Cardiac signaling proteins sensitive to changes in cardiac status may help predict the cardiac effects of doxorubicin in children with acute lymphoblastic leukemia (ALL). We determined the relationship between these proteins and biomarkers of cardiac injury and echocardiographic characteristics. Cardiotrophin-1 (CT-1), interleukin-6 (IL-6), neuregulin-1 (NRG-1), and vascular endothelial growth factor (VEGF) concentrations were measured in 83 children on Dana-Farber Cancer Institute ALL Protocol 95 − 01 before, during (T1: 0–50 days, T2: 51–100 days, T3: 151–300 days), and after treatment and compared to existing data for cardiac troponin-T (cTnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hsCRP), and echocardiograms. Compared to baseline, mean IL-6 concentrations were lower during doxorubicin treatment (P < 0.01 for all) and after (P = 0.03). Mean NRG-1 and CT-1 concentrations were significantly lower beginning at T2 and thereafter (P < 0.001 for all). Mean VEGF concentrations were significantly elevated from baseline at all on-treatment time points (P ≤ 0.02 for all). Lower odds of abnormal cTnT were marginally associated with increased NRG-1. Higher odds of abnormal NT-proBNP were associated with CT-1 concentrations (P = 0.03) and marginally associated with increased IL-6 and NRG-1 concentrations. Increased hsCRP concentrations were associated with increased IL-6, NRG-1, and CT-1 (P < 0.001 for all). No echocardiographic measurements were associated with signaling proteins. Decreased concentrations CT-1 and NRG-1 during doxorubicin treatment may increase cardiomyocyte death. Changes in IL-6 and VEGF suggest doxorubicin-related inflammation and angiogenesis. These markers may help identify children at greatest risk of long-term adverse outcomes.

Long-term studies on safety of beta-blockers in pediatric heart failure (HF) are scant. We describe the safety profile, dose ranges, and tolerability of carvedilol in pediatric dilated cardiomyopathy (DCM). The Pediatric Cardiomyopathy Registry (PCMR) was used to identify patients with DCM, treated with carvedilol from 1997 to 2005. Descriptive statistics were analyzed and echocardiographic parameters were compared longitudinally using ANOVA. Total 118 patients were included with median age 4.4 years (interquartile range (IQR) 1.0–13.3). The etiology of DCM was idiopathic (66

BACKGROUND:HIV infection is associated with cardiovascular events in adults. We compared mean blood pressure (BP) obtained at study visits between youth with/without perinatally acquired HIV infection and evaluated whether HIV disease severity was associated with BP. METHODS:BP was compared between participants with/without HIV in the Adolescent Master Protocol of the Pediatric HIV/AIDS Cohort Study. Marginal repeated measures analyses using generalized estimating equations evaluated the association of HIV disease severity with BP index (mean BP/95th percentile BP) and abnormal BP. RESULTS:447 youth with HIV and 226 youth without HIV were included. Youth with HIV were more often Black non-Hispanic (66% versus 54%), had greater household income (54% versus 35%), and lower measures of adiposity than those without. Systolic BP was similar between groups, but mean diastolic BP was lower for preadolescents (63.3 mm Hg [95% CI, 59.0-67.0] versus 65.0 [61.5-68.7]) with HIV. Although youth with HIV had lower diastolic BP index (-0.011 [95% CI, -0.021 to -0.001]) and lower prevalence of abnormal BP (odds ratio, 0.78 [95% CI, 0.62-0.97]) at study visits in initial adjusted models, these associations were attenuated after adjustment for body mass index (-0.007 [95% CI, -0.017 to 0.003], odds ratio, 0.94 [95% CI, 0.76, 1.17], respectively). HIV disease severity was not associated with systolic or diastolic BP. CONCLUSIONS:Youth with HIV had lower adiposity and BP than youth without HIV during study visits. Although youth with HIV had a lower risk of abnormal BP, this association did not persist after adjustment for adiposity. Prevention and treatment of other traditional cardiovascular disease risk factors remain important among youth living with HIV.

