BACKGROUND: Generalized arterial calcification of infancy (GACI), also known as idiopathic infantile arterial calcification, is a very uncommon genetic disorder characterized by calcifications and stenoses of large- and medium-size arteries that can lead to end-organ damage.

OBJECTIVE: To describe changes in imaging findings in 10 children with GACI at a single institution from 2010 to 2021.

MATERIALS AND METHODS: In this retrospective study we reviewed initial and follow-up body imaging in children with genetic confirmation of GACI at our hospital. All initial images were analyzed for the presence and distribution of arterial calcifications, stenoses and wall thickening/irregularity within the chest, abdomen and pelvis. We compared available follow-up studies to the initial imaging findings. We extracted clinical information including prenatal and postnatal treatment from the children's medical records.

RESULTS: We evaluated 10 children (five boys) with a diagnosis of GACI. Median age at first body imaging was 8 days (range: 1 day to 5 years). Six children were identified prenatally and four postnatally. Postnatal presentation included cardiac failure, seizures and hypertension. Images in newborns (n = 8) most commonly showed diffuse arterial calcifications (6/8; 75%), while stenoses were less common (2/8; 25%) during this period. Two children were diagnosed after the neonatal period - one in infancy and one during childhood. In total, half the children (5/10; 50%) had arterial stenoses - three cases visualized at first imaging and two identified on follow-up images during infancy. Stenoses had completely resolved in one child (1/5; 20%) at last follow-up. Eight children received prenatal or postnatal treatment or both. All children who received both prenatal and postnatal treatment (n = 4) had completely resolved calcifications at last follow-up.

CONCLUSION: Children with GACI might have characteristic vascular calcifications at birth that raise the suspicion of this disease. Arterial calcifications decrease or disappear spontaneously or after treatment, but arterial stenoses usually persist. Calcifications and arterial stenoses can be easily identified and followed with non-contrast CT and CT angiography.

Quality improvement efforts have focused on reducing interstage mortality for infants with hypoplastic left heart syndrome (HLHS). In 1/2016, two publications reported that use of digoxin was associated with reduced interstage mortality. The degree to which these findings have affected real world practice has not been evaluated. The discharge medications of neonates with HLHS undergoing Norwood operation between 1/2007 and 12/2018 at Pediatric Health Information Systems Database hospitals were studied. Mixed effects models were calculated to evaluate the hypothesis that the likelihood of digoxin prescription increased after 1/2016, adjusting for measurable confounders with furosemide and aspirin prescription measured as falsification tests. Interhospital practice variation was measured using the median odds ratio. Over the study period, 6091 subjects from 45 hospitals were included. After adjusting for measurable covariates, discharge after 1/2016 was associated with increased odds of receiving digoxin (OR 3.9, p < 0.001). No association was seen between date of discharge and furosemide (p = 0.26) or aspirin (p = 0.12). Prior to 1/2016, the likelihood of receiving digoxin was decreasing (OR 0.9 per year, p < 0.001), while after 1/2016 the rate has increased (OR 1.4 per year, p < 0.001). However, there remains significant interhospital variation in the likelihood of receiving digoxin even after adjusting for known confounders (median odds ratio = 3.5, p < 0.0001). Following publication of studies describing an association between digoxin and improved interstage survival, the likelihood of receiving digoxin at discharge increased without similar changes for furosemide or aspirin. Despite concerted efforts to standardize interstage care, interhospital variation in pharmacotherapy in this vulnerable population persists.

<p><strong>BACKGROUND: </strong>Generalized arterial calcification of infancy (GACI), also known as idiopathic infantile arterial calcification, is a very uncommon genetic disorder characterized by calcifications and stenoses of large- and medium-size arteries that can lead to end-organ damage.</p>

<p><strong>OBJECTIVE: </strong>To describe changes in imaging findings in 10 children with GACI at a single institution from 2010 to 2021.</p>

<p><strong>MATERIALS AND METHODS: </strong>In this retrospective study we reviewed initial and follow-up body imaging in children with genetic confirmation of GACI at our hospital. All initial images were analyzed for the presence and distribution of arterial calcifications, stenoses and wall thickening/irregularity within the chest, abdomen and pelvis. We compared available follow-up studies to the initial imaging findings. We extracted clinical information including prenatal and postnatal treatment from the children's medical records.</p>

