Single Ventricle Congenital Heart Disease Research Articles

Combined Exercise and Mindset Training During a Pediatric Cardiac Fitness and Rehabilitation Program Benefits Youth with a Range of Congenital Heart Disease.

Pediatric cardiac fitness and rehabilitation programs vary widely in structure and content. The Cardiac Fitness Program (CFP) is built on traditional training pillars of aerobic, strength, and flexibility, and adds a fourth, training a positive mindset. This study assesses whether the systematic and comprehensive framework of the CFP results in broad benefits for a range of patients with congenital heart disease (CHD). Data from participants between 01/2017 and 12/2022 were analyzed. Pre- and post-CFP cardiopulmonary exercise test parameters, strength and flexibility metrics, and mindset survey results were compared overall, and by sex, age, diagnosis, and hemodynamic level. Of 62 participants (median age 15.5years, range 8 to 23, 50% female), 3% had simple, 37% complex, 24% single ventricle CHD, and 35% arrhythmia, cardiomyopathy, or transplant. Significant improvements were noted in aerobic fitness (mean 9 ± 15% increase in % predicted peak oxygen consumption, p < 0.001). Strength metrics significantly improved (each p < 0.001), as did flexibility (p < 0.001). Patient-reported positive mindset scores did not improve significantly (mean increase 1.8 ± 5.1, p = 0.10, n = 25), whereas parents reported significant improvements (5.9 ± 10.4, p = 0.02, n = 20). Improvements were not significantly different by sex, age, diagnosis, or hemodynamic level. Comprehensive training across four pillars of fitness yields significant improvements in aerobic fitness, strength, flexibility, and parent-reported mindset scores for pediatric CHD patients, regardless of patient characteristics, diagnosis type, or severity of hemodynamic limitation. Further study is warranted into optimal standardization of training and whether a comprehensive approach amplifies individual pillars to create more than the sum of its parts.

High-Quality Hospital Status on Health Care Costs for Pediatric Congenital Heart Disease Care for U.S. Military Beneficiaries.

Congenital heart disease (CHD) is the most common and resource demanding birth defect managed in the United States, with approximately 40,000 children undergoing CHD surgery year. Researchers have compared high-volume to low-volume hospitals and found significant hospital-level variation in major complications, health resource utilization, and health care costs after CHD surgery. Using nationwide representative claim data from the United States Military Health System from 2016 to 2020, TRICARE beneficiaries diagnosed with CHD were tabulated based on ICD-10 codes (International Classification of Diseases, 10th revision). We examined the relationships between total costs and total hospitalizations costs post 1-year CHD diagnosis and presence or absence of High-Quality Hospital (HQH) designation. We applied both the naive generalized linear model (GLM) to control for the observed patient and hospital characteristics and the 2-stage least squares (2SLS) model to account for the unobserved confounding factors. This study was approved by University of Maryland, College Park Institutional Review Board (IRB) (Approval Number: 1576246-2). A relationship between HQH designation and total CHD related costs was not seen across 2SLS model specifications (marginal effect; -$41,579; 95% CI, -$83,429 to $271). For patients diagnosed with a moderate-complex or single ventricle CHD, the association of HQH status was a statistically significant reduction in total costs (marginal effect; -$84,395; 95% CI, -$140,560 to -$28,229) and hospitalization costs (marginal effect; -$73,958; 95% CI, -$121,878 to -$26,039). It is very imperative for clinicians and patient support advocates to urge policymakers to deliberate the establishment of a quality designation authority for CHD management. These efforts will not only help to identify and standardize quality care metrics but to improve long-term health, effectiveness, and equity in the management of CHD. Furthermore, these efforts can be used to navigate patients to proven HQH, thereby improving care and reducing associated treatment costs for CHD patients.

Retrospective Cohort Study of Additional Procedures and Transplant-Free Survival for Patients With Functionally Single Ventricle Disease Undergoing Staged Palliation in England and Wales.

