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We report a case of a 7-year old male with idiopathic pulmonary arterial hypertension, successfully transitioned from an intravenous infusion to inhaled treprostinil during inpatient admission, after his intentional removal of multiple central venous catheters. He had no clinical, echocardiographic, or serum biomarker evidence of loss of control of pulmonary arterial hypertension during the 4-day transition. The patient was discharged home without complications, and 3 weeks after discharge the patient's pulmonary hypertension remained well controlled per clinical and echocardiographic evidence, including a significantly improved 6-minute walk distance test., Competing Interests: Disclosures. The authors have no competing interests to disclose. The authors had full access to all patient information in this report and take responsibility for the integrity and accuracy of the report., (Copyright. Pediatric Pharmacy Association. All rights reserved. For permissions, email: membership@pediatricpharmacy.org 2023.)

Background: The molecular genetic basis of pulmonary arterial hypertension (PAH) is heterogeneous, with at least 26 genes displaying putative evidence for disease causality. Heterozygous variants in the ATP13A3 gene were recently identified as a new cause of adult-onset PAH. However, the contribution of ATP13A3 risk alleles to child-onset PAH remains largely unexplored., Methods and Results: We report three families with a novel, autosomal recessive form of childhood-onset PAH due to biallelic ATP13A3 variants. Disease onset ranged from birth to 2.5 years and was characterised by high mortality. Using genome sequencing of parent-offspring trios, we identified a homozygous missense variant in one case, which was subsequently confirmed to cosegregate with disease in an affected sibling. Independently, compound heterozygous variants in ATP13A3 were identified in two affected siblings and in an unrelated third family. The variants included three loss of function variants (two frameshift, one nonsense) and two highly conserved missense substitutions located in the catalytic phosphorylation domain. The children were largely refractory to treatment and four died in early childhood. All parents were heterozygous for the variants and asymptomatic., Conclusion: Our findings support biallelic predicted deleterious ATP13A3 variants in autosomal recessive, childhood-onset PAH, indicating likely semidominant dose-dependent inheritance for this gene., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Osteoarthritis results in chronic pain and loss of function. Proinflammatory cytokines create both osteoarthritis pathology and pain. Current treatments are poorly effective, have significant side effects, and have not targeted the cytokines central to osteoarthritis development and maintenance. Interleukin-10 is an anti-inflammatory cytokine that potently and broadly suppresses proinflammatory cytokine activity. However, interleukin-10 protein has a short half-life in vivo and poor joint permeability. For sustained IL-10 activity, we developed a plasmid DNA-based therapy that expresses a long-acting human interleukin-10 variant (hIL-10var). Here, we describe the 6-month GLP toxicology study of this therapy. Intra-articular injections of hIL-10var pDNA into canine stifle joints up to 1.5 mg bilaterally were well-tolerated and without pathologic findings. This represents the first long-term toxicologic assessment of intra-articular pDNA therapy. We also report results of a small double-blind, placebo-controlled study of the effect of intra-articular hIL-10var pDNA on pain measures in companion (pet) dogs with naturally occurring osteoarthritis. This human IL-10-based targeted therapy reduced pain measures in the dogs, based on veterinary and owner ratings, without any adverse findings. These results with hIL-10var pDNA therapy, well-tolerated and without toxicologic effects, establish the basis for clinical trials of a new class of safe and effective therapies for OA., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Although widely used in cardiology, relation of heart failure biomarkers to cardiac haemodynamics in patients with CHD (and in particular with pulmonary insufficiency undergoing pulmonary valve replacement) remains unclear. We hypothesised that the cardiac function biomarkers N-terminal pro-brain natriuretic peptide (NT-proBNP), soluble suppressor of tumorigenicity 2, and galectin-3 would have significant associations to right ventricular haemodynamic derangements., Methods: Consecutive patients ( n = 16) undergoing cardiac catheterisation for transcatheter pulmonary valve replacement were studied. NT-proBNP, soluble suppressor of tumorigenicity 2, and galectin-3 levels were measured using a multiplex enzyme-linked immunosorbent assay from a pre-intervention blood sample obtained after sheath placement. Spearman correlation was used to identify significant correlations (p ≤ 0.05) of biomarkers with baseline cardiac haemodynamics. Cardiac MRI data (indexed right ventricular and left ventricular end-diastolic volumes and ejection fraction) prior to device placement were also compared to biomarker levels., Results: NT-proBNP and soluble suppressor of tumorigenicity 2 were significantly correlated (p < 0.01) with baseline mean right atrial pressure and right ventricular end-diastolic pressure. Only NT-proBNP was significantly correlated with age. Galectin-3 did not have significant associations in this cohort. Cardiac MRI measures of right ventricular function and volume were not correlated to biomarker levels or right heart haemodynamics., Conclusions: NT-proBNP and soluble suppressor of tumorigenicity 2, biomarkers of myocardial strain, significantly correlated to invasive pressure haemodynamics in transcatheter pulmonary valve replacement patients. Serial determination of soluble suppressor of tumorigenicity 2, as it was not associated with age, may be superior to serial measurement of NT-proBNP as an indicator for timing of pulmonary valve replacement.

