Associations of Home Monitoring Data to Interventional Catheterization for Infants with Recurrent Coarctation of the Aorta and Hypoplastic Left Heart Syndrome.

The post-Norwood interstage period for infants with hypoplastic left heart syndrome is a high-risk time with 10-20% of infants having a complication of recurrent coarctation of the aorta (RCoA). Many interstage programs utilize mobile applications allowing caregivers to submit home physiologic data and videos to the clinical team. This study aimed to investigate if caregiver-entered data resulted in earlier identification of patients requiring interventional catheterization for RCoA. Retrospective home monitoring data were extracted from five high-volume Children's High Acuity Monitoring Program®-affiliated centers (defined as contributing > 20 patients to the registry) between 2014 and 2021 after IRB approval. Demographics and caregiver-recorded data evaluated include weight, heart rate (HR), oxygen saturation (SpO2), video recordings, and 'red flag' concerns prior to interstage readmissions. 27% (44/161) of infants required interventional catheterization for RCoA. In the 7 days prior to readmission, associations with higher odds of RCoA included (mean bootstrap coefficient, [90% CI]) increased number of total recorded videos (1.65, [1.07-2.62]) and days of recorded video (1.62, [1.03-2.59]); increased number of total recorded weights (1.66, [1.09-2.70]) and days of weights (1.56, [1.02-2.44]); increasing mean SpO2 (1.55, [1.02-2.44]); and increased variation and range of HR (1.59, [1.04-2.51]) and (1.71, [1.10-2.80]), respectively. Interstage patients with RCoA had increased caregiver-entered home monitoring data including weight and video recordings, as well as changes in HR and SpO2trends. Identifying these items by home monitoring teams may be beneficial in clinical decision-making for evaluation of RCoA in this high-risk population.

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. METHODS: The 400 enrolled participants were randomized 1:1 to udenafil or placebo. Protocol echocardiograms were obtained at baseline and 26 weeks after initiation of udenafil/placebo. Linear regression compared change from baseline indices of single ventricle systolic, diastolic and global function, atrioventricular valve regurgitation, and mean Fontan fenestration gradient in the udenafil cohort versus placebo, controlling for ventricular morphology (left ventricle versus right ventricle/other) and baseline value. RESULTS: The udenafil participants (n=191) had significantly improved between baseline and 26 weeks visits compared to placebo participants (n=195) in myocardial performance index (P=0.03, adjusted mean difference [SE] of changes between groups -0.03[0.01]), atrioventricular valve inflow peak E (P=0.009, 3.95 [1.50]), and A velocities (P=0.034, 3.46 [1.62]), and annular Doppler tissue imaging-derived peak e' velocity (P=0.008, 0.60[0.23]). There were no significant differences in change in single ventricle size, systolic function, atrioventricular valve regurgitation severity, or mean fenestration gradient. Participants with a dominant left ventricle had significantly more favorable baseline values of indices of single ventricle size and function (lower volumes and areas, E/e' ratio, systolic:diastolic time and atrioventricular valve regurgitation, and higher annular s' and e' velocity). CONCLUSIONS: FUEL participants who received udenafil demonstrated a statistically significant improvement in some global and diastolic echo indices. Although small, the changes in diastolic function suggest improvement in pulmonary venous return and/or augmented ventricular compliance, which may help explain improved exercise performance in that cohort. REGISTRATION: URL: https://clinicaltrials.gov; Unique Identifier: NCT02741115.

Results of the FUEL Trial.

BACKGROUND: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. METHODS: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. RESULTS: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (-0.2%) in the placebo group (P=0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus -9±193 [-0.9%] mL/min, P=0.012), ventilatory equivalents of carbon dioxide (-0.8 versus -0.06, P=0.014), and work rate (+3.8 versus +0.34 W, P=0.021). There was no difference in change of myocardial performance index, the natural log of the reactive hyperemia index, or serum brain-type natriuretic peptide level. CONCLUSIONS: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02741115.

Pathophysiology, adaptation, and imaging of the right ventricle in Fontan circulation.

The Fontan procedure, which creates a total cavopulmonary anastomosis and represents the final stage of palliation for hypoplastic left heart syndrome, generates a unique circulation relying on a functionally single right ventricle (RV). The RV pumps blood in series around the systemic and pulmonary circulation, which requires adaptations to the abnormal volume and pressure loads. Here, we provide a complete review of RV adaptations as the RV assumes the role of the systemic ventricle, the progression of RV dysfunction to a distinct pattern of heart failure unique to this disease process, and the assessment and management strategies used to protect and rehabilitate the failing RV of Fontan circulation.

