Revisiting the Effect of Udenafil on Exercise Performance in Patients With Fontan Circulation: Results of a Post Hoc Analysis of the FUEL Trial.

Background: In the FUEL (Fontan Udenafil Exercise Longitudinal) trial, a positive treatment effect was identified for outcomes at the ventilatory anaerobic threshold but not for the primary outcome, oxygen consumption (Vo) at peak exercise. This disparate response may be explained by the physiologic challenge of improving peak Vo in participants with near-normal baseline exercise performance.

Methods: Participants were divided into subgroups by baseline predicted peak Vo (<80% versus ≥80%).

Increased Endothelin-1 Is Associated With Morbidity in Single Ventricle Heart Disease in Children Undergoing Fontan Palliation.

Background: Endothelin-1 (ET1) is a potent vasoconstrictor and stimulator of pulmonary artery smooth muscle cell proliferation. We previously demonstrated that failure to suppress ET1 is associated with morbidity in infants with single ventricle heart disease (SVHD) undergoing stage 2 palliation.

Objectives: The aim of this study is to evaluate whether persistent failure to suppress ET1 is associated with impaired recovery among children with SVHD undergoing the stage 3 (Fontan) operation.

Pleural Drainage, Clinical Characteristics, and Management Strategies in the Perioperative Fontan Patient: A Multicenter Report.

Prolonged pleural drainage and chylothorax are common in postoperative Fontan patients and are associated with increased morbidity and mortality. Multiple medical and interventional treatment strategies exist and vary between centers. This is a retrospective multicenter observational cohort study of pediatric patients who underwent Fontan operation at 8 pediatric cardiac surgical institutions from 1/1/2019 to 12/31/2021.

Perturbations of tryptophan catabolism via the kynurenine pathway are associated with stage 2 postoperative outcomes in single ventricle heart disease.

Preliminary evidence suggests perturbations of the kynurenine pathway (KP) of tryptophan metabolism in infants with single ventricle heart disease (SVHD). In 72 infants with SVHD undergoing stage 2 palliation (S2P) and 41 controls, we quantified serum KP metabolite concentrations via tandem mass spectroscopy pre-S2P and post-S2P at 2, 24, and 48 h and assessed metabolite relationships with post-S2P outcomes (length of stay, hypoxemia burden, and intubation duration). Pre-S2P, SVHD infants had lower tryptophan and serotonin levels and higher kynurenic acid, 3-hydroxykynurenine, and picolinic acid levels than controls.

Principal component analysis identified neo-aortic diameter variations post Norwood surgery associated with the single ventricle performance and flow quality.

The purpose of this study was to investigate neo-aortic curvature and diameter variation using the principal component analysis in patients who underwent a Norwood procedure for hypoplastic left heart syndrome. We further assessed whether neo-aortic curvature and diameter features are associated with clinical outcomes, single right ventricle function and flow hemodynamic patterns derived by 4D-Flow MRI. 55 patients with Fontan circulation who underwent a Norwood procedure in infancy underwent cardiac MRI as part of surveillance of their Fontan circulation.

Application of Principal Component Analysis to Heterogenous Fontan Registry Data Identifies Independent Contributing Factors to Decline.

Single ventricle heart disease is a severe and life-threatening illness, and improvements in clinical outcomes of those with Fontan circulation have not yet yielded acceptable survival over the past two decades. Patients are at risk of developing a diverse variety of Fontan-associated comorbidities that ultimately requires heart transplant. Our observational cohort study goal was to determine if principal component analysis (PCA) applied to data collected from a substantial Fontan cohort can predict functional decline (N=140).

Arginine-NO metabolites are associated with morbidity in single ventricle infants undergoing stage 2 palliation.

Background: Infants with single ventricle heart disease (SVHD) suffer morbidity from insufficient pulmonary blood flow, which may be related to impaired arginine metabolism. No prior study has reported quantitative mapping of arginine metabolites to evaluate the relationship between circulating metabolite levels and outcomes.

Methods: Prospective cohort study of 75 SVHD cases peri-Stage 2 and 50 healthy controls.

Hemi-Fontan and bidirectional Glenn operations result in flow-mediated viscous energy loss at the time of stage II palliation.