Since the first successful case report in 1972, extracorporeal life support or extracorporeal membrane oxygenation (ECMO) has become a standard approach for severe respiratory failure unresponsive to other therapy. In the past, if there was no recovery by approximately 30 days or if right ventricular heart failure occurred, ECMO was discontinued and the patient died. More recently patients with severe lung disease have been maintained for months, as opposed to days, with eventual decannulation and recovery. We report the case of a child, 7 years old, with severe inhalational burn injury and rapid progression to multisystem organ failure. She was supported by ECMO with no lung function for almost 2 years. Central nervous system function remained normal and lung function recovered. This is the longest successful case of ECMO to date and prompts further discussion regarding "irreversible" lung injury.

While pediatric HeartWare HVAD application has increased, determining candidacy and timing for initiation of pediatric VAD support has remained a challenge. We present our experience with a systematic approach to HVAD implantation as a bridge to pediatric heart transplantation. We performed a retrospective, single center review of pediatric patients (n = 11) who underwent HVAD implantation between September 2014 and January 2018. Primary endpoints evaluated were survival to heart transplantation, need for right ventricular assist device (RVAD) at any point, ongoing HVAD support, or death. Median patient age was 11 years (range: 3-16). Median BSA was 1.25 m 2 (range: 0.56-2.1). Heart failure etiologies requiring support were dilated cardiomyopathy (n = 8), myocarditis (n = 1), congenital mitral valve disease (n = 1), and single ventricle heart failure (n = 1). Median time from cardiac ICU admission for heart failure to HVAD placement was 15 days (range 3-55), based on standardized VAD implantation criteria involving imaging assessment and noncardiac organ evaluation. The majority of patients (91%) were INTERMACS Level 2 at time of implant. Three patients (27%) had CentriMag RVAD placement at time of HVAD implantation. Two of these three patients had successful RVAD explanation within 2 weeks. Median length of HVAD support was 60 days (range 6-405 days). Among the 11 patients, survival during HVAD therapy to date is 91% (10/11) with 9 (82%) bridged to heart transplantation and one (9%) continuing to receive support. Posttransplant survival has been 100%, with median follow-up of 573 days (range 152-1126). A systematic approach to HVAD implantation can provide excellent results in pediatric heart failure management for a variety of etiologies and broad BSA range., (© 2018 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

An adolescent male with a recent history of streptococcal pharyngitis presented with severe substernal chest pain, troponin leak, and ST-segment elevation, which are suggestive of acute inferolateral myocardial infarction. The coronary angiogram was normal. The patient was subsequently diagnosed with non-rheumatic streptococcal myocarditis. He was treated with amoxicillin and had excellent recovery. Non-rheumatic streptococcal myocarditis is an important mimic of acute myocardial infarction in young adults.

