BACKGROUND:Echocardiography parameters of right ventricular (RV) dysfunction, fractional area change (RVFAC), and global longitudinal strain during the first interstage have been shown to be associated with death or transplantation in patients with HLHS. However, both parameters lack adequate discriminatory characteristics. This study sought to examine global post-systolic contraction (PSC), a marker of myocardial inefficiency, as a predictor of death or transplantation (Tx) in patients with classic hypoplastic left heart syndrome (HLHS). METHODS:We performed a post-hoc analysis of 62 prospectively recruited patients with HLHS prior to the bidirectional cavopulmonary anastomosis (BCPA) surgery. We measured RV function parameters: RVFAC, global longitudinal strain, strain rate, mechanical dispersion index (MDI), and PSC. For each parameter, the receiver operating characteristic analysis determined the optimal cut-offs for the primary endpoint of death/Tx, followed by a Kaplan-Meier analysis. Parameters interobserver variability testing was performed. RESULTS:Median follow-up from pre-BCPA echocardiogram was 7.4 years. HLHS with outcome of death/Tx (n = 14) had lower RVFAC, longitudinal strain and strain rate, and increased PSC when compared with survivors. PSC of >5% performed the best, with the greatest area under the curve 0.75, sensitivity 64% and specificity 83%, hazard ratio 5.54 (95% CI 1.63-18.66), for the primary endpoint of death/Tx. PSC and strain parameters had excellent reproducibility. CONCLUSION:Increased global post-systolic contraction during the first interstage is associated with an outcome of death or transplantation in the medium term follow up of patients with HLHS. PSC has a greater specificity and reproducibility than global longitudinal strain and RV FAC. Investigation into its use in clinical practice as a predictor of outcome is warranted.

BACKGROUND:Children with a Fontan operation represent a unique form of congenital heart disease (CHD) that requires multiple cardiac surgeries and procedures with an uncertain long-term outcome. Given the rarity of the types of CHD that require this procedure, many children with a Fontan do not know any others like them.METHODS:With the cancelation of medically supervised heart camps due to the COVID-19 pandemic, we have organized several physician-led virtual day camps for children with a Fontan operation to connect with others in their province and across Canada. The aim of this study was to describe the implementation and evaluation of these camps via the use of an anonymous online survey immediately after the event and reminders on days 2 and 4 postevent.RESULTS:Fifty-one children have participated in at least 1 of our camps. Registration data showed that 70% of participants did not know anyone else with a Fontan. Postcamp evaluations showed that 86% to 94% learned something new about their heart and 95% to 100% felt more connected to other children like them.CONCLUSION:We have demonstrated the implementation of a virtual heart camp to expand the support network for children with a Fontan. These experiences may help to promote healthy psychosocial adjustments through inclusion and relatedness.

Fontan associated liver disease (FALD) is an increasingly recognized complication of the single ventricle circulation characterized by hepatic venous congestion leading to hepatic fibrosis. Within the Fontan myocardium, fibrotic myocardial remodeling may occur and lead to ventricular dysfunction. Magnetic resonance imaging (MRI) T1 mapping can characterize both myocardial and liver properties. The aim of this study was to compare myocardial and liver T1 between single ventricle patients with and without a Fontan and biventricular controls. A retrospective study of 3 groups of patients: 16 single ventricle patients before Fontan (SVpre 2 newborns, 9 pre-Glenn, 5 pre-Fontan, 31