BACKGROUND: Fetal cardiomyopathy is a rare condition, often with an unknown cause and associated with high perinatal mortality. Recent years have seen improvement in fetal cardiac screening, genetic testing, and management. We sought to investigate genetic associations and clinical outcomes of fetal cardiomyopathy in the contemporary era. METHODS: A single-arm (descriptive) retrospective cohort study of fetal cardiomyopathy cases diagnosed from January 2017 to December 2021 at 26 North American centers in the Fetal Heart Society Research Collaborative was undertaken. Cases attributable to maternal diabetes, extra-cardiac conditions, structural heart disease, or arrhythmias were excluded. Genetic testing results, extra-cardiac structural anomalies, and outcomes were collected. Logistic regression was performed to determine prenatal risk factors for death or cardiac transplantation by 1-year of age. Descriptive competing-risk analyses (cumulative incidence functions) and Kaplan-Meier survival estimates were used to describe outcomes. Multivariable logistic regression with 5 prespecified covariates was performed to identify prenatal factors associated with death or cardiac transplantation by 1-year of age. RESULTS: In 148 cases of fetal cardiomyopathy, 6.7% (10/148) opted for pregnancy termination, 8.6% (12/138) of continuing pregnancies experienced fetal death, and 1.4% (2/138) were lost to follow-up. Among continuing pregnancies, overall 1-year survival was 61.5% (85/138) with 1-year transplant-free survival of 50.0% (69/138). Of live births, 8.8% (11/124) received palliative care from the outset, and 21.2% (24/113) of those with intention to treat were listed for cardiac transplant, of whom 75.0% (18/24) received transplantation by age 1-year. Genetic etiologies were found in 34.0% (50/147) of the cohort, with variants of uncertain significance detected in an additional 27.2% (40/147). Fetal hydrops at the time of prenatal diagnosis ( P =0.001) and a prenatal diagnosis of extracardiac structural anomalies ( P ≤0.001) were significantly associated with death or transplant by 1-year of age. CONCLUSIONS: Fetal cardiomyopathy outcomes have improved in the current era, although only half achieve 1-year cardiac transplant-free survival. Genetic testing identifies a cause in one-third of cases. Hydrops at the time of fetal cardiomyopathy diagnosis and a prenatal diagnosis of extra-cardiac structural anomalies remain important risk factors for mortality.

PURPOSE:Dexrazoxane has been associated with preservation of left ventricular (LV) systolic function in relatively small studies of long-term childhood cancer survivors. What remains less clear is whether this association is also seen in larger populations over time and what effect dexrazoxane has on cardiomyopathy screening recommendations. METHODS:We analyzed echocardiographic data from participants who received doxorubicin treatment and were enrolled on Children's Oncology Group protocols P9404, P9425, P9426, P9754, and Dana Farber Cancer Institute protocol 95-01. Except for P9754, all protocols featured up-front 1:1 random assignment with dexrazoxane administered uniformly as an intravenous bolus before doxorubicin (10:1 mg/m2 dexrazoxane:doxorubicin dose). Blinded central echocardiogram remeasurements were used when possible; otherwise, data were abstracted from institutional reports. Differences and associations by ± dexrazoxane were estimated using generalized estimating equations and Cox proportional hazard models, adjusting for age, sex, doxorubicin dose, chest radiotherapy, and echocardiogram data type. RESULTS:Among 895 patients (mean follow-up, 5.9 years, 230 with ≥10-year follow-up; median doxorubicin dose, 360 mg/m2; 51% dexrazoxane-exposed) with evaluable echocardiograms (n = 2,279; 1,581 centrally remeasured; 698 report only), preserved LV systolic function was observed in patients treated with dexrazoxane (z-score difference 0.4 [95% CI, 0.2 to 0.5]) versus without. Dexrazoxane was also associated with decreased hazards of reduced LV function (fractional shortening <30% or ejection fraction <50%) occurring after 1 (0.58 [95% CI, 0.41 to 0.82]) and 5 years (0.54 [95% CI, 0.31 to 0.93]) postdiagnosis. Finally, dexrazoxane appeared to decrease the incidence of reduced LV function among those classified by current cardiomyopathy screening guidelines as high risk to rates like a lower-risk group (from 40 to 21.8 events/1,000 person-years; P = .001). CONCLUSION:Dexrazoxane exerts a significant doxorubicin cardioprotective effect on LV systolic function long term and may reduce screening needs.

