<p><strong>BACKGROUND/PURPOSE: </strong>Prostaglandin E1 (PGE) has been used to maintain ductus arteriosus patency and unload the suprasystemic right ventricle (RV) in neonates with congenital diaphragmatic hernia (CDH) and severe pulmonary hypertension (PH). Here we evaluate the PH response in neonates with CDH and severe PH treated with PGE.</p>

<p><strong>METHODS: </strong>We performed a retrospective chart review of CDH infants treated at our center between 2011 and 2016. In a subset, PGE was initiated for echocardiographic evidence of severe PH, metabolic acidosis, or hypoxemia. To assess PH response, we evaluated laboratory data, including B-type natriuretic peptide (BNP) and echocardiograms before and after PGE treatment. Categorical and continuous data were analyzed with Fisher's exact tests and Mann-Whitney t-tests, respectively.</p>

<p><strong>RESULTS: </strong>Fifty-seven infants were treated with PGE a mean 17 ± 2 days. BNP levels declined after 1.4 ± 0.2 days of treatment and again after 5.2 ± 0.6 days. After 6 ± 0.8 days of treatment, echocardiographic estimates of severe PH by tricuspid regurgitation jet velocity, ductus arteriosus direction, and ventricular septum position also improved significantly. Treatment was not associated with postductal hypoxemia or systemic hypoperfusion.</p>

<p><strong>CONCLUSIONS: </strong>In patients with CDH and severe PH, PGE is well tolerated and associated with improved BNP and echocardiographic indices of PH, suggesting successful unloading of the RV.</p>

<p><strong>TYPE OF STUDY: </strong>Treatment study.</p>

<p><strong>LEVEL OF EVIDENCE: </strong>Level III.</p>

<p><strong>OBJECTIVE: </strong>To determine whether dual energy X-ray absorptiometry (DXA), a clinically available tool, mirrors the magnitude of deficits in trabecular and cortical bone mineral density (BMD) demonstrated on peripheral quantitative computed tomography in youth with Fontan physiology.</p>

<p><strong>STUDY DESIGN: </strong>We aimed to describe DXA-derived BMD at multiple sites and to investigate the relationship between BMD and leg lean mass, a surrogate for skeletal muscle loading. Subjects with Fontan (n&nbsp;=&nbsp;46; aged 5-20&nbsp;years) underwent DXA in a cross-sectional study of growth and bone and muscle health as described previously. Data from the Bone Mineral Density in Childhood Study were used to calculate age-, sex-, and race-specific BMD z-scores of the whole body, lumbar spine, hip, femoral neck, distal one-third radius, ultradistal radius, and leg lean mass z-score (LLMZ).</p>

<p><strong>RESULTS: </strong>Fontan BMD z-scores were significantly lower than reference at all sites-whole body, -0.34&nbsp;±&nbsp;0.85 (P&nbsp;=&nbsp;.01); spine, -0.41&nbsp;±&nbsp;0.96 (P&nbsp;=&nbsp;.008); hip, -0.75&nbsp;±&nbsp;1.1 (P&nbsp;&lt;&nbsp;.001); femoral neck, -0.73&nbsp;±&nbsp;1.0 (P&nbsp;&lt;&nbsp;.001); distal one-third radius, -0.87&nbsp;±&nbsp;1.1 (P&nbsp;&lt;&nbsp;.001); and ultradistal radius. -0.92&nbsp;±&nbsp;1.03 (P&nbsp;&lt;&nbsp;.001)-as was LLMZ (-0.93&nbsp;±&nbsp;1.1; P&nbsp;&lt;&nbsp;.001). Lower LLMZ was associated with lower BMD of the whole body (R&nbsp;=&nbsp;0.40; P&nbsp;&lt;&nbsp;.001), lumbar spine (R&nbsp;=&nbsp;0.16; P&nbsp;=&nbsp;.005), total hip (R&nbsp;=&nbsp;0.32; P&nbsp;&lt;&nbsp;.001), femoral neck (R&nbsp;=&nbsp;0.47; P&nbsp;&lt;&nbsp;.001), and ultradistal radius (R&nbsp;=&nbsp;0.35; P&nbsp;&lt;&nbsp;.001).</p>

<p><strong>CONCLUSIONS: </strong>Patients with Fontan have marked deficits in both cortical (hip, distal one-third radius) and trabecular (lumbar spine, femoral neck, ultradistal radius) BMD. Lower LLMZ is associated with lower BMD and may reflect inadequate skeletal muscle loading. Interventions to increase muscle mass may improve bone accrual.</p>