OBJECTIVES:This study examines fetuses with tetralogy of Fallot (TOF) and evaluates the right (RV) and left (LV) ventricular contractility and LV function using speckle-tracking analysis of the endocardium.METHODS:The study group consisted of 44 fetuses with TOF, of which 34% had pulmonary valve atresia (N = 15) and 59% (N = 26) had pulmonary valve stenosis. The RV and LV global fractional area change, longitudinal contractility (longitudinal strain, free wall strain, septal strain, free wall and septal annular fractional shortening, and free wall and septal wall annular plane systolic excursion), and transverse contractility (24-segment fractional shortening) as well as LV functional assessment (stroke volume, cardiac output, and ejection fraction) were measured using speckle-tracking analysis. The z-scores of the measurements were compared to 200 controls.RESULTS:Compared to controls, measurements of LV contractility in fetuses with TOF demonstrated significantly abnormal values for global contractility, longitudinal contractility, and transverse contractility of the mid and apical segments. LV function was abnormal for stroke volume (SV), cardiac output (CO), and ejection fraction (EF). In comparison, RV contractility demonstrated no significant difference between TOF and control z-score values for RV global contractility. Only two RV measurements were found to be abnormal: longitudinal contractility and transverse contractility of the apical segments.CONCLUSION:Using multiple measurement tools to evaluate global, longitudinal, and transverse contractility, this study identified significant differences between fetuses with TOF and healthy controls, with greater contractility abnormalities seen in the LV than in the RV.

OBJECTIVE:Prenatal detection rates for tetralogy of Fallot (TOF) vary between 23 and 85.7%, in part because of the absence of significant structural abnormalities of the 4-chamber view (4CV), as well as the relative difficulty in detection of abnormalities during the screening examination of the outflow tracts. The purpose of this study was to evaluate whether the 4CV and ventricles in fetuses with TOF may be characterized by abnormalities of size and shape of these structures.METHODS:This study retrospectively evaluated 44 fetuses with the postnatal diagnosis of TOF. Measurements were made from the 4CV (end-diastolic length, width, area, global sphericity index, and cardiac axis) and the right (RV) and left (LV) ventricles (area, length, 24-segment transverse widths, sphericity index, and RV/LV ratios). Logistic regression analysis was performed to identify variables that might separate fetuses with TOF from normal controls.RESULTS:The mean gestational age at the time of the last examination prior to delivery was 28 weeks 5 days (SD 4 weeks, 4 days). The mean z-scores were significantly lower in fetuses with TOF for the 4CV and RV and LV measurements of size and shape. Logistic regression analysis identified simple linear measurements of the 4CV, RV, and LV that had a sensitivity of 90.9 and specificity of 98.5% that outperformed the 4CV cardiac axis (sensitivity of 22.7%) as a screening tool for TOF.CONCLUSIONS:Measurements of the 4CV, RV, and LV can be used as an adjunct to the outflow tract screening examination to identify fetuses with TOF.

Abstract Background Single ventricle (SV) palliation, culminating with the Fontan operation, results in passive systemic venous blood flow directly to the pulmonary circulation. Resulting inevitable hepatic venous congestion can lead to hepatic fibrosis. Previous studies suggest hepatic changes can occur prior to the Fontan completion. Besides fibrotic myocardial remodeling may lead to systolic and diastolic ventricular dysfunction, transmitting back pressure to the pulmonary system. Purpose To compare quantitative T1 cardiovascular magnetic resonance (CMR) imaging of the myocardium and liver between SV patients and controls, as a potential measure of myocardial and hepatic fibrosis. Methods Retrospective review of 16 SV patients with dominant single left ventricle (SLV, n=6) or single right ventricle (SRV, n=10), at various stages of palliation (pre-Glenn=6, post-Glenn=3, Fontan=7) underwent CMR with myocardial T1 mapping with the liver also in the plane of view. Biventricular patients found to have structurally normal hearts and normal cardiac function on CMR were used as controls (n=21). Native T1 times using a modified Look-Locker inversion recovery (MOLLI) approach in free-wall of the dominant ventricle at a mid-ventricular short axis in SV and the ventricular septum in controls and, a region of interest in the liver (avoiding any vessels) were measured in all patients. Median and inter-quartile ranges of continuous variables were compared between SV and controls using the Mann-Whitney U test. Results As compared to controls SV patients were (1) significantly younger, (2) had lower ejection fraction, (3) higher median myocardial T1, and (4) higher median liver T1. Also, there was no difference between SLV vs. SRV median myocardial T1 (1056 vs. 1065ms, p=0.43) or liver T1 (678 vs. 729ms, p=0.30) Conclusion Despite younger age, findings of increased myocardial T1 may suggest an element of myocardial fibrosis responsible for the ventricular dysfunction in this population, and that raised liver T1 may be an earlier marker of liver fibrosis, which warrants further study. Funding Acknowledgement Type of funding source: None