Reinterventions may influence the outcomes of children with functionally single-ventricle (f-SV) congenital heart disease. We undertook a retrospective cohort study of children starting treatment for f-SV between 2000 and 2018 in England, using the national procedure registry. Patients were categorized based on whether they survived free of transplant beyond 1 year of age. Among patients who had transplant-free survival beyond 1 year of age, we explored the relationship between reinterventions in infancy and the outcomes of survival and Fontan completion, adjusting for complexity. Of 3307 patients with f-SV, 909 (27.5%), had no follow-up beyond 1 year of age, among whom 323 (35.3%) had ≥1 reinterventions in infancy. A total of 2398 (72.5%) patients with f-SV had transplant-free survival beyond 1 year of age, among whom 756 (31.5%) had ≥1 reinterventions in infancy. The 5-year transplant-free survival and cumulative incidence of Fontan, among those who survived infancy, were 93.4% (95% CI, 92.4%-94.4%) and 79.3% (95% CI, 77.4%-81.2%), respectively. Both survival and Fontan completion were similar for those with a single reintervention and those who had no reinterventions. Patients who had >1 additional surgery (adjusted hazard ratio, 3.93 [95% CI, 1.87-8.27] P<0.001) had higher adjusted risk of mortality. Patients who had >1 additional interventional catheter (adjusted subdistribution hazard ratio, 0.71 [95% CI, 0.52-0.96] P=0.03) had a lower likelihood of achieving Fontan. Among children with f-SV, the occurrence of >1 reintervention in the first year of life, especially surgical reinterventions, was associated with poorer prognosis later in childhood.

Meta-regression of sulcal patterns, clinical and environmental factors on neurodevelopmental outcomes in participants with multiple CHD types.

Congenital heart disease affects 1% of infants and is associated with impaired neurodevelopment. Right- or left-sided sulcal features correlate with executive function among people with Tetralogy of Fallot or single ventricle congenital heart disease. Studies of multiple congenital heart disease types are needed to understand regional differences. Further, sulcal pattern has not been studied in people with d-transposition of the great arteries. Therefore, we assessed the relationship between sulcal pattern and executive function, general memory, and processing speed in a meta-regression of 247 participants with three congenital heart disease types (114 single ventricle, 92 d-transposition of the great arteries, and 41 Tetralogy of Fallot) and 94 participants without congenital heart disease. Higher right hemisphere sulcal pattern similarity was associated with improved executive function (Pearson r = 0.19, false discovery rate-adjusted P = 0.005), general memory (r = 0.15, false discovery rate P = 0.02), and processing speed (r = 0.17, false discovery rate P = 0.01) scores. These positive associations remained significant in for the d-transposition of the great arteries and Tetralogy of Fallot cohorts only in multivariable linear regression (estimated change β = 0.7, false discovery rate P = 0.004; β = 4.1, false discovery rate P = 0.03; and β = 5.4, false discovery rate P = 0.003, respectively). Duration of deep hypothermic circulatory arrest was also associated with outcomes in the multivariate model and regression tree analysis. This suggests that sulcal pattern may provide an early biomarker for prediction of later neurocognitive challenges among people with congenital heart disease.

A prospective multicenter feasibility study of a miniaturized implantable continuous flow ventricular assist device in smaller children with heart failure

There is no FDA-approved left ventricular assist device (LVAD) for smaller children permitting routine hospital discharge. Smaller children supported with LVADs typically remain hospitalized for months awaiting heart transplant-a major burden for families and a challenge for hospitals. We describe the initial outcomes of the Jarvik 2015, a miniaturized implantable continuous flow LVAD, in the NHLBI-funded Pumps for Kids, Infants, and Neonates (PumpKIN) study, for bridge-to-heart transplant. Children weighing 8 to 30 kg with severe systolic heart failure and failing optimal medical therapy were recruited at 7 centers in the United States. Patients with severe right heart failure and single-ventricle congenital heart disease were excluded. The primary feasibility endpoint was survival to 30 days without severe stroke or non-operational device failure. Of 7 children implanted, the median age was 2.2 (range 0.7, 7.1) years, median weight 10 (8.2 to 20.7) kilograms; 86% had dilated cardiomyopathy; 29% were INTERMACS profile 1. The median duration of Jarvik 2015 support was 149 (range 5 to 188) days where all 7 children survived including 5 to heart transplant, 1 to recovery, and 1 to conversion to a paracorporeal device. One patient experienced an ischemic stroke on day 53 of device support in the setting of myocardial recovery. One patient required ECMO support for intractable ventricular arrhythmias and was eventually transplanted from paracorporeal biventricular VAD support. The median pump speed was 1600 RPM with power ranging from 1-4 Watts. The median plasma free hemoglobin was 19, 30, 19 and 30 mg/dL at 7, 30, 90 and 180 days or time of explant, respectively. All patients reached the primary feasibility endpoint. Patient-reported outcomes with the device were favorable with respect to participation in a full range of activities. Due to financial issues with the manufacturer, the study was suspended after consent of the eighth patient. The Jarvik 2015 LVAD appears to hold important promise as an implantable continuous flow device for smaller children that may support hospital discharge. The FDA has approved the device to proceed to a 22-subject pivotal trial. Whether this device will survive to commercialization remains unclear because of the financial challenges faced by industry seeking to develop pediatric medical devices. (Supported by NIH/NHLBI HHS Contract N268201200001I, clinicaltrials.gov 02954497).

