Sacubitril/Valsartan in Pediatric Heart Failure (PANORAMA-HF): A Randomized, Multicenter, Double-Blind Trial.

BACKGROUND: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), is an established treatment for heart failure (HF) with reduced left ventricular ejection fraction. It has not been rigorously compared with angiotensin-converting enzyme inhibitors in children. PANORAMA-HF (Prospective Trial to Assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatment of Pediatric HF) is a randomized, double-blind trial that evaluated the pharmacokinetics and pharmacodynamics (PK/PD), safety, and efficacy of sacubitril/valsartan versus enalapril in children 1 month to <18 years of age with HF attributable to systemic left ventricular systolic dysfunction (LVSD). METHODS: Children with HF attributable to LVSD were randomized to sacubitril/valsartan versus enalapril to assess the efficacy and safety of sacubitril/valsartan at 52 weeks of follow-up. The primary end point of the study was to determine whether sacubitril/valsartan was superior to enalapril for the treatment of pediatric patients with HF attributable to systemic LVSD, assessed using a primary global rank end point consisting of ranking patients from worst to best on the basis of clinical events such as death, listing for urgent heart transplant, mechanical life support requirement, worsening HF, New York Heart Association (NYHA)/Ross class, Patient Global Impression of Severity (PGIS), and Pediatric Quality of Life Inventory physical functioning domain. The change from baseline to 52 weeks in NT-proBNP (N-terminal pro-B-type natriuretic peptide) was an exploratory end point. RESULTS: A total of 375 children (mean age, 8.1±5.6 years; 52% female) were randomized to sacubitril/valsartan (n=187) or enalapril (n=188). At week 52, no significant difference was observed between the 2 treatment arms in the global rank end point (Mann-Whitney probability, 0.52 [95% CI, 0.47-0.58]; Mann-Whitney odds, 0.91 [95% CI, 0.72-1.14]; P=0.42). At week 52, clinically meaningful reductions were observed in both treatment arms in NYHA/Ross, PGIS, Patient Global Impression of Change, and NT-proBNP, without significant differences between groups. Adverse events were similar between treatment arms (incidence: sacubitril/valsartan, 88.8%; enalapril, 87.8%), and the safety profile of sacubitril/valsartan was acceptable in children. CONCLUSIONS: In this study, sacubitril/valsartan did not show superiority over enalapril in the treatment of children with HF attributable to systemic LVSD using the prespecified global rank end point. However, both treatment arms showed clinically meaningful improvements over 52 weeks. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02678312.

The Future of Kawasaki Disease Diagnosis: Liquid Biopsy May Hold the Key.

Kawasaki disease (KD) is a febrile illness characterised by systemic inflammation of small- and medium-sized blood vessels, which commonly occurs in young children. Although self-limiting, there is a risk of developing coronary artery lesions as the disease progresses, with delay in diagnosis and treatment. Unfortunately, the diagnosis of KD continues to remain a clinical dilemma. Thus, this article not only summarises the key research gaps associated with KD, but also evaluates the possibility of using circulating endothelial injury biomarkers, such as circulating endothelial cells, endothelial microparticles and vascular endothelial cell-free DNA, as diagnostic and prognostic tools for KD: a "liquid biopsy" approach. The challenges of translating liquid biopsies to use in KD and the opportunities for improvement in its diagnosis and management that such translation may provide are discussed. The use of endothelial damage markers, which are easily obtained via blood collection, as diagnostic tools is promising, and we hope this will be translated to clinical applications in the near future.

Effects of extended pharmacological disruption of zebrafish embryonic heart biomechanical environment on cardiac function, morphology, and gene expression.