Post‐transplant lymphoproliferative disorders (PTLD) are the main malignancy seen after pediatric heart transplant and are a significant cause of morbidity and mortality. Prior to the development of detailed guidelines, we sought to identify trends in screening, diagnosis, and treatment of pediatric PTLD. All Pediatric Heart Transplant Society (PHTS) institutions were surveyed. No identifiable patient information was shared. From 56 PHTS centers, 22 responses were received (39.3%). 100% agree PTLD cannot be diagnosed solely based on elevated Epstein‐Barr virus (EBV) load. All respondents routinely screen for EBV by blood PCR, but frequency of screening varies. There was intermediate consensus regarding the use of computed tomography (CT) and/or positron emission tomography (PET) in surveillance management for PTLD. Most centers require a diagnostic biopsy before initiating new treatment for PTLD (14 of 18, 77.8%), but many reduce immune suppression based on elevated EBV without pathologic PTLD (16 of 22, 72.7%). Beyond immune modulation, rituximab is most commonly used (9 of 13, 69.2%). Consultation with oncology is common (17 of 17, 100%), but timing varies widely. Our survey highlights significant elements of agreement and significant practice variation among PHTS institutions regarding pediatric PTLD. Reduction of immune suppression prior to pathologic diagnosis of PTLD is a common management strategy. When this fails, rituximab is used, but is most often reserved until after confirmation of the diagnosis. Oncology subspecialists are commonly involved in these cases. Our findings highlight the need to develop improved guidelines for evaluation and treatment of pediatric PTLD.

Purpose Post-transplant lymphoproliferative disorders (PTLD) are a significant cause of morbidity and mortality following pediatric orthotopic heart transplant (OHT), with a reported incidence of 5-20%. In the absence of accepted guidelines, we sought to identify the overall trends in North American pediatric transplant centers in the screening, diagnosis, treatment, and follow-up of PTLD. Methods All 56 Pediatric Heart Transplant Society (PHTS) institutions were asked to complete an anonymous survey in March 2019. No identifiable patient information was shared. Results From 56 PHTS centers, 22 responses were received (39.3%). 100% indicated that PTLD cannot be diagnosed solely based on elevated EBV load. All respondents routinely screen for Epstein Barr virus (EBV) by qualitative or quantitative EBV PCR, but the frequency of screening varies widely - some screen each visit, others once annually. Twelve of 19 (63.2%) obtain CT and/or PET evaluation for PTLD when EBV load is substantially or persistently elevated, whereas 5 of 19 (26.3%) also require clinical suspicion that PTLD is developing before obtaining imaging. Most centers require a positive biopsy to establish a diagnosis of PTLD (14 of 18, 77.8%), but many will reduce immune suppression in response to a persistently elevated EBV load without pathologic evidence of PTLD (16 of 22, 72.7%). Beyond reduction in immune suppression, rituximab is the most commonly used treatment agent used (9 of 13, 69.2%). Subspecialty consultation with pediatric oncology (17 of 17, 100%) and infectious disease (ID, 8 of 17, 47.1%) are common, but the timing of such consultation varies widely, some triggered by the diagnosis of EBV viremia (2 oncology, 5 ID), others only in rituximab-refractory PTLD (1 oncology). Conclusion Our survey highlights significant practice variation amongst PHTS institutions in screening, diagnosing and treating PTLD in pediatric OHT patients. Reduction in immune suppression prior to pathologic diagnosis of PTLD is common but not universal. Treatment with rituximab is most often reserved until after establishing the PTLD diagnosis. This study highlights the need for multi-center collaboration to develop evidence-based guidelines for screening, treatment and surveillance of pediatric PTLD. Post-transplant lymphoproliferative disorders (PTLD) are a significant cause of morbidity and mortality following pediatric orthotopic heart transplant (OHT), with a reported incidence of 5-20%. In the absence of accepted guidelines, we sought to identify the overall trends in North American pediatric transplant centers in the screening, diagnosis, treatment, and follow-up of PTLD. All 56 Pediatric Heart Transplant Society (PHTS) institutions were asked to complete an anonymous survey in March 2019. No identifiable patient information was shared. From 56 PHTS centers, 22 responses were received (39.3%). 100% indicated that PTLD cannot be diagnosed solely based on elevated EBV load. All respondents routinely screen for Epstein Barr virus (EBV) by qualitative or quantitative EBV PCR, but the frequency of screening varies widely - some screen each visit, others once annually. Twelve of 19 (63.2%) obtain CT and/or PET evaluation for PTLD when EBV load is substantially or persistently elevated, whereas 5 of 19 (26.3%) also require clinical suspicion that PTLD is developing before obtaining imaging. Most centers require a positive biopsy to establish a diagnosis of PTLD (14 of 18, 77.8%), but many will reduce immune suppression in response to a persistently elevated EBV load without pathologic evidence of PTLD (16 of 22, 72.7%). Beyond reduction in immune suppression, rituximab is the most commonly used treatment agent used (9 of 13, 69.2%). Subspecialty consultation with pediatric oncology (17 of 17, 100%) and infectious disease (ID, 8 of 17, 47.1%) are common, but the timing of such consultation varies widely, some triggered by the diagnosis of EBV viremia (2 oncology, 5 ID), others only in rituximab-refractory PTLD (1 oncology). Our survey highlights significant practice variation amongst PHTS institutions in screening, diagnosing and treating PTLD in pediatric OHT patients. Reduction in immune suppression prior to pathologic diagnosis of PTLD is common but not universal. Treatment with rituximab is most often reserved until after establishing the PTLD diagnosis. This study highlights the need for multi-center collaboration to develop evidence-based guidelines for screening, treatment and surveillance of pediatric PTLD.