Pulmonary hypertension (PH) is a syndrome that is of growing concern to pediatricians worldwide. Recent data led to concerns about the safety of phosphodiesterase type 5 (PDE5) inhibitors in children and a US Food and Drug Administration safety advisory. Our objective is to provide insight into therapies for PH in children and to systematically review the comparative effectiveness and safety of PDE5 inhibitors in the management of pediatric patients with PH. We searched the following databases through February 2015: Medline, Embase, SCOPUS, and the Cochrane Central Register of Controlled Trials. We included studies that examined PDE5 inhibitor use in children with PH. Allowed comparators were either no medication or other classes of medication for management of PH. Study inclusion was via a 2-stage process with 2 reviewers and a predesigned form. Of 1270 papers identified by the literature search, 21 were included: 8 randomized controlled trials and 13 observational studies (9 retrospective, 4 prospective). There is strong evidence that PDE5 inhibitor use improves echocardiography measurements, cardiac catheterization parameters, and oxygenation compared with baseline or placebo in pediatric patients with PH. Evidence suggests that low- and moderate-dose sildenafil are safe regimens for children. There are a relatively small number of randomized controlled trials that address use of PDE5 inhibitors in pediatric patients with PH. PDE5 inhibitors are effective agents for cardiovascular and oxygenation end points in pediatric PH and important components of a multimodal pharmacotherapeutic approach to this growing challenge. Additional studies are needed to define optimal PH therapy in childhood., (Copyright © 2017 by the American Academy of Pediatrics.)

Background and Objectives: Pulmonary hypertension (PH) has been associated with substantial morbidity and mortality in children, but existing analyses of inpatient care are limited to small single-institution series or focused registries representative of selected patient subgroups. We examined US national data on pediatric PH hospitalizations to determine trends in volume, demographics, procedures performed during admission, and resource utilization., Methods: Retrospective cohort study using a national administrative database of pediatric hospital discharges: the Kids' Inpatient Database., Results: Children with PH accounted for 0.13% of the 43 million pediatric hospitalizations in the United States between 1997 and 2012, and discharges demonstrated an increasing trend over the study period (P < .0001). Cumulative, inflation-adjusted national hospital charges for PH hospitalizations rose (P = .0003) from $926 million in 1997 to $3.12 billion in 2012. Patients with PH without associated congenital heart disease (CHD) comprised an increasing and majority (56.4%) proportion over the study period (P < .0001), children without associated CHD admitted at urban teaching hospitals comprised the fastest-growing subgroup. In-hospital, all-cause mortality was high (5.9%) in children with PH, but demonstrated a decreasing trend (P < .0001)., Conclusions: Morbidity and mortality of pediatric PH continue to represent substantial and growing health care burdens. Shifts in case mix toward PH not associated with CHD, toward noncardiac procedures, and toward care in urban teaching hospitals will increase pressure to manage resource utilization in this small but growing patient group and to improve expertise and define excellence in PH care across a wide range of clinical settings., (Copyright © 2015 by the American Academy of Pediatrics.)

This study aimed to assess the technical aspects of atrial septal defect (ASD) closure using the Amplatzer septal occluder (ASO) and the Gore Helex septal occluder (GHSO) for infants weighing less than 8 kg and to determine the safety, effectiveness, and near-to-intermediate-term outcome of the closure. The Mid-Atlantic Group of Interventional Cardiology Registry of percutaneous, transcatheter ASD closure procedures was reviewed for this analysis. Patients from 10 hospitals in the United States were included. The cohort for this report consisted of 68 patients weighing less than 8 kg (range, 2.3-7.8 kg; mean, 5.5 ± 1.6 kg) and ranging in age from 1 to 24 months (mean, 8.6 ± 4.7 months). The indications for ASD closure were failure to thrive, significant right heart enlargement, shunts otherwise thought to be hemodynamically significant, and poor overall clinical status. Devices were successfully implanted in 66 of the 68 infants (97.1 % procedural success rate). Five minor procedure-related complications occurred. At follow-up assessment, clinical status had improved significantly as measured by improved weight gain and decreased ventilator or oxygen dependence. All residual shunts spontaneously closed during the follow-up period. Six late deaths occurred, none of which were clearly device related. The ASO and GHSO can be safely and effectively implanted for ASD closure in infants weighing less than 8 kg. These procedures usually are successful and seldom complicated, resulting in significant clinical improvement.