Single-cell multiomics guided mechanistic understanding of Fontan-associated liver disease.

The Fontan operation is the current standard of care for single-ventricle congenital heart disease. Individuals with a Fontan circulation (FC) exhibit central venous hypertension and face life-threatening complications of hepatic fibrosis, known as Fontan-associated liver disease (FALD). The fundamental biology and mechanisms of FALD are little understood. Here, we generated a transcriptomic and epigenomic atlas of human FALD at single-cell resolution using multiomic snRNA-ATAC-seq. We found profound cell type-specific transcriptomic and epigenomic changes in FC livers. Central hepatocytes (cHep) exhibited the most substantial changes, featuring profound metabolic reprogramming. These cHep changes preceded substantial activation of hepatic stellate cells and liver fibrosis, suggesting cHep as a potential first "responder" in the pathogenesis of FALD. We also identified a network of ligand-receptor pairs that transmit signals from cHep to hepatic stellate cells, which may promote their activation and liver fibrosis. We further experimentally demonstrated that activins A and B promote fibrotic activation in vitro and identified mechanisms of activin A's transcriptional activation in FALD. Together, our single-cell transcriptomic and epigenomic atlas revealed mechanistic insights into the pathogenesis of FALD and may aid identification of potential therapeutic targets.

Objective Quantification of Bilateral Bubble Contrast Echocardiography Correlates with Systemic Oxygenation in Patients with Single Ventricle Circulation.

Bubble contrast echocardiography is commonly used to diagnose pulmonary arteriovenous malformations (PAVMs) in single ventricle congenital heart disease (CHD), yet previous studies inconsistently report a correlation between bubble echoes and oxygenation. In this study, we sought to re-evaluate the correlation between bubble echoes and oxygenation by assessing total bilateral shunting and unilateral shunting. We conducted a single-center, retrospective study of patients with single ventricle CHD and previous Glenn palliation who underwent a cardiac catheterization and bubble echocardiogram during the same procedure from 2011 to 2020. Spearman's rank correlation was performed to examine the relationship between total bilateral shunting and measures of systemic oxygenation, as well as unilateral shunting and ipsilateral pulmonary vein oxygenation. For all patients (n = 72), total bilateral shunting moderately correlated with peripheral oxygen saturation (SpO2) (rs = -0.44, p < 0.0001). For patients with Glenn/Kawashima circulation (n = 49), total bilateral shunting was moderately correlated (SpO2: rs = -0.38, p < 0.01). In contrast, unilateral shunting did not correlate with ipsilateral pulmonary vein oxygenation for any vein measured (p = 0.16-p > 0.99). In conclusion, the total burden of bilateral bubble shunting correlated with systemic oxygenation and may better reflect the total PAVM burden from all lung segments. Unilateral correlation may be adversely influenced by non-standardized approaches to pulmonary vein sampling.

Characteristics and outcomes of children determined to be noncandidates for heart transplant

BackgroundChildren being considered for heart transplantation (HT) undergo structured evaluation to determine HT candidacy. Some are determined not to be candidates after evaluation, but outcomes in these patients are not well known. MethodsWe retrospectively reviewed patients evaluated for HT at our institution (freestanding children’s hospital) between 2013 and 2022. Patients who completed HT evaluation but were determined not to be candidates were identified. Clinical characteristics, reasons for non-candidacy, and outcomes of these non-candidates were described using summary statistics. ResultsDuring the study period, 264 patients were evaluated for HT. Of these, 75 patients (28.4%) were determined not to be candidates. The median age of non-candidates was 2.5 years. The most common diagnosis was single ventricle congenital heart disease (SV CHD) in 61.3%; cardiomyopathy was seen in 21.3%. The most common reason for non-candidacy was being too well for HT (36.7%), followed by too sick for HT (27.8%). With median follow-up duration of 3.5 years, 49.3% of patients were alive without undergoing HT; for non-candidates on the basis of being too well, 81.5% were alive without undergoing HT. Of the 36% of patients who died after determination of non-candidacy, 58.6% had SV CHD. ConclusionsA substantial proportion of children undergoing evaluation for HT are ultimately determined not to be candidates. Outcomes for non-candidates vary depending on the reason for non-candidacy. The majority of patients who died after determination of non-candidacy had single ventricle CHD, indicating opportunities for increasing access to HT and other advanced therapies in this patient population.