Background: Echocardiography is the definitive diagnostic test for neonates when pre-and post-natal assessments indicate critical congenital heart defects (CCHDs), but it is not practical for surveillance screening of all neonates. Pulse-oximetry is routinely used for newborn screening for heart defects. Objective: To determine the value of additional information beyond pulse-oximetry provided by an electrocardiogram (ECG) in identifying and managing neonates with CCHDs. Methods: We retrospectively compared pulse-oximetry and ECGs from 56 neonates with CCHD who received neonatal cardiovascular surgery to 56 demographically-matched neonates with normal echocardiograms. Conduction intervals, QRS axis, QRS and P-wave durations, and P, QRS, and T-wave voltages were quantified. Classification and Regression Tree (CART) and random forest analyses were used to explore the additional utility of ECG information beyond that provided by prenatal ultrasound and pulse-oximetry and to determine the most informative predictors. Results: There were twenty-three neonates with CCHD (78% with left obstructive defects) and a negative pulseoximetry screen. Among the neonates with a negative pulse-oximetry screen, the T-wave and R-wave voltages in lead V6 and the presence of a prenatal diagnosis excluded 54/56 (96%) of controls and correctly identified 17/23 (74%) of neonates with CCHD in the CART analysis. Random forests correctly classified 54/56 neonates with CCHD and 52/56 controls and determined the variables most important for predicting CCHD were in descending order: pulse-oximetry, presence of a prenatal diagnosis of heart disease, T-wave voltage in V6, QTc interval, Pwave voltage in V2, R-wave voltage in V6, T-wave voltage in V2, R-wave voltage in V5, and atrial enlargement. Conclusions: In neonates who have negative prenatal ultrasound or postnatal pulse-oximetry screening for CCHD, the R-and T-wave amplitudes in V6 are discriminating factors for the presence or absence of CCHD. Electrocardiography may help guide the urgency of further diagnostic interventions.

BACKGROUND AND OBJECTIVES:Childhood obesity has remained persistently high in the United States. This study aimed to (1) assess changes in obesity prevalence and (2) examine the associations of ultra-processed food (UPF) intake and physical activity (PA) patterns with obesity, by obesity severity, before and during the COVID-19 pandemic among US 2- to 19-year-olds. METHODS:A serial cross-sectional analysis using the National Health and Nutrition Examination Survey compared data from before (2017 to March 2020) and during (August 2021 to August 2023) the COVID-19 pandemic. Obesity was determined using body-mass-index-for-age percentiles: class I obesity (≥95th percentile to <120% of the 95th percentile), class II (≥120% to <140%), and class III (≥140% of the 95th percentile). UPF intake was assessed via 24-hour dietary recalls. Participants self-reported the number of days/week they engaged in moderate to vigorous PA. Survey logistic regression models assessed the odds of increasing obesity severity by UPF intake and PA, age, sex, race, ethnicity, and household income. RESULTS:Analysis included 4756 participants in the pre-pandemic period and 2501 in the pandemic period. Obesity prevalence was 21.2% pre-pandemic (N = 1072) and 22.6% during the pandemic (N = 694; P = .30). Mean %UPF intake decreased from 66.0% to 62.7% (P < .01). Before the pandemic, adjusted analysis showed youth with higher PA days had lower odds of class II obesity (odds ratio [OR] = 0.86, 95% CI: 0.76-0.97) and overall obesity (OR = 0.91, 95% CI: 0.85-0.97), with a protective effect across class I and III that did not reach significance. During the pandemic, meeting PA guidelines was also protective against overall obesity (OR = 0.86, 95% CI: 0.76-0.99). Although no significant predictors of obesity by class emerged during the pandemic, protective nonsignificant effects of PA were also observed. CONCLUSIONS:Obesity prevalence trended up from before to during the pandemic, and PA was associated with obesity, whereas no distinct associations of UPF and increasing obesity severity emerged.