<p><strong>OBJECTIVE: </strong>We previously described lower leg lean mass Z-scores (LLMZ) in Fontan patients associated with worse peak oxygen consumption on metabolic exercise testing. We hypothesised that LLMZ correlates with indexed systemic flow (Qsi) and cardiac index (CI) on exercise cardiac magnetic resonance (eCMR).</p>

<p><strong>METHODS: </strong>Thirteen patients had LLM measured by dual-energy X-ray absorptiometry within mean 40 (range 0-258) days of eCMR. LLM was converted to sex and race-specific Z-scores based on healthy reference data. Ventricular volumes and flow measurements of the ascending and descending (DAO) aorta and superior vena cava (SVC) were obtained by CMR at rest and just after supine ergometer exercise to a heart rate associated with anaerobic threshold on prior exercise test. Baseline and peak exercise measures of Qsi (SVC+DAO/BSA) and CI, as well as change in Qsi and CI with exercise, were compared with LLMZ by linear regression.</p>

<p><strong>RESULTS: </strong>LLMZ was not correlated with resting flows, stroke volume or CI. There was a strong linear correlation between LLMZ and change in both CI (r=0.77, p=0.002) and Qsi (r=0.73, p=0.005) from rest to exercise. There was also a significant correlation between LLMZ and Qsi at exercise (r=0.70, p=0.008). The correlation between LLMZ and CI at exercise did not reach significance (r=0.3, p=0.07).</p>

<p><strong>CONCLUSIONS: </strong>In our cohort, there was a strong linear correlation between LLMZ and change in both CI and Qsi from rest to exercise, suggesting that Fontan patients with higher LLMZ may be better able to augment systemic output during exercise, improving performance.</p>

<p><strong>BACKGROUND: </strong>Survival of patients with congenital heart disease has improved such that there are now more adults than children living with these conditions. Complex single ventricle congenital heart disease requiring Fontan palliation is associated with multiple risk factors for impaired bone accrual. Bone density and structure have not been characterized in these patients.</p>

<p><strong>METHODS: </strong>Tibia peripheral quantitative computed tomography (pQCT) was used to assess trabecular and cortical volumetric bone mineral density (vBMD), cortical dimensions, and calf muscle area in 43 Fontan participants (5-33 years old), a median of 10 years following Fontan palliation. pQCT outcomes were converted to sex- and race-specific Z-scores relative to age based on &gt;700 healthy reference participants. Cortical dimensions and muscle area were further adjusted for tibia length.</p>

<p><strong>RESULTS: </strong>Height Z-scores were lower in Fontan compared to reference participants (mean ± SD: -0.29 ± 1.00 vs. 0.25 ± 0.93, p &lt; 0.001); BMI Z-scores were similar (0.16 ± 0.88 vs. 0.35 ± 1.02, p = 0.1). Fontan participants had lower trabecular vBMD Z-scores (-0.85 ± 0.96 vs. 0.01 ± 1.02, p &lt; 0.001); cortical vBMD Z-scores were similar (-0.17 ± 0.98 vs. 0.00 ± 1.00, p = 0.27). Cortical dimensions were reduced with lower cortical area (-0.59 ± 0.84 vs. 0.00 ± 0.88, p&lt;0.001) and periosteal circumference (-0.50 ± 0.82 vs. 0.00 ± 0.84, p &lt; 0.001) Z-scores, compared to reference participants. Calf muscle area Z-scores were lower in the Fontan participants (-0.45 ± 0.98 vs. 0.00 ± 0.96, p = 0.003) and lower calf muscle area Z-scores were associated with smaller periosteal circumference Z-scores (R = 0.62, p &lt; 0.001). Musculoskeletal deficits were not associated with age, Fontan characteristics, parathyroid hormone or vitamin D levels.</p>

<p><strong>CONCLUSIONS: </strong>Children and young adults demonstrate low trabecular vBMD, cortical structure and muscle area following Fontan. Muscle deficits were associated with smaller periosteal dimensions. Future studies should determine the fracture implications of these deficits and identify interventions to promote musculoskeletal development.</p>

<p><strong>OBJECTIVE: </strong>We sought to evaluate body composition in children and young adults with Fontan physiology. Leg lean mass (LM) deficits correlate with diminished exercise capacity in other populations and may contribute to exercise limitations in this cohort.</p>

<p><strong>METHODS: </strong>This cross-sectional study included whole body dual energy X-ray absorptiometry scans in 50 Fontan participants ≥5 years, and measures of peak oxygen consumption (VO2) in 28. Whole body and leg LM (a measure of skeletal muscle) were converted to sex- and race-specific Z-scores, relative to age and stature, based on 992 healthy reference participants.</p>