Parental Impressions and Perspectives of Efficacy in Prenatal Counseling for Single Ventricle Congenital Heart Disease

Although commonly performed, optimal techniques, strategies, and content to achieve the most effective prenatal counseling have not been explored. We investigate the efficacy of prenatal counseling via survey feedback of parents of children with prenatally diagnosed single ventricle. Grades of counseling using a Likert scale (1–5) were solicited to assess: (1) overall impression of quantity of counseling, (2) explanation of the heart defect, (3) preparation for heart surgery, (4) preparation for hospital course and care, (5) preparation for complications and outcomes of a Fontan circulation, and (6) preparation for neurological, school-related, or behavioral problems. Impressions were solicited concerning specific providers. A comprehensive fetal counseling score was calculated for each participant. Burden of care including length of hospitalization was explored as impacting prenatal counseling grades. There were 59 survey respondents. Average age of the children at the time of survey was 4.6 ± 3.3 years (range 1–10 years). Highest grades were for explanation of the heart condition, with lowest grades for preparation for neurological, school-related, or behavioral problems. Cardiac surgeon received the highest with social worker lowest grade for provider. Negative correlation was found between the composite fetal counseling score and parental recollection of length of hospitalization (Pearson r = − 0.357, p < 0.01). Prenatal counseling for neurological, school-related, and behavioral problems in single ventricle is deficient. Further studies analyzing prenatal counseling techniques and content can help improve upon the delivery of this important aspect of prenatal care.

Neuroimaging and Neurodevelopmental Outcomes Among Individuals With Complex Congenital Heart Disease: JACC State-of-the-Art Review.

Although neuroimaging advances have deepened our understanding of brain health in individuals with congenital heart disease (CHD), it is less clear how neuroimaging findings relate to neurodevelopmental and mental health outcomes across the lifespan. We systematically synthesized and critically evaluated evidence on associations between neuroimaging and neurodevelopmental, neurocognitive, psychiatric, or behavioral outcomes among individuals with transposition of great arteries or single-ventricle CHD (Protocol CRD42021229617). Six databases were searched and 45 papers from 25 unique studies were identified. Structural brain injury was generally linked to poorer neurodevelopment in infancy. Brain volumes and microstructural and functional brain changes appear linked to neurocognitive outcomes, including deficits in attention, learning, memory, and executive function in children and adolescents. Fetal neuroimaging studies were limited. Four papers investigated psychiatric outcomes; none found associations with neuroimaging. Multicenter, longitudinal studies incorporating functional neuroimaging and mental health outcomes are much-needed to inform early neuroprotective and therapeutic strategies in CHD.

Quantifying Additional Procedures in Functionally Single-Ventricle Disease: A National Cohort Study

BackgroundGiven their importance as a metric for health care evaluation, this study’s aim was to evaluate the rates of surgical and catheter reinterventions for children with functionally single-ventricle (f-SV) congenital heart disease (CHD) undergoing staged palliation. MethodsWe undertook a retrospective cohort study of children born with f-SV CHD between 2000 and 2018 in England and Wales, using the national registry, with survival ascertained in 2020. Competing risk analysis was used to describe the incidence of additional procedures that occurred first, during follow-up, accounting for competing events of death or transplantation. ResultsOf 56,039 patients who received an intervention for CHD, 3307 (5.9%) had f-SV. The largest diagnostic subcategories were hypoplastic left heart syndrome (1266 [38.3%]), tricuspid atresia (448 [13.5%]), and double-inlet left ventricle (328 [9.9%]). During a median follow-up of 5.4 (interquartile range, 0.8-10.8) years, 921 (27.9%) patients had at least 1 additional interstage surgery and 1293 (39.1%) had at least 1 additional interstage catheter intervention. The cumulative incidence of additional surgery at 6 months after stage 1 was 17.6% (95% CI, 16.2%-19.0%); at 2 years after stage 2, 8.3% (7.2%-9.5%); and at 5 years after stage 3, 8.4% (7.0%-9.9%). The cumulative incidence of additional catheter at 6 months after stage 1 was 18.0% (16.6%-19.4%); at 2 years after stage 2, 14.7% (13.3%-16.2%); and at 5 years after stage 3, 23.7% (21.5%-26.0%). ConclusionsIt is important to quantify additional procedures for children with f-SV disease to inform parents and health professionals, potentially facilitating the development of interventions that aim to reduce these important adverse outcomes.

Association of genetic and sulcal traits with executive function in congenital heart disease.