BACKGROUND: Biomechanical stimuli are known to be important to cardiac development, but the mechanisms are not fully understood. Here, we pharmacologically disrupted the biomechanical environment of wild-type zebrafish embryonic hearts for an extended duration and investigated the consequent effects on cardiac function, morphological development, and gene expression. RESULTS: Myocardial contractility was significantly diminished or abolished in zebrafish embryonic hearts treated for 72 hours from 2 dpf with 2,3-butanedione monoxime (BDM). Image-based flow simulations showed that flow wall shear stresses were abolished or significantly reduced with high oscillatory shear indices. At 5 dpf, after removal of BDM, treated embryonic hearts were maldeveloped, having disrupted cardiac looping, smaller ventricles, and poor cardiac function (lower ejected flow, bulboventricular regurgitation, lower contractility, and slower heart rate). RNA sequencing of cardiomyocytes of treated hearts revealed 922 significantly up-regulated genes and 1,698 significantly down-regulated genes. RNA analysis and subsequent qPCR and histology validation suggested that biomechanical disruption led to an up-regulation of inflammatory and apoptotic genes and down-regulation of ECM remodeling and ECM-receptor interaction genes. Biomechanics disruption also prevented the formation of ventricular trabeculation along with notch1 and erbb4a down-regulation. CONCLUSIONS: Extended disruption of biomechanical stimuli caused maldevelopment, and potential genes responsible for this are identified.

Echocardiographic assessment of fetal cardiac function in the uterine artery ligation rat model of IUGR.

BACKGROUND: Intrauterine growth restriction (IUGR) leads to cardiac dysfunction and adverse remodeling of the fetal heart, as well as a higher risk of postnatal cardiovascular diseases. The rat model of IUGR, via uterine artery ligation, is a popular model but its cardiac sequelae is not well investigated. Here, we performed an echocardiographic evaluation of its cardiac function to determine how well it can represent the disease in humans. METHODS: Unilateral uterine artery ligation was performed at embryonic day 17 (E17) and echocardiography was performed at E19 and E20. RESULTS: Growth-restricted fetuses were significantly smaller and lighter, and had an higher placenta-to-fetus weight ratio. Growth-restricted fetal hearts had reduced wall thickness-to-diameter ratio, indicating left ventricular (LV) dilatation, and they had elevated trans-mitral and trans-tricuspid E/A ratios and reduced left and right ventricular fractional shortening (FS), suggesting systolic and diastolic dysfunction. These were similar to human IUGR fetuses. However, growth-restricted rat fetuses did not demonstrate head-sparing effect, displayed a lower LV myocardial performance index, and ventricular outflow velocities were not significantly reduced, which were dissimilar to human IUGR fetuses. CONCLUSIONS: Despite the differences, our results suggest that this IUGR model has significant cardiac dysfunction, and could be a suitable model for studying IUGR cardiovascular physiology. IMPACT: Animal models of IUGR are useful, but their fetal cardiac function is not well studied, and it is unclear if they can represent human IUGR fetuses. We performed an echocardiographic assessment of the heart function of a fetal rat model of IUGR, created via maternal uterine artery ligation. Similar to humans, the model displayed LV dilatation, elevated E/A ratios, and reduced FS. Different from humans, the model displayed reduced MPI, and no significant outflow velocity reduction. Despite differences with humans, this rat model still displayed cardiac dysfunction and is suitable for studying IUGR cardiovascular physiology.

Human fetal hearts with tetralogy of Fallot have altered fluid dynamics and forces.

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.

Prelisting predictions of early postoperative survival in infant heart transplantation using classification and regression tree analysis.

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.

Association of trisomy 18 with hepatoblastoma and its implications.

UNLABELLED: 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.

Analysis of the hospitalization costs of surgical patients with congenital heart disease in the plateau region of western China, 2010-2019.