Background: Superior cavopulmonary connection (SCPC) for stage II palliation of hypoplastic left heart syndrome (HLHS) is achieved most frequently by either a bidirectional Glenn (BDG) or hemi-Fontan (HF) operation. The comparison of flow hemodynamic efficiency at the region of surgical reconstruction and in proximal pulmonary arteries has been evaluated primarily using computational modeling techniques with conflicting reports. The purpose of this descriptive study was to compare flow hemodynamics following stage II (BDG vs HF) using 4-dimensional flow magnetic resonance imaging (4D-Flow MRI) with particular focus on flow-mediated viscous energy loss () under matched hemodynamic conditions.

Central Venous Waveform Patterns in the Fontan Circulation Independently Contribute to the Prediction of Composite Survival.

It is well appreciated that the Fontan circulation perturbs central venous hemodynamics, with elevated pressure being the clearest change associated with Fontan comorbidities, such as Fontan-associated liver disease (FALD) and protein-losing enteropathy (PLE). Our group has better quantity of these venous perturbations through single- and multi-location analyses of flow waveforms obtained from magnetic resonance imaging of Fontan patients. Here, we determine if such analyses, which yield principal components (PC) that describe flow features, are associated with Fontan survival.

Circulating biomarkers of extracellular matrix dysregulation are associated with adverse post-stage 2 outcomes in infants with single ventricle heart disease.

Children with single ventricle heart disease (SVHD) experience morbidity due to inadequate pulmonary blood flow. Using proteomic screening, our group previously identified members of the matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinase (TIMP), and fibroblast growth factor (FGF) families as potentially dysregulated in SVHD. No prior study has taken a targeted approach to mapping circulating levels of these protein families or their relationship to pulmonary vascular outcomes in SVHD.

Myocardial strain-curve deformation patterns after Fontan operation.

Myocardial deformation analysis by cardiac MRI (CMR) yielding global circumferential and longitudinal strain (GCS and GLS) is an increasingly utilized method to accurately quantify systolic function and predict clinical events in patients with Fontan circulation. The purpose of this study was to use principal component analysis (PCA) to investigate myocardial temporal deformation patterns derived from strain-time curves to learn about latent strain features beyond peak values. We conducted the study with specific attention to dominant single left or right ventricle (SLV and SRV) morphologies.

Ventricular global function index is associated with clinical outcomes in pediatric pulmonary hypertension.

Background: Multiple right ventricular (RV) metrics have prognostic value in pulmonary hypertension (PH). A cardiac magnetic resonance imaging (CMR) derived global ventricular function index (GFI) provided improved prediction of composite adverse outcome (CAO) in adults with atherosclerosis. GFI has not yet been explored in a PH population.

The Fontan Udenafil Exercise Longitudinal Trial: Subgroup Analysis.

The Pediatric Heart Network's Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT02741115) demonstrated improvements in some measures of exercise capacity and in the myocardial performance index following 6 months of treatment with udenafil (87.

Interstage Single Ventricle Heart Disease Infants Show Dysregulation in Multiple Metabolic Pathways: Targeted Metabolomics Analysis.

Background: Infants with SVHD experience morbidity related to pulmonary vascular inadequacy. Metabolomic analysis involves a systems biology approach to identifying novel biomarkers and pathways in complex diseases. The metabolome of infants with SVHD is not well understood and no prior study has evaluated the relationship between serum metabolite patterns and pulmonary vascular readiness for staged SVHD palliation.

Coupled waveform patterns in the arterial and venous fontan circulation are related to parameters of pulmonary, lymphatic and cardiac function.

The lack of a sub-pulmonary ventricle in patients with a Fontan circulation contributes to circulatory decline, largely related to increased central venous pressure. Our group has determined that single-site waveform analysis correlates with clinical features of Fontan patients. The goal of this study was to determine if multi-site waveform analysis yielded additional associations with functional status or cardiac performance.

Impact of Udenafil on Echocardiographic Indices of Single Ventricle Size and Function in FUEL Study Participants.

Background: The FUEL trial (Fontan Udenafil Exercise Longitudinal) demonstrated statistical improvements in exercise capacity following 6 months of treatment with udenafil (87.5 mg po BID). The effect of udenafil on echocardiographic measures of single ventricle function in this cohort has not been studied.