Background: Three-dimensional echocardiography (3DE) improves visualization of cardiac lesions. Current viewing of 3DE studies on a conventional display diminishes the encoded stereoscopic (stereo) information for depth perception. This study aims to evaluate clinician subjective and objective experience of stereo display compared with nonstereo display of 3DE in congenital heart disease. Methods: In this prospective study, 22 cardiologists, advanced cardiology trainees, and cardiothoracic surgeons used a commercially available stereo display system with proprietary software to view 10 3DE data sets, alternating between simple and complex lesions. In part A, participants viewed each data set, randomized to 1 minute of stereo display followed by 1 minute of nonstereo display, or vice versa. In part B, participants could freely toggle between stereo and nonstereo display for an additional 90 seconds per data set. Participants answered a series of questions and rated their subjective experience using stereo versus nonstereo display mode on a Likert scale. Objective data on time spent in each display mode during part B and duration of interaction and degree of movement of the 3DE data set in parts A and B were also collected. Results: All clinician groups found stereo display preferable to nonstereo display of 3DE (P < .0001). Viewing complex lesions was rated lower than simple lesions when using nonstereo display (P < .01). Simple and complex lesions were equally well rated when using stereo display (P = .14). When given a choice of display modes in part B, participants spent more time in stereo display (P < .0001) and interacted more with the 3DE data sets in stereo display (P < .0001). Conclusions: Interactive stereoscopic display of 3DE was preferred over conventional nonstereo display by all clinician groups for viewing both simple and complex lesions. This preference is especially true for viewing complex lesions.

Introduction: The bidirectional Glenn operation for congenital heart disease produces anatomical constraints to conventional transvenous pacemaker implantation. An iliac approach, although not previously described in this population, is potentially a preferable alternative to a thoracotomy for epicardial pacing. Methods and results: A single-center retrospective review was performed for all patients that underwent transvenous pacemaker implantation following the bidirectional Glenn operation with partial biventricular repair. Follow-up data, implant indications, and techniques were recorded. Five patients underwent a transvenous iliac approach (median age 26.9 years, interquartile range [IQR] 25.8-27.6). Pacing indications included AV block in 3 patients (2 requiring cardiac resychronization therapy) and sinus node dysfunction in 2. Implanted leads were atrial in 4 and ventricular in 3 (1 of the latter was placed in the coronary sinus). In two cases, transvenous leads were tunneled to a preexisting epicardial abdominal generator. Median follow-up was 4.1 years (range 1.0-16.7 years). One patient underwent device revision for lead position-related groin discomfort; a second patient developed atrial lead failure following a Maze operation and underwent lead replacement by the iliac approach. Patients were not routinely anticoagulated postprocedure given lead position in the subpulmonary circulation. At last follow-up, all patients were alive. One patient underwent heart transplantation 6 months after implant with only partial resolution of pacing-induced cardiomyopathy. Conclusions: Trans-iliac pacemaker placement may be an effective alternative to surgery for patients requiring permanent pacing after the Glenn operation.