Background: Congenital heart disease (CHD) is one of the most common birth defects and consumes a substantial amount of health care resources. CHD leads to heavy economic burdens for families. However, there are limited data regarding the utilization of healthcare resources for CHD. The objectives of this study were to evaluate the composition, changing trends, and factors affecting hospitalization costs for patients with CHD in the western highlands area of China over a 10-year period. Methods: We conducted a study using the International Quality Improvement Collaborative for Congenital Heart Surgery (IQIC) database and information management system of The First Hospital of Lanzhou University between January 2010 and December 2019. Results: Among 3,087 patients hospitalized for CHD surgery, annual CHD hospitalization costs saw an increasing trend over the 10-year period, with an average growth rate of 4.6% per year. The major contributors to the hospitalization costs were surgery, surgical material, and drug costs. Length of stay (ß=0.203; 0.379; 0.474, P<0.01), age at hospitalization (ß=0.293, P<0.01), proportion of surgery (ß=0.090; -0.102; -0.122; -0.110, P<0.01) and drug costs (ß=-0.114; -0.147; -0.069, P<0.01), and use of traditional Chinese medicine (ß=0.141, P<0.01) were independent factors affecting average hospitalization costs. Conclusions: The financial burden of patients with CHD in the Chinese western highland region is high. Independent of inflation, CHD hospitalization costs are increasing. Measures taken by medical institutions to control the increase in drug costs, and to shorten the length of stay may be expected to have positive effects on reducing the financial burden of individuals with CHD and their families.

Fetal congenital heart diseases: Diagnosis by anatomical scans, echocardiography and genetic tests.

Objective: To determine the distribution of major fetal congenital heart diseases (CHDs) diagnosed antenatally during routine second-trimester obstetric anatomical scans in an unselected population at a single tertiary centre and to characterise and stratify risk factors, genetic diagnosis and long-term health at 4 years old. Method: A single-centre cohort study of all major fetal CHDs detected on routine obstetric fetal anatomical ultrasound scans between January 2014 and December 2017 was performed in an unselected population. Demographic details, fetal echocardiogram reports, genetic test results, delivery outcomes and postnatal progress were stratified by CHD subtype. Results: Of 20,031 screened pregnancies, 109 pregnancies (0.53%) had major fetal CHDs. The most common subtypes were coarctation of aorta (17.4%), transposition of great arteries (16.5%), and tetralogy of Fallot and univentricular hearts (13.8% each). Of the 60.5% that underwent confirmatory genetic testing-mostly conventional karyotyping and testing for 22q11 microdeletion-about a quarter had abnormalities, of which 22q microdeletion was the most common. We had complete obstetric data in 85 pregnancies (78%), of which 76.5% progressed to live birth. Among these, 92.1% of postnatal echocardiograms concurred with antenatal ones. At 4 years old, 43.2% of offspring had no medical or developmental issues, 20.0% had mild medical or developmental issues, 21.5% had major medical or developmental issues, and 12.3% had deceased. Conclusion: Fetal echocardiograms accurately diagnose CHDs. Future studies should evaluate the roles of chromosomal microarray and next-generation sequencing in diagnosing CHD.

Causative Variants for Inherited Cardiac Conditions in a Southeast Asian Population Cohort.

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.

The Associations Between Preoperative Anthropometry and Postoperative Outcomes in Infants Undergoing Congenital Heart Surgery.

Aim: We explored the association between preoperative anthropometry and biochemistry, and postoperative outcomes in infants with CHD after cardiac surgery, as infants with congenital heart disease (CHD) often have feeding difficulties and malnutrition. Methodology: This was a retrospective review of infants (≤ 1-year-old) who underwent congenital heart surgery. Preoperative anthropometryin terms of preoperative weight-for-age z-score (WAZ), length-for-age z-score (LAZ), as well as preoperative serum albumin and hemoglobin concentrations, were evaluated against 6-month mortality, and morbidity outcomes including postoperative complications, vasoactive inotrope score, duration of mechanical ventilation, length of stay in the pediatric intensive care unit and in hospital, using the logistic regression or median regression models accounting for infant-level clustering. Results: One hundred and ninety-nine operations were performed in 167 infants. Mean gestational age at birth was 38.0 (SD 2.2) weeks (range 26 to 41 weeks). Thirty (18.0%) infants were born preterm (<37 weeks). The commonest acyanotic and cyanotic lesions were ventricular septal defect (26.3%, 44/167), and tetralogy of Fallot (13.8%, 23/167), respectively. Mean age at cardiac surgery was 94 (SD 95) days. Feeding difficulties, including increased work of breathing during feeding, diaphoresis, choking or coughing during feeding, and inability to complete feeds, was present in 54.3% (108/199) of infants prior to surgery, of which 21.6% (43/199) required tube feeding. The mean preoperative WAZ was-1.31 (SD 1.79). Logistic regression models showed that low preoperative WAZ was associated with increased risk of postoperative complications (odds ratio 1.82; p = 0.02), and 6-month mortality (odds ratio 2.38; p = 0.008) following CHD surgery. There was no meaningful association between the other preoperative variables and other outcomes. Conclusion: More than 50% of infants with CHD undergoing cardiac surgery within the first year of life have feeding difficulties, of which 22% require to be tube-fed. Low preoperative WAZ is associated with increased postoperative complications and 6-month mortality.