Design and rationale of the Fontan Udenafil Exercise Longitudinal (FUEL) trial.

The Fontan operation creates a circulation characterized by elevated central venous pressure and low cardiac output. Over time, these characteristics result in a predictable and persistent decline in exercise performance that is associated with an increase in morbidity and mortality. A medical therapy that targets the abnormalities of the Fontan circulation might, therefore, be associated with improved outcomes. Udenafil, a phosphodiesterase type 5 inhibitor, has undergone phase I/II testing in adolescents who have had the Fontan operation and has been shown to be safe and well tolerated in the short term. However, there are no data regarding the long-term efficacy of udenafil in this population. The Fontan Udenafil Exercise Longitudinal (FUEL) Trial is a randomized, double-blind, placebo-controlled phase III clinical trial being conducted by the Pediatric Heart Network in collaboration with Mezzion Pharma Co, Ltd. This trial is designed to test the hypothesis that treatment with udenafil will lead to an improvement in exercise capacity in adolescents who have undergone the Fontan operation. A safety extension trial, the FUEL Open-Label Extension Trial (FUEL OLE), offers the opportunity for all FUEL subjects to obtain open-label udenafil for an additional 12 months following completion of FUEL, and evaluates the long-term safety and tolerability of this medication. This manuscript describes the rationale and study design for FUEL and FUEL OLE. Together, these trials provide an opportunity to better understand the role of medical management in the care of those who have undergone the Fontan operation.

Development and Implementation of a Standardized Heparin Protocol for Left-Sided Pediatric Electrophysiology Procedures.

Heparin is used to decrease the risk of thromboembolic complications during electrophysiology studies (EPS); however, there is wide practice variation and minimal evidence to guide heparin dosing, particularly in pediatric patients. This study retrospectively analyzed heparin dosing and response, measured via activated clotting time (ACT), in patients undergoing EPS and used these data (pre-protocol cohort, n = 40), as well as guidance from available literature to implement a standardized heparin protocol (phase 1, n = 43). We utilized quality improvement methodology to refine this protocol (phase 2, n = 40) to improve therapeutic heparin response. Prior to the protocol, patients achieved therapeutic ACT levels (250-350 s) only 35% of the time which improved to 60% during phase 1 (p < 0.05) and to 73% during phase 2 (p < 0.001 compared to pre-protocol). There were no thromboses or significant adverse events in any group. These results demonstrate the effectiveness of a standardized heparin protocol in achieving effective antithrombotic therapy during left-sided pediatric EPS.

Total Anomalous Pulmonary Venous Connection: Preoperative Anatomy, Physiology, Imaging, and Interventional Management of Postoperative Pulmonary Venous Obstruction.

Total anomalous pulmonary venous connection refers to a spectrum of cardiac anomalies where the pulmonary veins fail to return to the left atrium and the pulmonary venous blood returns through a systemic vein or directly to the right atrium. There is a wide anatomical variety of venous connections and degrees of pulmonary venous obstruction that affect the presentation, surgical repair, and outcomes. In this review, we explore the preoperative physiology, echocardiographic diagnosis, and approach to postoperative complications.

Infected Congenital Epicardial Cyst Presenting as Acute Abdomen.

A previously healthy 3-year-old boy presented to the emergency department with abdominal pain, fever, and emesis. Laboratory and radiologic evaluation for causes of acute abdomen were negative; however, review of the abdominal x-ray demonstrated cardiomegaly with the subsequent diagnosis of pericardial cyst by echocardiogram and computed tomography. The patient underwent surgical decompression and attempted removal of the cystic structure revealing that the cyst originated from the epicardium. His abdominal pain and fever resolved postoperatively and he completed a 3-week course of ceftriaxone for treatment of Propionibacterium acnes infected congenital epicardial cyst. Emergency department physicians must maintain a broad differential in patients with symptoms of acute abdomen to prevent complications from serious cardiac or pulmonary diseases that present with symptoms of referred abdominal pain.

Preoperative Physiology, Imaging, and Management of Transposition of the Great Arteries.