P-type ATPases function to provide homeostasis in higher eukaryotes, but they are essentially ubiquitous, being found in all domains of life. Thever and Saier [J Memb Biol 2009;229:115–130] recently reported analyses of eukaryotic P-type ATPases, dividing them into nine functionally characterized and 13 functionally uncharacterized (FUPA) families. In this report, we analyze P-type ATPases in all major prokaryotic phyla for which complete genome sequence data are available, and we compare the results with those for eukaryotic P-type ATPases. Topological type I (heavy metal) P-type ATPases predominate in prokaryotes (approx. tenfold) while type II ATPases (specific for Na+,K+, H+ Ca2+, Mg2+ and phospholipids) predominate in eukaryotes (approx. twofold). Many P-type ATPase families are found exclusively in prokaryotes (e.g. Kdp-type K+ uptake ATPases (type III) and all ten prokaryotic FUPA familes), while others are restricted to eukaryotes (e.g. phospholipid flippases and all 13 eukaryotic FUPA families). Horizontal gene transfer has occurred frequently among bacteria and archaea, which have similar distributions of these enzymes, but rarely between most eukaryotic kingdoms, and even more rarely between eukaryotes and prokaryotes. In some bacterial phyla (e.g. Bacteroidetes, Flavobacteria and Fusobacteria), ATPase gene gain and loss as well as horizontal transfer occurred seldom in contrast to most other bacterial phyla. Some families (i.e. Kdp-type ATPases) underwent far less horizontal gene transfer than other prokaryotic families, possibly due to their multisubunit characteristics. Functional motifs are better conserved across family lines than across organismal lines, and these motifs can be family specific, facilitating functional predictions. In some cases, gene fusion events created P-type ATPases covalently linked to regulatory catalytic enzymes. In one family (FUPA Family 24), a type I ATPase gene (N-terminal) is fused to a type II ATPase gene (C-terminal) with retention of function only for the latter. Several pseudogene-encoded nonfunctional ATPases were identified. Genome minimalization led to preferential loss of P-type ATPase genes. We suggest that in prokaryotes and some unicellular eukaryotes, the primary function of P-type ATPases is protection from extreme environmental stress conditions. The classification of P-type ATPases of unknown function into phylogenetic families provides guides for future molecular biological studies.

Pediatric cardiomyopathies, which are rare but serious disorders of the muscles of the heart, affect at least one in every 100,000 children in the USA. Approximately 40% of children with symptomatic cardiomyopathy undergo heart transplantation or die from cardiac complications within 2 years. However, a significant number of children suffering from cardiomyopathy are surviving into adulthood, making it an important chronic illness for both pediatric and adult clinicians to understand. The natural history, risk factors, prevalence and incidence of this pediatric condition were not fully understood before the 1990s. Questions regarding optimal diagnostic, prognostic and treatment methods remain. Children require long-term follow-up into adulthood in order to identify the factors associated with best clinical practice including diagnostic approaches, as well as optimal treatment approaches. In this article, we comprehensively review current research on various presentations of this disease, along with current knowledge about their causes, treatments and clinical outcomes.