Persons with congenital heart disease (CHD) are at increased risk of neurodevelopmental disabilities, including impairments to executive function. Sulcal pattern features correlate with executive function in adolescents with single-ventricle heart disease and tetralogy of Fallot. However, the interaction of sulcal pattern features with genetic and participant factors in predicting executive dysfunction is unknown. We studied sulcal pattern features, participant factors, and genetic risk for executive function impairment in a cohort with multiple CHD types using stepwise linear regression and machine learning. Genetic factors, including predicted damaging de novo or rare inherited variants in neurodevelopmental disabilitiesrisk genes, apolipoprotein E genotype, and principal components of sulcal pattern features were associated with executive function measures after adjusting for age at testing, sex, mother's education, and biventricular versus single-ventricle CHD in a linear regression model. Using regression trees and bootstrap validation, younger participant age and larger alterations in sulcal pattern features were consistently identified as important predictors of decreased cognitive flexibility with left hemisphere graph topology often selected as the most important predictor. Inclusion of both sulcal pattern and genetic factors improved model fit compared to either alone. We conclude that sulcal measures remain important predictors of cognitive flexibility, and the model predicting executive outcomes is improved by inclusion of potential genetic sources of neurodevelopmental risk. If confirmed, measures of sulcal patterning may serve as early imaging biomarkers to identify those at heightened risk for future neurodevelopmental disabilities.

Trends in mortality risk of patients with congenital heart disease during the COVID-19 pandemic

Cardiovascular conditions are considered risk factors for poor outcomes associated with COVID-19. However, the effect of the COVID-19 pandemic on the mortality of patients with congenital heart disease (CHD) is unclear. Our study aims to examine the trends in mortality risk of CHD patients during the COVID-19 pandemic. This is a retrospective cohort study from the Pediatric Cardiac Care Consortium, a US-based registry of interventions for CHD. We included patients having US residence and direct identifiers; death events were captured by matching with the National Death Index. The observation window (2017-2022) was divided into pre-COVID-19 and COVID-19 era defined around the national onset of COVID-19 disease in 2020. Stratified Cox model was used to assess all-cause mortality between the pre- and the COVID-19 era. Among 45,130 patients with CHD (median age in 2017: 23.3 years, IQR: 19.0-28.4), 503 deaths occurred during the pandemic with 44 deaths (8.7%) attributed to COVID-19 (COVID-19 mortality rate of 0.09%). The overall risk of death for patients with all types of CHD during the pandemic was significantly higher compared to the pre-COVID-19 era (aHR 1.28, 95%CI: 1.08-1.53), with a differential trend towards increased risk in patients with two-ventricle (aHR 1.44, 95% CI: 1.19-1.76) vs unchanged risk for those with single ventricle CHD (aHR=0.83, 95% CI: 0.57-1.21). Adjusted subgroup analysis revealed a higher risk of death during the pandemic for CHD patients with male and chromosomal abnormalities. The excess deaths during the pandemic were attributed to COVID-19 itself rather than CHD or cardiovascular conditions. In this large CHD cohort study, there was a higher risk of death among CHD patients with male and chromosomal abnormalities. A differential trend towards higher risk for those with two vs. unchanged risk for single ventricle CHD was presented. The excess mortality was attributed to the COVID-19 itself and not to conditions potentially related to deferral of care. These results justify targeted protective measures towards the CHD population and may provide guidance for public health and medical care response in future epidemics.

Eight-year follow-up of cardiosphere-derived cell transplantation in patients with single ventricle congenital heart disease

Abstract Background Although transcoronary infusion of cardiosphere-derived cells (CDCs) in patients with single ventricles provides short-term improvement in cardiac function, the long-term efficacy is still unknown. Purpose: We tested the hypothesis that CDC infusion is associated with improved long-term clinical outcome in patients with single ventricles and heart failure. Methods: Patients were enrolled in the TICAP phase 1 (Transcoronary Infusion of Cardiac Progenitor Cells in Patients With Single Ventricle Physiology) and PERSEUS phase 2 (Cardiac Progenitor Cell Infusion to Treat Univentricular Heart Disease) trials between January 5, 2011, and January 30, 2015. The inclusion criteria were that patients were aged &amp;lt;6 years who were diagnosed with single ventricle lesions undergoing stage 2 (bidirectional Glenn: BDG) or stage 3 (total cavopulmonary connection: TCPC) palliation. Ventricular ejection fraction should be &amp;lt;60% during the initial screening through the final enrollment. Medical records of patients with single ventricles were obtained and analyzed as a control group who were eligible but were treated by staged palliation alone. We evaluated the effectiveness of CDCs using an integrated cohort study in 93 patients with single ventricles, including 41 patients who received CDC infusion and 52 controls. Results: At the time of this study, 36 patients with CDC infusion and 42 controls were alive without cardiac transplantation, with mean follow-up of 9.7±1.2 years. Survival rate did not differ between the 2 groups (log-rank P = 0.351), whereas overall patients treated by CDCs had lower incidents of late failure defined as late death, protein-losing enteropathy, plastic bronchitis, BDG or TCPC take down, disqualified TCPC candidate, Ross classification 3 or 4, or rehospitalization for heart failure (P = 0.048) compared with controls. Adverse events defined as unplanned cardiac operation, arrhythmia, thromboembolic events, cerebral hemorrhage, or tumor formation (P = 0.057) and unplanned catheter intervention (P = 0.094) did not differ between 2 groups. Conclusions: Intracoronary delivery of CDCs in patients with single ventricles did not improve all-cause mortality rate but significantly reduced the incidence of late failure at 8 years of follow-up.