<p><strong>RESULTS: </strong>Median age was 11.5 (range 5.1-33.5) years at 9.3 (1.1-26.7) years from Fontan. Height Z-scores were lower in Fontan compared with reference participants (-0.47±1.08 vs 0.25±0.93, p&lt;0.0001). Body mass index Z-scores were similar (0.15±0.98 vs 0.35±1.02, p=0.18). LM Z-scores were lower in Fontan compared with reference participants (whole body LM -0.33±0.77 vs 0.00±0.74, p=0.003; leg LM -0.89±0.91 vs 0.00±0.89, p&lt;0.0001). LM Z-scores were not associated with age or Fontan characteristics. Leg LM Z-scores were lower in vitamin D deficient versus sufficient Fontan participants (-1.47±0.63 vs -0.71±0.92, p=0.01). Median per cent predicted peak VO2 was 81% (range 13%-113%) and was associated with leg LM Z-scores (r=0.54, p=0.003).</p>

<p><strong>CONCLUSIONS: </strong>Following Fontan, children and young adults are shorter than their peers and have significant LM deficits. Skeletal muscle deficits were associated with vitamin D deficiency and reduced exercise capacity. Future studies should examine the progression of these deficits to further understand the contribution of peripheral musculature to Fontan exercise capacity.</p>

<p>For infants with shunt-dependent or ductal-dependent single ventricle heart disease, poor growth is common and associated with morbidity and impaired neurodevelopmental outcomes. Although attention has focused on nutrition to promote weight gain, little is known about the relation between heart failure and growth factors. A prospective observational pilot study was performed to assess the relation between heart failure, assessed by brain natriuretic peptide (BNP), and growth factors (insulin-like growth factor 1 [IGF-1] and insulin-like growth factor-binding protein 3) at 3 visits: (1) before discharge from neonatal intervention with the establishment of stable pulmonary blood flow, (2) immediately before superior cavopulmonary connection, and (3) before discharge after superior cavopulmonary connection operation. The relation between BNP and growth factors was analyzed using Spearman pairwise correlations at each visit and modeled over time with a linear mixed-effects model. Correlations were considered worthy of further exploration using a p &lt;0.10, given the exploratory nature of the study. The study included 38 infants (66% male, 68% hypoplastic left heart syndrome). Median BNP was elevated at visit 1 and decreased over time (287&nbsp;pg/dl [interquartile range 147 to 794], 85&nbsp;pg/dl [52 to 183], and 90&nbsp;pg/dl [70 to 138]). Median IGF-1 Z&nbsp;score was &lt;0 at each visit but increased over time (-0.9 [interquartile range -1.1 to 0.1], -0.7 [-1.2 to 0.1], and -0.5 [-1.2 to 0]). Inverse correlations were found between BNP and IGF-1 at visit 1 (r&nbsp;=&nbsp;-0.40, p&nbsp;=&nbsp;0.097), BNP and IGF-1 and insulin-like growth factor-binding protein 3 at visit 2 (r&nbsp;=&nbsp;-0.33, p&nbsp;=&nbsp;0.080 and r&nbsp;=&nbsp;-0.33, p&nbsp;=&nbsp;0.085, respectively) and BNP and IGF-1 Z&nbsp;score at visit 3 (r&nbsp;=&nbsp;-0.42, p&nbsp;=&nbsp;0.049). Significant relations were likewise found between the change in BNP and the change in IGF-1 between visits 1 and 3 (p&nbsp;=&nbsp;0.046) and between visits 2 and 3 (p&nbsp;=&nbsp;0.048). In conclusion, this pilot study demonstrates an inverse correlation between BNP and growth factors, suggesting that the heart failure state associated with this physiology may play a mechanistic role in impaired growth.</p>

<p><strong>BACKGROUND: </strong>Survivors of Fontan palliation are at life-long risk of thrombosis, arrhythmia, and circulatory failure. To our knowledge, no studies have evaluated current United States pharmaceutical prescription practice in this population.</p>

<p><strong>METHODS: </strong>A retrospective observational study evaluating the prevalent use of prescription medications in children and adolescents with hypoplastic left heart syndrome or tricuspid atresia after Fontan completion (identified using ICD9/10 codes) was performed using data contained in the MarketScan® Commercial and Medicaid databases for the years 2013 through 2018. Cardiac pharmaceuticals were divided by class. Anticoagulant agents other than platelet inhibitors, which are not uniformly a prescription medication, were also studied. Associations between increasing age and the likelihood of a filled prescription for each class of drug were evaluated. Annualized retail costs of pharmaceutical regimens were calculated.</p>

