatric heart transplant recipients before catheter-based diagnosis of CAV (no-CAV mean: 144.0 ± 89.05 pg/ml; pre-CAV mean: 316.2 ± 118.3 pg/ml; p = 0.0002). Receiver-operating characteristic curve analysis of pre-CAV VEGF levels demonstrated an area under the curve of 87.7% (p = 0.0002), with a VEGF level of 226.3 pg/ml predicting CAV development with 77.8% sensitivity and 91.7% specificity. VEGF is similarly elevated in subjects with angiographically diagnosed CAV and in those with normal angiography but intravascular ultrasound (IVUS) evidence of CAV. CONCLUSIONS: The increase in serum VEGF before onset of detectable CAV is fundamental to its utility as a predictive biomarker and suggests further investigations of VEGF in the pathogenesis of CAV are warranted in the pediatric heart transplant population.

Improved Detection of Circulating miRNAs in Serum and Plasma Following Rapid Heat/Freeze Cycling.

BACKGROUND: The measurement of circulating miRNAs has proven to be a powerful biomarker tool for several disease processes. Current protocols for the detection of miRNAs usually involve an RNA extraction step, requiring a substantial volume of patient serum or plasma to obtain sufficient input material. OBJECTIVE: Here, we describe a novel methodology that allows detection of a large number of miRNAs from a small volume of serum or plasma without the need for RNA extraction. METHODS: Three µl of serum or plasma was subjected to three cycles of high and low temperatures (heat/freeze cycles) followed by miRNA arrays. RESULTS: Our results indicate that miRNA detection following this process is highly reproducible when comparing multiple samples from the same subject. Moreover, this protocol increases the reproducibility of miRNA detection in samples that were previously subjected to multiple freeze-thaw cycles. Importantly, the detection of miRNAs from serum vs. plasma following heat/freeze cycling are highly comparable, indicating that this heat/freeze process effectively eliminates differences in detection between serum and plasma samples that have been reported using other sample preparation methodologies. CONCLUSION: We propose that this method is a potent alternative to current RNA extraction protocols, substantially reducing the amount of sample necessary for miRNA detection while simultaneously improving miRNA detection and reproducibility.

Worsening in Longitudinal Strain and Strain Rate Anticipates Development of Pediatric Transplant Coronary Artery Vasculopathy as Soon as One Year Following Transplant.

Transplant coronary artery vasculopathy (TCAV) following orthotopic heart transplantation (OHT) continues to be the primary reason for late graft failure in children. The current gold standard of diagnosis of TCAV is coronary angiography with or without intravascular ultrasound. This study investigates the longitudinal use of speckle-tracking echocardiographic strain imaging as an early non-invasive marker to screen for development of TCAV. Echocardiograms from patients who underwent OHT between 2006 and 2010 at Children's Hospital Colorado (n = 50) were retrospectively assessed. Studies were evaluated at baseline (within a month of transplant), then at each annual clinical follow-up for peak longitudinal (LS) and circumferential (CS) strain, systolic strain rate, and diastolic strain rate using Siemens Velocity Vector Imaging software. Comparisons were made between subjects who did and did not develop TCAV. Mean time to TCAV diagnosis following OHT was 3.2 years (range 1-5.1 years). One year after transplant, significant differences were seen between groups in LS (non-TCAV mean -19.6%, TCAV mean -17.3%, p = 0.03) and longitudinal strain rate (non-TCAV mean -1.7%/s, TCAV mean -1.4%/s, p = 0.04). These differences persisted in subsequent years. Differences in LS preceded the catheterization-based diagnosis of TCAV in pediatric heart recipients and were noted as early as one year post transplant. Additionally, within-subject LS changes may have utility as a non-invasive screening tool to predict those patients at increased risk for development of TCAV.

Safety of mTOR inhibitor continuation in pediatric heart transplant recipients undergoing surgical procedures.

mTOR inhibitors have been associated with SWC when used in the perioperative period. Limited literature is available to guide providers in managing chronic mTOR inhibitor use in the perioperative period, especially in the pediatric setting. The primary aim of this study was to describe the prevalence of SWC with mTOR inhibitor continuation during the perioperative period for major surgeries. Heart transplant recipients ≤25 years old at the time of primary heart transplant receiving sirolimus maintenance therapy during a surgical procedure and within the study period were included. Surgeries identified within the study period included otolaryngology procedures (46.2%), such as tonsillectomies with or without adenoidectomies, cardiac surgeries (30.8%) including a sternal revision, pulmonary vein repair, and pacemaker placement in two patients, orthopedic surgeries (15.4%) including a posterior spinal fusion and an Achilles tendon lengthening with ankle and subtalar joint release, and a neurosurgery (7.7%), which was a ventriculoperitoneal shunt revision. Thirteen surgical encounters were examined. One SWC was observed, an infected pacemaker requiring systemic antibiotics and removal of the device. The results of this study suggest that sirolimus may be continued in the perioperative period based on the low rate of SWC observed.