Transposition of the great arteries (TGA) refers to hearts with concordant atrioventricular connections but discordant ventriculoarterial connections. In this lesion, the aorta arises from the right ventricle and the pulmonary artery arises from the left ventricle. As such, the pulmonary and aortic circulations run in parallel as opposed to in series, and this lesion is not compatible with survival without adequate mixing of these circulations. The management and outcomes of TGA parallels the field of pediatric cardiac surgery itself. Uniformly fatal in childhood, palliative procedures from the 1950s to 1970s offered survival, albeit at a high early and late cost. In the 1970s, the arterial switch operation (ASO) provided an anatomical "cure," with survival to adulthood in the current era of around 90%. Detailed perioperative imaging, attention to associated lesions, and comprehension of the physiology are critical to medical and surgical management.

Triiodothyronine facilitates weaning from extracorporeal membrane oxygenation by improved mitochondrial substrate utilization.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) provides a bridge to recovery after myocardial injury in infants and children, yet morbidity and mortality remain high. Weaning from the circuit requires adequate cardiac contractile function, which can be impaired by metabolic disturbances induced either by ischemia-reperfusion and/or by ECMO. We tested the hypothesis that although ECMO partially ameliorates metabolic abnormalities induced by ischemia-reperfusion, these abnormalities persist or recur with weaning. We also determined if thyroid hormone supplementation (triiodothyronine) during ECMO improves oxidative metabolism and cardiac function. METHODS AND RESULTS: Neonatal piglets underwent transient coronary ischemia to induce cardiac injury then were separated into 4 groups based on loading status. Piglets without coronary ischemia served as controls. We infused into the left coronary artery [2-(13)C]pyruvate and [(13)C6, (15)N]l-leucine to evaluate oxidative metabolism by gas chromatography-mass spectroscopy and nuclear magnetic resonance methods. ECMO improved survival, increased oxidative substrate contribution through pyruvate dehydrogenase, reduced succinate and fumarate accumulation, and ameliorated ATP depletion induced by ischemia. The functional and metabolic benefit of ECMO was lost with weaning, yet triiodothyronine supplementation during ECMO restored function, increased relative pyruvate dehydrogenase flux, reduced succinate and fumarate, and preserved ATP stores. CONCLUSIONS: Although ECMO provides metabolic rest by decreasing energy demand, metabolic impairments persist, and are exacerbated with weaning. Treating ECMO-induced thyroid depression with triiodothyronine improves substrate flux, myocardial oxidative capacity and cardiac contractile function. This translational model suggests that metabolic targeting can improve weaning.

'Shovel-Ready' applications of stem cell advances for pediatric heart disease.

PURPOSE OF REVIEW: The past decade has seen remarkable advances in the field of stem cell biology. Many new technologies and applications are passing the translational phase and likely will soon be relevant for the clinical pediatric cardiologist. RECENT FINDINGS: This review will focus on two advances in basic science that are now translating into clinical trials. The first advance is the recognition, characterization, and recent therapeutic application of resident cardiac progenitor cells (CPCs). Early results of adult trials and scattered case reports in pediatric patients support expanding CPC-based trials for end-stage heart failure in pediatric patients. The relative abundance of CPCs in the neonate and young child offers greater potential benefits in heart failure treatment than has been realized to date. The second advance is the technology of induced pluripotent stem cells (iPSCs), which reprograms differentiated somatic cells to an undifferentiated embryonic-like state. When iPSCs are differentiated into cardiomyocytes, they model a patient's specific disease, test pharmaceuticals, and potentially provide an autologous source for cell-based therapy. SUMMARY: The therapeutic recruitment and/or replacement of CPCs has potential for enhancing cardiac repair and regeneration in children with heart failure. Use of iPSCs to model heart disease holds great potential to gain new insights into diagnosis, pathophysiology, and disease-specific management for genetic-based cardiovascular diseases that are prevalent in pediatric patients.

A child with eosinophilia, Loeffler endocarditis, and acute lymphoblastic leukemia.

We present an 8-year-old male with Loeffler endocarditis and acute lymphoblastic leukemia with hypereosinophilia (ALL/Eo) who initially presented with a 3-month history of peripheral eosinophilia thought to be due to visceral larval migrans. Despite treatment for Toxocara, his leukocytosis persisted and he developed mitral valve insufficiency and congestive heart failure. Myocardial biopsy revealed fibrosis and thrombus formation indicative of Loeffler endocarditis, and a peripheral smear showed pre-B-cell acute lymphoid leukemia. This unique case highlights a rare, yet serious sequella of prolonged eosinophilia.