Objective: To assess health-care utilization and risk of respiratory morbidities in preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH)., Study Design: Retrospective data were obtained from subjects (n=109) attending a BPD clinic. Subjects were stratified by the presence or absence of PH before and after 2 months of age. Analytic methods included t-tests, χ(2) tests and regression., Result: Subjects with BPD and PH present after 2 months of age were hospitalized for 2.2 months longer than those without PH (P=0.02). These subjects were 4.5 times more likely to receive home supplemental oxygen or mechanical ventilation (P=0.03). No difference in the risk of respiratory morbidities after initial hospital discharge was seen with PH., Conclusion: PH in preterm infants is associated with longer initial hospitalizations and a higher likelihood of requiring home respiratory support. This has implications for counseling families and reducing the medical, psychosocial, and economic burden of BPD and PH.

Pulmonary hypertension (PH) is an increasingly recognized complication of premature birth and bronchopulmonary dysplasia (BPD), and is associated with increased morbidity and mortality. Extreme phenotypic variability exists among preterm infants of similar gestational ages, making it difficult to predict which infants are at increased risk for developing PH. Intrauterine growth retardation or drug exposures, postnatal therapy with prolonged positive pressure ventilation, cardiovascular shunts, poor postnatal lung and somatic growth, and genetic or epigenetic factors may all contribute to the development of PH in preterm infants with BPD. In addition to the variability of severity of PH, there is also qualitative variability seen in PH, such as the variable responses to vasoactive medications. To reduce the morbidity and mortality associated with PH, a multi-pronged approach is needed. First, improved screening for and increased recognition of PH may allow for earlier treatment and better clinical outcomes. Second, identification of both prenatal and postnatal risk factors for the development of PH may allow targeting of therapy and resources for those at highest risk. Third, understanding the pathophysiology of the preterm pulmonary vascular bed may help improve outcomes through recognizing pathways that are dysregulated in PH, identifying novel biomarkers, and testing novel treatments. Finally, the recognition of conditions and exposures that may exacerbate or lead to recurrent PH is needed to help with developing treatment guidelines and preventative strategies that can be used to reduce the burden of disease., (Copyright © 2012 Wiley Periodicals, Inc.)

A 9-month-old male with asplenia and complex congenital heart disease experienced progressive stenosis of an anomalous pulmonary venous connection. He developed pulmonary edema and growth failure. Two stents were placed concentrically to relieve the stenosis, and the pulmonary edema and growth failure resolved. Definitive surgery was accomplished 8 months later.

This study was performed to evaluate the utility and safety of catheterizing the right subscapular artery for balloon valvuloplasty of critical aortic stenosis in infants. Twenty-one patients, age 20 days to 17 months, underwent attempted valvuloplasty through the surgically exposed right subscapular artery. Five or 7Fr catheters with balloon diameters of 7 to 10 mm were used. Valvuloplasty was successfully performed using this approach in 11 patients. In 2 other patients, the subscapular artery would not accommodate the balloon angioplasty catheter (7Fr), and the arteriotomy was extended into the axillary artery. In these 13 patients, the peak systolic pressure gradient across the aortic valve was decreased from 85 +/- 23 to 33 +/- 7 mm Hg. Moderate aortic regurgitation developed in 3 patients. In the remaining 8 patients, valvuloplasty could not be performed through the right subscapular artery. In 2 patients, the right subclavian artery was anomalous and led to the descending aorta. In 6 small patients, no catheter could be advanced across the aortic valve. In 1 of these patients, a guidewire perforated a coronary sinus of Valsalva causing death. Overall, valvuloplasty using the right subscapular arterial approach was successful in 13 of 19 infants (68%) with normal right subclavian arteries, including all 10 such patients weighing > or = 5.5 kg. No clinically significant peripheral vascular complications or brachial plexus injuries occurred. Thus, the right subscapular arterial approach is an alternative route to be considered when planning balloon aortic valvuloplasty in infants.