Abstract 18596: Sildenafil Modulates Metabolic Remodeling by Increasing Fatty Acid β-Oxidation in Single Ventricle Congenital Heart Disease

Introduction: Sildenafil, a phosphodiesterase-5 inhibitor (PDE5i), is used to treat heart and circulatory failure (HF) in single ventricle congenital heart disease (SV). We previously demonstrated that human SVHF myocardium is characterized by increased PDE5 activity and impaired mitochondrial energetics, which are improved with PDE5i. Using an in vitro model in combination with SV myocardial tissue, we test the hypothesis that mitochondrial fatty acid β-oxidation (FAO) is improved with PDE5i therapy via activation of sirtuin-3 (Sirt3) and resulting protein deacetylation. Methods: Primary cardiomyocytes (neonatal rat ventricular myocytes, NRVMs) were treated with 2% serum from SVHF patients or non-failing (NF) controls +/-PDE5i (72 hours). To mechanistically interrogate whether PDE5i acts via Sirt3, we utilized siRNAs against Sirt3 +/-PDE5i. FAO was directly assessed via the Seahorse Bioanalyzer (Agilent). Mitochondrial protein levels and acetylation profiles were quantified via Western blot. Sirt3 activity was measured in isolated mitochondria from SVHF myocardium using a fluorescent-based enzymatic assay. Statistical analysis was performed using a Welch ANOVA with post-hoc Dunnett’s multiple comparisons test (FAO) or a paired T test (Sirt3 activity). Results: NRVMs treated with SVHF serum have impaired mitochondrial FAO and while PDE5i therapy results in improved FAO, siRNA knockdown of Sirt3 abolishes the PDE5i protective effect (A). Mitochondria isolated from SVHF myocardium are hyperacetylated, and ex vivo PDE5i treatment enhances Sirt3 deacetylase activity (B-C), and deacetylates mitochondrial proteins. Conclusions: SVHF serum treatment of cardiomyocytes is a novel in vitro platform for mechanistic investigations of SV-related pathophysiology. These data suggest PDE5i directly augments mitochondrial FAO via Sirt3-mediated protein deacetylation and provides important insight into the myocardial specific mechanisms of PDE5i.

Abstract 18567: Acute Inhibition of Phosphodiesterase 1 (PDE1) Decreases Tension Generation in Pediatric Heart Failure

Introduction: Children with heart failure (HF) due to dilated cardiomyopathy (DCM) or single ventricle congenital heart disease (SV) ultimately require heart transplantation due to the lack of effective medical therapies. Inhibition of PDE1 (PDE1i) is currently being investigated in adult HF, however it is unclear if PDE1i use should be extrapolated to pediatric HF. Objective: To evaluate the acute effect of PDE1i on loaded myocardial contractility in pediatric DCM and SV trabeculae. Methods: Hearts were obtained from DCM (N=25) and SV (N=27) children who underwent transplant between 2010-2020. Right ventricular trabeculae are freshly isolated and mounted in a multi-chamber muscle bath. Ex vivo contractile response of isolated trabeculae was measured in response to 10uM PDE1i, the non-selective β-agonist isoproterenol (Iso), and untreated. To assess contractile response with increased cyclic adenosine monophosphate (cAMP) from β-adrenergic stimulation, a subset of baths received Iso and PDE1i. Percent change in max tension was determined by the difference between max tension and baseline tension, divided by baseline tension. Results: In pediatric DCM and SV trabeculae, acute PDE1i resulted in lower max tension generation when compared to untreated trabeculae (DCM p=0.003 and SV p=0.01). In DCM trabeculae, % change in tension was also lower with PDE1i when compared to Iso (p=0.0053) however there was only a trend toward significance in SV (p=0.06). There was no difference between % change in tension between Iso and PDE1i+Iso in either DCM or SV. Conclusions: Although PDE1 has high expression and activity in human cardiomyocytes, acute PDE1i treatment of explanted trabeculae results in decreased max tension generation. Even in the setting of elevated cAMP, PDE1i does not alter max tension generation. Thus, while there may be beneficial effects of PDE1i in pediatric HF, the consequences are unlikely related to a direct increase in cardiomyocyte contractility.