Pressure-Strain Loops, a Novel Non-invasive Approach for Assessment of Children with Cardiomyopathy.

Non-invasive myocardial work (MW) by left ventricular (LV) pressure-strain loops (PSL) is a novel method for assessing myocardial function while adjusting for afterload, yet pediatric data remain lacking. The aims of this study were to investigate the different patterns of LV PSL and non-invasive MW in pediatric patients with hypertrophic (HCM) and dilated cardiomyopathy (DCM) and their association with exercise tolerance. We included 110 pediatric subjects (mean age, 13 ± 4 years, 35 DCM, 40 HCM, and 35 healthy controls).

Increased Circulating Endothelin 1 Is Associated With Postoperative Hypoxemia in Infants With Single-Ventricle Heart Disease Undergoing Superior Cavopulmonary Anastomosis.

Background Inadequate pulmonary vascular growth results in morbidity for many children with single-ventricle heart disease (SVHD). Endothelin 1 (ET1) is a potent vasoconstrictor and stimulator of pulmonary artery smooth muscle proliferation. Circulating ET1 levels and their association with outcomes have not been studied during early SVHD palliation.

Diastolic inflow is associated with inefficient ventricular flow dynamics in Fontan patients.

Objective: This study used cardiac magnetic resonance imaging to evaluate flow characteristics and ventricular hemodynamics for children with single right (hypoplastic left heart syndrome) and single left (hypoplastic right heart syndrome) systemic ventricle anatomy after Fontan palliation compared with normal biventricular controls.

Methods: Twenty children with single ventricle anatomy (hypoplastic left heart syndrome, n = 10; hypoplastic right heart syndrome, n = 10) underwent standardized 4-dimensional flow cardiac magnetic resonance and were compared with age-matched controls (n = 10). End-diastolic volume was partitioned into 4 defined components of variable kinetic energy (direct flow, retained inflow, delayed ejection, and residual volume) and compared between groups.

High-degree Norwood neoaortic tapering is associated with abnormal flow conduction and elevated flow-mediated energy loss.

Objective: The Norwood neoaortic arch biomechanical properties are abnormal due to reduced vessel wall compliance and abnormal geometry. Others have previously described neoaortic geometric distortion by the degree of diameter reduction (tapering) and associated this with mismatched ventricular-neoaortic coupling, abnormal flow hemodynamic parameters, and worse patient outcome. Our purposes were to investigate the influence of neoaortic tapering (ie, diameter reduction) on flow-mediated viscous energy loss (E') in post-Norwood palliated hypoplastic left heart syndrome patients, and correlate flow-geometry with single ventricle power generation.

Review on Mechanical Support and Cell-Based Therapies for the Prevention and Recovery of the Failed Fontan-Kreutzer Circulation.

Though the current staged surgical strategy for palliation of single ventricle heart disease, culminating in a Fontan circulation, has increased short-term survival, mounting evidence has shown that the single ventricle, especially a morphologic right ventricle (RV), is inadequate for long-term circulatory support. In addition to high rates of ventricular failure, high central venous pressures (CVP) lead to liver fibrosis or cirrhosis, lymphatic dysfunction, kidney failure, and other comorbidities. In this review, we discuss the complications seen with Fontan physiology, including causes of ventricular and multi-organ failure.

Use of compressed sensing to reduce scan time and breath-holding for cardiac cine balanced steady-state free precession magnetic resonance imaging in children and young adults.

Background: Conventional pediatric volumetric MRI acquisitions of a short-axis stack typically require multiple breath-holds under anesthesia.

Objective: Here, we aimed to validate a vendor-optimized compressed-sensing approach to reduce scan time during short-axis balanced steady-state free precession (bSSFP) cine imaging.

Materials And Methods: Imaging was performed in 28 patients (16±9 years) in this study on a commercial 3-tesla (T) scanner using retrospective electrocardiogram-gated cine bSSFP.

Patient and Family Experience in a Multidisciplinary Clinic for Children With Single-Ventricle Heart Disease.

Children with single-ventricle heart disease (SVHD) are at risk for morbidity across multiple organ systems. A single-ventricle multidisciplinary clinic (SVMDC) may address complex health-care needs by providing access to, and coordination among, pediatric subspecialties. However, the patient and family experience of multidisciplinary care for SVHD remains unexplored.