Advances in cancer treatment have greatly improved survival rates of children with cancer. However, these same chemotherapeutic or radiologic treatments may result in long-term health consequences. Anthracyclines, chemotherapeutic drugs commonly used to treat children with cancer, are known to be cardiotoxic, but the mechanism by which they induce cardiac damage is still not fully understood. A higher cumulative anthracycline dose and a younger age of diagnosis are only a few of the many risk factors that identify the children at increased risk of developing cardiotoxicity. While cardiotoxicity can develop at anytime, starting from treatment initiation and well into adulthood, identifying the best cardioprotective measures to minimize the long-term damage caused by anthracyclines in children is imperative. Dexrazoxane is the only known agent to date, that is associated with less cardiac dysfunction, without reducing the oncologic efficacy of the anthracycline doxorubicin in children. Given the serious long-term health consequences of cancer treatments on survivors of childhood cancers, it is essential to investigate new approaches to improving the safety of cancer treatments.

P-type ATPases function to provide homeostasis in higher eukaryotes, but they are essentially ubiquitous, being found in all domains of life. Thever and Saier [J Memb Biol 2009;229:115-130] recently reported analyses of eukaryotic P-type ATPases, dividing them into nine functionally characterized and 13 functionally uncharacterized (FUPA) families. In this report, we analyze P-type ATPases in all major prokaryotic phyla for which complete genome sequence data are available, and we compare the results with those for eukaryotic P-type ATPases. Topological type I (heavy metal) P-type ATPases predominate in prokaryotes (approx. tenfold) while type II ATPases (specific for Na(+),K(+), H(+) Ca(2+), Mg(2+) and phospholipids) predominate in eukaryotes (approx. twofold). Many P-type ATPase families are found exclusively in prokaryotes (e.g. Kdp-type K(+) uptake ATPases (type III) and all ten prokaryotic FUPA familes), while others are restricted to eukaryotes (e.g. phospholipid flippases and all 13 eukaryotic FUPA families). Horizontal gene transfer has occurred frequently among bacteria and archaea, which have similar distributions of these enzymes, but rarely between most eukaryotic kingdoms, and even more rarely between eukaryotes and prokaryotes. In some bacterial phyla (e.g. Bacteroidetes, Flavobacteria and Fusobacteria), ATPase gene gain and loss as well as horizontal transfer occurred seldom in contrast to most other bacterial phyla. Some families (i.e. Kdp-type ATPases) underwent far less horizontal gene transfer than other prokaryotic families, possibly due to their multisubunit characteristics. Functional motifs are better conserved across family lines than across organismal lines, and these motifs can be family specific, facilitating functional predictions. In some cases, gene fusion events created P-type ATPases covalently linked to regulatory catalytic enzymes. In one family (FUPA Family 24), a type I ATPase gene (N-terminal) is fused to a type II ATPase gene (C-terminal) with retention of function only for the latter. Several pseudogene-encoded nonfunctional ATPases were identified. Genome minimalization led to preferential loss of P-type ATPase genes. We suggest that in prokaryotes and some unicellular eukaryotes, the primary function of P-type ATPases is protection from extreme environmental stress conditions. The classification of P-type ATPases of unknown function into phylogenetic families provides guides for future molecular biological studies.

As the pediatric OHT population expands, there is increasing demand for convenient, yet sensitive screening techniques to identify children with acute rejection when they present to acute care facilities. In children, symptoms of acute rejection or other causes of graft dysfunction are often non-specific and can mimic other childhood illnesses. The aim of this study was to assess the utility of BNP as a biomarker to assist providers in clinical decision-making when evaluating symptomatic pediatric heart transplant patients. One hundred twenty-two urgent care and emergency room visits from 53 symptomatic pediatric OHT patients were retrospectively reviewed to evaluate the relationship between BNP levels, symptoms, and clinical diagnosis at these visits. An ROC curve was generated to determine the accuracy of BNP as a screening tool for acute rejection in this patient population. In this group of patients, a BNP value of >700 pg/mL was 100% sensitive and 92% specific for detecting allograft acute rejection (NPV of 100%). We concluded that BNP is a highly sensitive screening test for acute rejection in symptomatic pediatric heart transplant patients.

Purpose: Pediatric orthotopic heart transplant (OHT) patients often have non-specific symptoms of rejection. The ability of the serum B-type natriuretic peptide (BNP) level to screen for rejection in pediatric OHT patients has never been formally evaluated. Thus, the presenting features of a large group of symptomatic pediatric OHT patients presenting to emergent care facilities and the ability of their BNP level to indicate rejection were examined.