8-Oxoguanine DNA Glycosylase (OGG1) Deficiency Exacerbates Doxorubicin-Induced Cardiac Dysfunction.

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.

The Role of Epigenetics in Congenital Heart Disease.

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.

Mending a broken heart: In vitro, in vivo and in silico models of congenital heart disease.

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.

Multiscale modeling of a modified Blalock-Taussig surgery in a patient-specific tetralogy of Fallot.

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.

Cardiotoxicity After Anthracycline Chemotherapy for Childhood Cancer in a Multiethnic Asian Population.

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 <28% on echocardiography) and its risk factors using univariate logistic regression as well as survival estimates through the Kaplan-Meier method to compare survival distribution between patients with and without cardiotoxicity. 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.

Dynamic Myocardial Response to Exercise in Childhood Cancer Survivors Treated with Anthracyclines.

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.

Changes in Near-Infrared Spectroscopy After Congenital Cyanotic Heart Surgery.

BACKGROUND: Since oxygen saturation from pulse oximetry (SpO2) and partial pressure of arterial oxygen (PaO2) are observed to improve immediately after surgical correction of cyanotic congenital heart disease (CHD), we postulate that cerebral (CrO2) and somatic (SrO2) oximetry also improves immediately post-correction. We aim to prospectively examine CrO2 and SrO2, before, during, and after surgical correction as well as on hospital discharge in children with cyanotic CHD to determine if and when these variables increase. METHODS: This is a prospective observational trial. Eligibility criteria included children below 18 years of age with cyanotic CHD who required any cardiac surgical procedure. CrO2 and SrO2 measurements were summarized at six time-points for comparison: (1) pre-cardiopulmonary bypass (CPB); (2) during CPB; (3) post-CPB; (4) Day 1 in the pediatric intensive care unit (PICU); (5) Day 2 PICU; and (6) discharge. Categorical and continuous variables are presented as counts (percentages) and median (interquartile range), respectively. RESULTS: Twenty-one patients were analyzed. 15 (71.4%) and 6 (28.6%) patients underwent corrective and palliative surgeries, respectively. In the corrective surgery group, SpO2 increased immediately post-CPB compared to pre-CPB [99 (98, 100) vs. 86% (79, 90); p < 0.001] and remained in the normal range through to hospital discharge. Post-CPB CrO2 did not change from pre-CPB [72.8 (58.8, 79.0) vs. 72.1% (63.0, 78.3); p = 0.761] and even decreased on hospital discharge [60.5 (53.6, 62.9) vs. 72.1% (63.0, 78.3); p = 0.005]. Post-CPB SrO2 increased compared to pre-CPB [87.3 (77.2, 89.5) vs. 72.7% (65.6, 77.3); p = 0.001] but progressively decreased during PICU stay to a value lower than baseline at hospital discharge [66.9 (57.3, 76.9) vs. 72.7% (65.6, 77.3); p = 0.048]. CONCLUSION: CrO2 and SrO2 did not increase after corrective surgery of cyanotic CHD even up to hospital discharge. Future larger studies are required to validate these findings. (This study is registered with ClinicalTrials.gov ID: NCT02417259.).

Intramyocardial Hematoma After Ebstein Anomaly Repair.

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.

The Utility of Cardiopulmonary Exercise Testing for the Prediction of Outcomes in Ambulatory Children With Dilated Cardiomyopathy.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.