Exosomes from pediatric dilated cardiomyopathy patients modulate a pathological response in cardiomyocytes.

Stimulation of the renin-angiotensin-aldosterone system (RAAS) and ß-adrenergic receptors plays an important role in adult heart failure (HF). Despite the demonstrated benefits of RAAS inhibition and ß-adrenergic receptor blockade in adult HF patients, no substantial improvement in survival rate has been observed in children with HF. This suggests that the underlying disease mechanism is uniquely regulated in pediatric HF. Here, we show that treatment of human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and neonatal rat ventricular myocytes (NRVMs) with serum from pediatric dilated cardiomyopathy (DCM) patients induces pathological changes in gene expression, which occur independently of the RAAS and adrenergic systems, suggesting that serum circulating factors play an important role in cardiac remodeling. Furthermore, exosomes purified from DCM serum induced pathological changes in gene expression in NRVMs and iPSC-CMs. Our results suggest that DCM serum exosomes mediate pathological responses in cardiomyocytes and may propagate the pediatric HF disease process, representing a potential novel therapeutic target specific to this population.NEW & NOTEWORTHY The results of this work could alter the present paradigm of basing clinical pediatric heart failure (HF) treatment on outcomes of adult HF clinical trials. The use of serum-treated primary cardiomyocytes may define age-specific mechanisms in pediatric HF with the potential to identify unique age-appropriate and disease-specific therapy.

Myocardial Response to Milrinone in Single Right Ventricle Heart Disease.

OBJECTIVES: Empiric treatment with milrinone, a phosphodiesterase (PDE) 3 inhibitor, has become increasingly common in patients with single ventricle heart disease of right ventricular (RV) morphology (SRV); our objective was to characterize the myocardial response to PDE3 inhibition (PDE3i) in the pediatric population with SRV. STUDY DESIGN: Cyclic adenosine monophosphate levels, PDE activity, and phosphorylated phospholamban (PLN) were determined in explanted human ventricular myocardium from nonfailing pediatric donors (n = 10) and pediatric patients transplanted secondary to SRV. Subjects with SRV were further classified by PDE3i treatment (n = 13 with PDE3i and n = 12 without PDE3i). RESULTS: In comparison with nonfailing RV myocardium (n = 8), cyclic adenosine monophosphate levels are lower in patients with SRV treated with PDE3i (n = 12, P = .021). Chronic PDE3i does not alter total PDE or PDE3 activity in SRV myocardium. Compared with nonfailing RV myocardium, SRV myocardium (both with and without PDE3i) demonstrates equivalent phosphorylated PLN at the protein kinase A phosphorylation site. CONCLUSIONS: As evidenced by preserved phosphorylated PLN, the molecular adaptation associated with SRV differs significantly from that demonstrated in pediatric heart failure because of dilated cardiomyopathy. These alterations support a pathophysiologically distinct mechanism of heart failure in pediatric patients with SRV, which has direct implications regarding the presumed response to PDE3i treatment in this population.

Maintenance steroid use at 30 days post-transplant and outcomes of pediatric heart transplantation: A propensity matched analysis of the Pediatric Heart Transplant Study database.