Abstract 18334: Altered in-vivo Placental Microstructure Predicts Adverse Neurodevelopmental Outcomes in Toddlers With Congenital Heart Disease

Introduction: Pregnancies complicated by fetal congenital heart disease (CHD) are at risk for disrupted placenta function; placental insufficiency, in turn, is a risk factor that may adversely impact offspring neurodevelopment. However, the relationship between altered in-vivo placenta function and infant neurobehavioral outcomes in CHD is unknown. Hypothesis: We hypothesized that altered in-vivo placenta microstructural diffusion in CHD would be associated with impaired infant neurodevelopment. Methods: We prospectively recruited women with pregnancies complicated by CHD diagnosis and low-risk pregnancies. Women underwent an MRI on a GE 1.5T scanner at 20-39 gestational weeks. T2w sequence and pulsed gradient spin echo were acquired for placenta volume and diffusion kurtosis measures. Bayley-III and Infant-Toddler Social and Emotional Assessment were completed at around 18 months. Generalized estimating equation was used to examine the association between placenta measures and infant outcomes, adjusting for potential confounders. Results: We enrolled 236 mother/baby dyads (111 CHD; 125 controls) who underwent 394 MRIs (175 CHD; 219 controls). Forty-seven had single-ventricle (SV) CHD and 64 had two-ventricle (2V) CHD. In CHD, 32 subjects died, and 71 infants had neurodevelopment testing at a mean age of 20 months. Placenta diffusion coefficient (dki_d), reflecting tissue cellularity, was higher in CHD vs controls (p=0.009). In CHD, placenta diffusional kurtosis (dki_k), reflecting tissue heterogeneity, was lower in neonates who died pre-operatively vs those who survived (p=0.05). Compared to 2V CHD, pregnancies with SV fetuses had lower placenta dki_k and trending higher placenta dki_d. In CHD, higher placenta dki_d was associated with poorer language skills (p=0.05) while lower placenta dki_k was associated with higher behavioral dysregulation (p=0.03). Conclusions: We report for the first time disturbances in placenta microstructural diffusion in CHD. We also demonstrate that altered placenta diffusion was associated with impaired language and behavioral dysregulation in CHD toddlers. These data suggest that altered placenta microstructure may be an important biomarker for later neurodevelopmental dysfunction in CHD.

Associations of Liver Stiffness Measured by Ultrasound Shear-Wave Elastography With Portal Hypertension and Circulatory Failure in Individuals With Fontan Circulation.

BACKGROUND. The Fontan operation palliates single-ventricle congenital heart disease but causes hepatic congestion with associated progressive hepatic fibrosis. OBJECTIVE. The purpose of this study was to evaluate associations between liver stiffness measured using ultrasound (US) shear-wave elastography (SWE) in patients with Fontan palliation and the occurrence of portal hypertension and Fontan circulatory failure during follow-up. METHODS. This retrospective study included 119 individuals 10 years old or older (median age, 19.1 years; 61 female patients, 58 male patients) with Fontan circulation who underwent liver US with 2D SWE from January 1, 2015, to January 1, 2022, and had 1 year or more of clinical follow-up (unless experiencing earlier outcome-related events). Median liver stiffness from the initial US examination was documented. Varices, ascites, splenomegaly, and thrombocytopenia (VAST) scores (range, 0-4) were determined as a marker of portal hypertension on initial US examination and 1 year or more of follow-up imaging (US, CT, or MRI). Composite clinical outcome for Fontan circulatory failure (death, mechanical circulatory support, cardiac transplant, or unexpected Fontan circulation-related hospitalization) was assessed. Analysis included the Wilcoxon rank sum test, logistic regression analysis with stepwise variable selection, and ROC analysis. RESULTS. Median initial liver stiffness was 2.22 m/s. Median initial VAST score was 0 (IQR, 0-1); median follow-up VAST score was 1 (IQR, 0-2) (p = .004). Fontan circulatory failure occurred in 37 of 119 (31%) patients (median follow-up, 3.4 years). Initial liver stiffness was higher in patients with a follow-up VAST score of 1 or greater (2.37 m/s) than in those with a follow-up VAST score of 0 (2.08 m/s) (p = .005), and initial liver stiffness was higher in patients with (2.43 m/s) than without (2.10 m/s) Fontan circulatory failure during follow-up (p < .001). Initial liver stiffness was the only significant independent predictor of Fontan circulatory failure (OR = 3.76; p < .001); age, sex, Fontan operation type, dominant ventricular morphology, and initial VAST score were not independent predictors. Initial liver stiffness had an AUC of 0.70 (sensitivity, 79%; specificity, 57%; threshold, > 2.11 m/s) for predicting a follow-up VAST score of 1 or greater and an AUC of 0.74 (sensitivity, 84%; specificity, 52%; threshold, > 2.12 m/s) for predicting Fontan circulatory failure. CONCLUSION. In patients with Fontan circulation, increased initial liver stiffness was associated with portal hypertension and circulatory failure during follow-up, although it had moderate performance in predicting these outcomes. CLINICAL IMPACT. US SWE may play a role in post-Fontan surveillance, supporting tailored medical and surgical care.