<p><strong>RESULTS: </strong>We evaluated 10 children (five boys) with a diagnosis of GACI. Median age at first body imaging was 8&nbsp;days (range: 1&nbsp;day to 5&nbsp;years). Six children were identified prenatally and four postnatally. Postnatal presentation included cardiac failure, seizures and hypertension. Images in newborns (n = 8) most commonly showed diffuse arterial calcifications (6/8; 75%), while stenoses were less common (2/8; 25%) during this period. Two children were diagnosed after the neonatal period - one in infancy and one during childhood. In total, half the children (5/10; 50%) had arterial stenoses - three cases visualized at first imaging and two identified on follow-up images during infancy. Stenoses had completely resolved in one child (1/5; 20%) at last follow-up. Eight children received prenatal or postnatal treatment or both. All children who received both prenatal and postnatal treatment (n = 4) had completely resolved calcifications at last follow-up.</p>

<p><strong>CONCLUSION: </strong>Children with GACI might have characteristic vascular calcifications at birth that raise the suspicion of this disease. Arterial calcifications decrease or disappear spontaneously or after treatment, but arterial stenoses usually persist. Calcifications and arterial stenoses can be easily identified and followed with non-contrast CT and CT angiography.</p>

<p><strong>BACKGROUND: </strong>Plastic bronchitis is a rare, potentially life-threatening complication after Fontan operation. Hemodynamic alterations (elevated central venous pressure and low cardiac output) likely contribute to the formation of tracheobronchial casts composed of inflammatory debris, mucin, and fibrin. Pathologic studies of cast composition support medical treatment with fibrinolytics such as inhaled tissue plasminogen activator (t-PA).</p>

<p><strong>METHODS: </strong>This was a retrospective case series of medical, surgical, and catheter-based treatment of patients with plastic bronchitis after cavopulmonary palliation.</p>

<p><strong>RESULTS: </strong>Included were 14 patients (86% male, 93% white). Median age at Fontan operation was 2.7 years (range, 1.2 to 4.1 years), with median interval to plastic bronchitis presentation of 1.5 years (range, 9 days to 15.4 years). Cast composition was available for 11 patients (79%) and included fibrin deposits in 7. All patients were treated with pulmonary vasodilators, and 13 (93%) were treated with inhaled t-PA. Hemodynamically significant lesions in the Fontan pathway were addressed by catheter-based (n=9) and surgical (n=3) interventions. Three patients (21%) underwent heart transplantation. Median follow-up was 2.7 years (range, 0.6 to 8.7 years). Symptoms improved, such that 6 of 13 patients (46%) were weaned off t-PA. Rare or episodic casts are successfully managed with outpatient t-PA in most of the other patients. Of the 3 patients who underwent heart transplant, 2 are asymptomatic and 1 has recurrent casts in the setting of elevated filling pressures and rejection.</p>

<p><strong>CONCLUSIONS: </strong>A systematic step-wise algorithm that includes optimization of hemodynamics, aggressive pulmonary vasodilation, and inhaled t-PA is an effective treatment strategy for patients with plastic bronchitis after cavopulmonary connection.</p>

<p>The Fontan operation can create a stable circulation from childhood through early adulthood. However, the absence of a sub-pulmonary pumping chamber leads to a physiology in which exercise capacity is limited and decreases with age starting in adolescence. The limitation in exercise capacity is more pronounced at peak levels of exercise, but is still present during more modest levels of activity. The underlying causes of exercise impairment relate to both central cardiovascular factors (oxygen delivery) and peripheral factors (oxygen extraction). Interventions to improve cardiac preload and to improve lean muscle mass may help to improve exercise capacity and, perhaps, will alter the "natural history" of the progressive decline.</p>

<p>Protein-losing enteropathy (PLE) is a rare but potentially devastating complication of single-ventricle physiology after the Fontan operation. Although abnormal bone mineral density (BMD) is a known complication of chronic disease and congenital heart disease, no reports have described BMD in patients with PLE. This study investigated a cross-sectional sample of children and young adults with a confirmed diagnosis of PLE. Serum levels of 25(OH)D, calcium, total protein, and albumin were recorded from the first outpatient encounter with each subject. Corrected calcium (cCa) was calculated from the serum calcium and albumin levels. Dual-energy X-ray absorptiometry (DXA) was used to measure BMD, and z-scores were generated using appropriate software. DXA results were available for 12 patients (eight males and four females). The age at DXA ranged from 7.2 to 25.2 years. The mean z-score was -1.73 standard deviation (SD) for the entire cohort, with 42 % z-scores below -2 SDs. Serum 25(OH)D levels were abnormal in 58 % of the patients. There was a positive correlation between cCa and DXA z-score and a negative correlation between total protein and DXA z-score. Patients receiving corticosteroid therapy had a significantly lower DXA z-score than those not receiving corticosteroids (-3.15 vs. -0.31; p = 0.02). Children with PLE are at risk for abnormal BMD compared with age- and sex-matched control subjects. In the study cohort, corticosteroid exposure, a marker of disease severity, appeared to be associated with decreased BMD. Routine bone health screening is warranted for children with PLE, particularly those receiving corticosteroid therapy.</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>