BACKGROUND: Maintenance steroid (MS) use in pediatric heart transplantation is variable. The purpose of this study was to evaluate the impact of MS use on graft outcomes. METHODS: All patients <18 years old in the Pediatric Heart Transplant Study database at the time of first heart transplant between 1993 and 2011 who survived ≥30 days post-transplant and were from centers with a protocolized approach to MS use were included (N = 2,178). Patients were grouped by MS use at 30 days post-transplant as MS+ or MS- (no MS use). Propensity score analysis was used to generate matched groups of MS+ and MS- patients based on pre-transplant and peri-transplant factors. Kaplan-Meier survival analysis was used to compare freedom from graft loss, graft loss secondary to rejection, rejection, rejection with severe hemodynamic compromise (RSHC), malignancy, and infection between groups. RESULTS: Of patients, 1,393 (64%) were MS+ and 785 (36%) were MS-. There were 315 MS- patients who had propensity matched MS+ controls. Kaplan-Meier estimates showed no difference in graft loss (p = 0.9) or graft loss secondary to rejection (p = 0.09). At 1 year post-transplant, there was no difference in freedom from rejection (p = 0.15) or malignancy (p = 0.07), but there was lower freedom from RSHC and infection in the MS- group (p = 0.05 and p = 0.02, respectively). CONCLUSIONS: MS use at 30 days post-transplant was not associated with enhanced graft survival after pediatric heart transplant. MS- patients had a higher incidence of RSHC and infection. These risks should be taken into consideration when determining MS use for pediatric recipients of heart transplants.

Micro-RNA expression in hypoplastic left heart syndrome.

OBJECTIVE: Micro-RNAs (miRNAs) are important regulators of gene expression through interaction with the 3'UTR of target messenger RNAs (mRNAs). The role of miRNAs has been extensively studied in adult human and nonhuman animal models of heart disease. Hypoplastic left heart syndrome (HLHS) is the most common form of severe congenital heart disease and is an important cause of morbidity and mortality in infants and children. The objective of this work was to analyze the miRNA profile in HLHS patients. METHODS AND RESULTS: miRNA profile was determined in the right ventricle with the use of miRNA array, and expression was validated with the use of reverse-transcription polymerase chain reaction (RT-PCR). Based on bioinformatics analysis, targets were selected and their expression analyzed with the use of RT-PCR.We found that the miRNA profile of HLHS is novel, with few similarities between pediatric and adult idiopathic dilated cardiomyopathy. Moreover, our analysis identified putative targets for these miRNAs that are known to be important for cardiac development and disease, and that miRNAs and their putative targets are antithetically regulated. We also found that miRNA expression changes with stage of surgery, suggesting that volume unloading of the ventricle has important consequences for gene expression. CONCLUSIONS: Our data suggest a unique miRNA profile for HLHS that may be associated with defects in cardiac development and disease.

Gene expression and ß-adrenergic signaling are altered in hypoplastic left heart syndrome.

BACKGROUND: The purpose of the current study was to define the myocellular changes and adaptation of the ß-adrenergic receptor (ß-AR) system that occur in the systemic right ventricle (RV) of children with hypoplastic left heart syndrome (HLHS). METHODS: Explanted hearts from children with HLHS and non-failing controls were used for this study. HLHS patients were divided into 2 groups: "compensated" (C-HLHS), infants listed for primary transplant with normal RV function and absence of heart failure symptoms, and "decompensated" (D-HLHS), patients listed for transplant after failed surgical palliation with RV failure and/or refractory protein-losing enteropathy or plastic bronchitis. RESULTS: Compared with non-failing control RVs, the HLHS RV demonstrated decreased sarcoplasmic reticulum calcium-adenosine triphosphatase 2a and α-myosin heavy chain (MHC) gene expression, decreased total ß-AR due to down-regulation of ß1-AR, preserved cyclic adenosine monophosphate levels, and increased calcium/calmodulin-dependent protein kinase II (CaMKII) activity. There was increased atrial natriuretic peptide expression only in the C-HLHS group. Unique to those in the D-HLHS group was increased ß-MHC and decreased α-MHC protein expression (MHC isoform switching), increased adenylyl cyclase 5 expression, and increased phosphorylation of the CaMK target site on phospholamban, threonine 17. CONCLUSIONS: The HLHS RV has an abnormal myocardial gene expression pattern, downregulation of ß1-AR, preserved cyclic adenosine monophosphate levels, and increased CaMKII activity compared with the non-failing control RV. There is MHC isoform switching, increased adenylyl cyclase 5, and increased phosphorylation of phospholamban threonine 17 only in the D-HLHS group. Although abnormal gene expression and changes in the ß-AR system precede clinically evident ventricular failure in HLHS, additional unique adaptations occur in those with HLHS and failed surgical palliation.

Left ventricular strain and strain rates are decreased in children with normal fractional shortening after exposure to anthracycline chemotherapy.