<p><strong>RESULTS: </strong>A cohort of 4056 subjects [median age 12 years (IQR: 8-16), 61% male, 60% commercial insurance] was identified. Of the cohort, 50% received no prescription medications. Angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB) (38%), diuretics (15%), and mineralocorticoid receptor antagonists (8%) were prescribed with the highest frequency. Pulmonary vasodilators were received by 6% of subjects. Older age was associated with increased likelihood of filled prescriptions for anticoagulants (p=0.008), antiarrhythmic agents, digoxin, ACEi/ARB, and beta blockers (each p&lt;0.0001), but also lower likelihood of filled prescriptions for pulmonary vasodilators, conventional diuretics (both p&lt;0.0001), and mineralocorticoid receptor antagonists (p=0.02).</p>

<p><strong>CONCLUSION: </strong>Pharmaceuticals typically used to treat heart failure and pulmonary hypertension are the most commonly prescribed medications following Fontan palliation. While the likelihood of treatment with a particular class of medication is associated with the age of the patient, determining the optimal regimen for individual patients and the population at large is an important knowledge gap for future research.</p>

<p><strong>Context: </strong>Diazoxide, the only U.S. Food and Drug Administration-approved drug to treat hyperinsulinemic hypoglycemia, has been associated with several adverse events, which has raised concerns about the safety of this drug. Existing reports are limited to small studies and case reports.</p>

<p><strong>Objective: </strong>To determine prevalence of and clinical factors associated with adverse events in infants and children treated with diazoxide.</p>

<p><strong>Design: </strong>Retrospective cohort study of children with hyperinsulinism (HI) treated with diazoxide between 2003 and 2014.</p>

<p><strong>Setting: </strong>The Congenital Hyperinsulinism Center at the Children's Hospital of Philadelphia.</p>

<p><strong>Patients: </strong>Children and infants with laboratory-confirmed diagnosis of HI.</p>

<p><strong>Main Outcome Measures: </strong>Prevalence of pulmonary hypertension (PH), edema, neutropenia, thrombocytopenia, and hyperuricemia was determined. Tests of association and logistic regression were used to identify potential risk factors.</p>

<p><strong>Results: </strong>A total of 295 patients (129 female) met inclusion criteria. The median age at diazoxide initiation was 29 days (interquartile range, 10 to 142 days; n = 226 available start dates); 2.4% of patients were diagnosed with PH after diazoxide initiation. Children with PH (P = 0.003) or edema (P = 0.002) were born at earlier gestational age and more frequently had potential PH risk factors, including respiratory failure and structural heart disease (P &lt; 0.0001 and P = 0.005). Other adverse events included neutropenia (15.6%), thrombocytopenia (4.7%), and hyperuricemia (5.0%).</p>

<p><strong>Conclusion: </strong>In this large cohort, PH occurred in infants with underlying risk factors, but no identifiable risk profile emerged for other adverse events. The relatively high prevalence of neutropenia, thrombocytopenia, and hyperuricemia suggests the value in proactively screening for these side effects in children treated with diazoxide.</p>

<p>Little data are available on the accuracy of phase-contrast magnetic resonance imaging (PC-MRI) velocity mapping in the vicinity of intravascular metal stents other than nitinol stents. Therefore, we sought to determine this accuracy using in vitro experiments. An in vitro flow phantom was used with 3 stent types: (1) 316L stainless steel, (2) nitinol self-expanding, and (3) platinum-iridium. Steady and pulsatile flow was delivered with a magnetic resonance imaging-compatible pump (CardioFlow 5000, Shelley Medical, London, Ontario, Canada). Flows were measured using a transit time flow meter (ME13PXN, Transonic, Inc, Ithaca, New York). Mean flows ranged from 0.5 to 7 L/min. For each condition, 5 PC-MRI acquisitions were made: within the stent, immediately adjacent to both edges of the stent artifact, and 1 cm upstream and downstream of the artifact. Mean PC-MRI flows were calculated by segmenting the tube lumen using clinical software (ARGUS, Siemens, Inc, Erlangen, Germany). PC-MRI and flow meter flows were compared by location and stent type using linear regression, Bland-Altman, and intraclass correlation (ICC). PC-MRI flows within the stent artifact were inaccurate for all stents studied, generally underestimating flow meter-measured flow. Agreement between PC-MRI and flow meter-measured flows was excellent for all stent types, both immediately adjacent to and 1 cm away from the edge of the stent artifact. Agreement was highest for the platinum-iridium stent (R = 0.999, ICC = 0.999) and lowest for the nitinol stent (R = 0.993, ICC = 0.987). In conclusion, PC-MRI flows are highly accurate just upstream and downstream of a variety of clinically used stents, supporting its use to directly measure flows in stented vessels.</p>