The Effect of Udenafil on Heart Rate and Blood Pressure in Adolescents With the Fontan Circulation

The Fontan Udenafil Exercise Longitudinal (FUEL) trial showed that treatment with udenafil was associated with improved exercise performance at the ventilatory anaerobic threshold in children with Fontan physiology. However, it is not known how the initiation of phosphodiesterase 5 inhibitor therapy affects heart rate and blood pressure in this population. These data may help inform patient selection and monitoring after the initiation of udenafil therapy. The purpose of this study is to evaluate the effects of udenafil on vital signs in the cohort of patients enrolled in the FUEL trial. This international, multicenter, randomized, double-blind, placebo-controlled trial of udenafil included adolescents with single ventricle congenital heart disease who had undergone Fontan palliation. Changes in vital signs (heart rate [HR], systolic [SBP] and diastolic blood pressure [DBP]) were compared both to subject baseline and between the treatment and the placebo groups. Additional exploratory analyses were performed to evaluate changes in vital signs for prespecified subpopulations believed to be most sensitive to udenafil initiation. Baseline characteristics were similar between the treatment and placebo cohorts (n=200 for each). The groups demonstrated a decrease in HR, SBP, and DBP 2 hours after drug/placebo administration, except SBP in the placebo group. There was an increase in SBP from baseline to after 6-min walk test in the treatment and placebo groups, and the treatment group showed an increase in HR (87.4 ± 15.0 to 93.1 ± 19.4 beats/min, p <0.01) after exercise. When comparing changes from baseline to the 26-week study visit, small decreases in both SBP (-1.9 ± 12.3 mm Hg, p=0.03) and DBP (-3.0 ± 9.6 mm Hg, p <0.01) were seen in the treatment group. There were no clinically significant differences between treatment and placebo group in change in HR or blood pressure in the youngest age quartile, lightest weight quartile, or those on afterload-reducing agents. In conclusion, initiation of treatment with udenafil in patients with Fontan circulation was not associated with clinically significant changes in vital signs, implying that for patients similar to those enrolled in the FUEL trial, udenafil can be started without the requirement for additional monitoring after initial administration.

Three decades of collaboration through the Pediatric Heart Transplant Society Registry: A journey through registry data with a highlight on children with single ventricle anatomy.

The Pediatric Heart Transplant Society (PHTS) Registry was founded 30 years ago as a collaborative effort among like-minded providers of this novel life-saving technique for children with end-stage heart failure. In the intervening decades, the data from the Registry have provided invaluable knowledge to the field of pediatric heart transplantation. This report of the PHTS Registry provides a comprehensive look at the data, highlighting both the longevity of the registry and one unique aspect of the PHTS registry, allowing for exploration into children with single ventricle anatomy. The PHTS database was queried from January 1, 1993 to December 31, 2019 to include pediatric (age < 18 years) patients listed for HT. For our analysis, we primarily analyzed patients by era. The early era was defined as children listed for HT from January 1, 1993 to December 31, 2004; middle era January 1, 2005 to December 31, 2009; and recent era January 1, 2010 to December 31, 2019. Outcomes after listing and transplant, including mortality and morbidities, are presented as unadjusted for risk, but compared across eras. Since 1993, 11 995 children were listed for heart transplant and entered into the PHTS Registry with 9755 listed during the study period. The majority of listings occurred within the most recent era. Waitlist survival improved over the decades as did posttransplant survival. Other notable changes over time include fewer patients experiencing allograft rejection or infection after transplant. Waitlist and posttransplant survival have changed dramatically in patients with single ventricle physiology and significantly differ by stage of single ventricle palliation. Key points from this PHTS Registry summary and focus on patients with single ventricle congenital heart disease in particular, include the changing landscape of candidates and recipients awaiting heart transplant. There is clear improvement in waitlist and transplant outcomes for children with both cardiomyopathy and congenital heart disease alike.