BACKGROUND: Anthracycline chemotherapeutic agents carry the well-recognised risk of cardiotoxicity. Previous methods to evaluate cardiac function are useful, but have significant limitations. We sought to determine the left ventricular strain and strain rate of paediatric cancer patients with normal fractional shortening treated with anthracyclines using the latest ultrasound feature-tracking technology. PATIENTS AND METHODS: Echocardiograms on cancer patients before anthracycline exposure and following completion of treatment were retrospectively analysed using Velocity Vector Imaging software in the circumferential and longitudinal planes. The same analysis was performed on matched controls. Only patients with a fractional shortening ≥28% were included. RESULTS: In all, 71 patients were identified with an age at diagnosis of 10.5 ± 4.7 years. The time from diagnosis to follow-up was 3.9 ± 4.0 years and the cumulative anthracycline dose was 356 ± 106 mg/m². Following anthracycline exposure, paediatric cancer patients had a higher heart rate and a lower longitudinal strain, longitudinal diastolic strain rate, circumferential strain, and circumferential systolic and diastolic strain rate when compared with controls. Diastolic strain rate showed the greatest percent difference following anthracycline exposure versus controls. CONCLUSION: Despite having a normal fractional shortening, children exposed to anthracyclines have subclinical derangement of their left ventricular deformation as measured by decreases in strain and strain rate in both the circumferential and longitudinal axis. In particular, there was a profound decrease in diastolic strain rate following anthracycline exposure compared with controls. Whether the decline of strain or strain rate can predict future risk of developing cardiomyopathy requires further investigation.

Beta-adrenergic adaptation in paediatric idiopathic dilated cardiomyopathy.

BACKGROUND: Although the pathophysiology and treatment of adult heart failure (HF) are well studied, HF in children remains poorly understood. In adults, adrenergic receptor (AR)-mediated adaptation plays a central role in cardiac abnormalities in HF, and these patients respond well to ß-blocker (BB) therapy. However, in children with HF, there is a growing body of literature suggesting a lack of efficacy of adult HF therapies. Due to these unanticipated differences in response to therapy and the paucity of data regarding the molecular adaptation of the paediatric heart, we investigated the molecular characteristics of HF in children. METHODS AND RESULTS: Explanted hearts from adults and children with idiopathic dilated cardiomyopathy and non-failing controls were used in the study. Our results show that the molecular characteristics of paediatric HF are strikingly different from their adult counterparts. These differences include: (i) down-regulation of ß1- and ß2-AR in children, whereas ß2-AR expression is maintained in adults; (ii) up-regulation of connexin43 in children, whereas down-regulation is observed in adults; (iii) no differences in phosphatase expression, whereas up-regulation is observed in adults; (iv) no decrease in the phosphorylation of phospholamban at the Ser16 or Thr17 sites in children, which are known characteristics of adult HF. CONCLUSION: There is a different adaptation of ß-AR and adrenergic signalling pathways in children with HF compared with adults. Our results begin to address the disparities in cardiovascular research specific to children and suggest that age-related differences in adaptation could influence the response to therapy. These findings could lead to a paradigm shift in the contemporary management of children with HF.

Graft survival is better without prior surgery in cardiac transplantation for functionally univentricular hearts.

BACKGROUND: The effect of surgical history on graft outcomes in patients with functionally univentricular hearts (UH) is not well understood. We compared graft outcomes after heart transplantation in children with a UH between patients who received allografts without prior cardiac surgery (Group A) and patients who underwent transplantation after prior cardiac surgery (Group B). METHODS: We reviewed all patients who received allografts for UH at our institution from 1990 to 2009. Differences in the probability of acute rejection (AR), incidence of graft vasculopathy (GV), and incidence of death or retransplantation were compared between Group A and Group B. Student's t-test, Mann-Whitney U-test, the log-rank test, logistic regression, and Cox proportional hazards modeling were used as appropriate. RESULTS: During the study period, 180 patients with a UH received allografts: 105 in Group A and 75 in Group B at a median (interquartile range) age of 84 (47-120) days vs 584 (168-2,956) days, respectively (p < 0.001). The odds of AR were higher in Group B (odds ratio, 2.7, 95% confidence interval, 1.3-5.4). Group A had lower univariable risks of GV (p = 0.034) and graft loss (p = 0.003). Median graft survival was 18 years in Group A vs 8 years in Group B. The risk of graft loss after 5 years post-transplant was higher in Group B patients who were aged ≥ 1 year at time of transplant (p < 0.001). CONCLUSIONS: Heart transplantation without prior cardiac surgery in patients with a UH was associated with better graft survival and lower probability of AR. The effect of age is complex and time-dependent, with age affecting outcomes after 5 years.