Pulmonary venous atrial stenosis developed after a modified Senning procedure in an infant with transposition of the great arteries. The pulmonary venous atrium was surgically revised, but the obstruction recurred. The stenosis was then enlarged by percutaneous balloon catheter dilatation. There was an immediate haemodynamic and echocardiographic improvement. Clinical and echocardiographic improvement persisted nine months after dilatation. The procedure was complicated by staphylococcal endarteritis.

Although still considered to be a rare and mostly fatal illness, the reported incidence of neonatal bacterial endocarditis has increased during the past decade. This parallels the establishment of intensive supportive management of severely ill newborns with multiple medical problems. An extremely difficult diagnostic problem with protean manifestations, the presence of neonatal endocarditis should be vigorously sought in the at risk neonate. The authors report the first known case in America of successfully diagnosed and treated neonatal endocarditis involving the mitral valve.

Some degree of obstruction of the superior vena cava is common after the Mustard operation for transposition of the great arteries. This can cause superior vena cava syndrome, which in extreme cases may lead to hydrocephalus in young children. While revision of the intra-atrial baffle can be performed, this procedure is associated with significant morbidity and mortality and may not resolve the problem. We describe an alternative operative approach in a group of patients who had superior vena cava syndrome after the Mustard procedure: anastomosis of the innominate vein to the left atrial appendage. This procedure is not complicated to perform and is safe; symptoms were relieved in all patients.

Normal pulmonary arterial development in the relatively hypoxic intrauterine environment and pulmonary arterial remodeling in hypoxic infants include extension of the smooth muscle layer into normally nonmuscular arteries and thickening of the arterial media in the muscular arteries. These changes require proliferation of immature smooth muscle cells or differentiation of smooth muscle cell precursors. Because the mechanisms that regulate these processes have not been clearly defined, we asked whether decreased oxygen tensions could promote either hyperplasia or hypertrophy of smooth muscle cell precursors in vitro. We have studied cells that proliferate and migrate out of explants from the media of the pulmonary arteries of near-term bovine fetuses, because these cells are representative of those that are involved in normal arterial development and possibly also in arterial remodeling. Decreases in oxygen tension within and below the physiologic range do not cause hyperplasia or hypertrophy of these cells. Instead, cell proliferation decreased at oxygen tensions below 60 mm Hg. The effects of hypoxia on proliferation of aortic and pulmonary arterial smooth muscle cells were identical, but effects on proliferation of dermal fibroblasts and endothelial cells were smaller in magnitude and evident only at lower oxygen tensions. These findings suggest that hypoxia does not act directly on smooth muscle cells to produce increased quantities of these cells in the pulmonary arteries during normal prenatal development or during remodeling of the pulmonary arteries of the hypoxic neonate, implying that other factors mediate these phenomena.

Proliferation of smooth muscle cells from the pulmonary arteries and aortas of fetal calves is inhibited by heparin in vitro. This effect is reversible and dose dependent. Comparisons with effects of other polysaccharides indicate that only extensively sulfated polysaccharides inhibit proliferation of smooth muscle cells but that specific structural features of heparin are required to achieve maximum effect. Heparin-Sepharose chromatography of medium containing fetal calf serum reduces the ability of that medium to promote growth of smooth muscle cells from fetal pulmonary arteries, suggesting that heparin may remove soluble growth factors in serum. However, inhibition of fetal pulmonary artery smooth muscle cell proliferation by heparin is identical in media supplemented either with serum prepared from fetal calf plasma, in which platelet-derived growth factor (PDGF) is not detectable, or with fetal calf serum, which contains relatively abundant PDGF (114 pg/ml). Thus, inhibition of fetal pulmonary artery smooth muscle cell proliferation by heparin is not mediated solely by decreased availability or activity of exogenous PDGF. These studies suggest that morphogenesis of the smooth muscle investment of the pulmonary arteries could be regulated by local production of heparin-like inhibitors of smooth muscle cell growth.