OBJECTIVES:To compare changes in inflammatory biomarkers among youth with perinatally-acquired HIV (PHIV) and perinatal HIV-exposure without infection (PHEU), and to examine their associations with antiretroviral therapy (ART) and HIV disease status. DESIGN:A substudy within a longitudinal cohort study conducted across 14 U.S. sites. METHODS:We measured inflammatory biomarkers at baseline and ~11 years later in 99 PHIV participants receiving ART and 59 PHEU participants. Univariable and multivariable linear regression models evaluated changes within and between groups and associations between biomarker concentrations at follow-up and ART regimens, CD4 + cell count, and viral loads (VL). RESULTS:At baseline, the median ages of PHIV and PHEU were 13 and 11 years. Median baseline concentrations of interleukin-18 (IL-18) and tumor necrosis factor alpha (TNF-α) were significantly higher in PHIV than PHEU. At follow-up, only the median sTNF-R2 concentration was significantly higher in PHIV than PHEU. In both groups, median biomarker concentrations decreased from baseline to follow-up except for TNF-α (increased in PHEU) and hsCRP (increased in both). A greater decrease in IL-10 in PHIV than PHEU was the only significant difference between groups. At follow-up, a nadir CD4 + <15% was associated with lower IL-8 concentrations; CD4 + cell count ≤500 cells/mm 3 was associated with higher IL-18 concentrations; and VL ≥400 copies/ml was associated with higher sTNF-R2 concentrations. Longer duration of integrase inhibitor (INSTI) use was associated with increases in IL-6, IL-8, and IL-10. CONCLUSIONS:Among PHIV on ART, inflammation decreases over time, associated with better HIV disease control, and likely reduces the risk of HIV-related comorbidities. However, inflammation may increase with INSTI exposure.

Children diagnosed with cancer are now living longer, thanks to advances in treatment. However, though cured of cancer, they are at risk for chronic health conditions. Cardiovascular diseases are among the most common cause of morbidity and mortality after recurrence and secondary malignancies. Cardiotoxicity is associated with certain cancer treatments, such as anthracyclines and radiation, and if left undetected or untreated can lead to heart failure, heart transplant, or death. This chapter will provide the latest evidence on risk factors, preventative strategies, screening, and treatment of cardiotoxicity in childhood cancer survivors. Though advances have been made, particularly in prevention by use of the cardioprotectant dexrazoxane, there is still much to be done to find a balance between oncologic efficacy and cardiotoxic late effects.

This cross-sectional study analyzed adolescent metabolic and bariatric surgery (MBS) utilization before and after glucagon-like peptide-1 receptor agonist (GLP-1RA) medication approval, comparing trends across race and ethnic groups. Although both MBS and GLP-1RA are effective weight management strategies, adolescent MBS utilization increased, while adult rates declined from 2021 through 2023.

BACKGROUND:Studies have demonstrated that patients with myocarditis may have a higher burden of cardiomyopathy-associated genetic variants than the general population. However, data on children are limited. We compared the prevalence of rare predicted-damaging variants and clinically pathogenic variants in children with dilated cardiomyopathy (DCM) secondary to myocarditis with that in children with DCM alone and in heart-healthy controls. METHODS:Children with DCM secondary to myocarditis and children with DCM alone who underwent exome sequencing as part of a prior cross-sectional study were identified in the Pediatric Cardiomyopathy Registry, a large multicenter registry of children with cardiomyopathy. Controls from the Indiana University Biobank were matched 4:1 with myocarditis cases on genomic similarity. Rare predicted-damaging variants in cardiomyopathy-associated genes were identified using a bioinformatics approach. Clinical guidelines were used to determine clinical pathogenicity. The prevalence of variants was compared across the 3 groups. RESULTS:There were 32 patients with DCM secondary to myocarditis. The prevalence of rare predicted-damaging variants was 34.4% (11/32 [95% CI, 18.6%-53.2%]) in cases compared with 6.3% (8/128 [95% CI, 2.7%-11.9%]) in controls (P<0.001). Clinical review indicated all rare predicted-damaging variants in cases were pathogenic (1/12), likely pathogenic (3/12), or variants of uncertain significance (8/12), whereas most variants in controls were benign (2/8) or likely benign (4/8). The prevalence of pathogenic/likely pathogenic variants in cases was 12.5% (95% CI, 3.5%-29.0%) compared with 0% (95% CI, 0%-2.3%) in controls (P<0.01). Rare predicted-damaging and clinically pathogenic/likely pathogenic variant prevalence was not significantly different in children with DCM secondary to myocarditis and DCM without myocarditis (P=0.17 and P=1.00, respectively). CONCLUSIONS:Children with DCM secondary to myocarditis had a higher burden of variants in cardiomyopathy-associated genes than that of heart-healthy controls. Larger studies will be needed to determine the utility of routine genetic testing in this population.

Supplementary Data from Cardiometabolic Risk in Childhood Cancer Survivors: A Report from the Children's Oncology Group

This cross-sectional study analyzed adolescent metabolic and bariatric surgery (MBS) utilization before and after glucagon like receptor agonist (GLP-1RA) medication approval, comparing trends across race and ethnic groups. Although both MBS and GLP-1RA are effective weight management strategies, adolescent MBS utilization increased, while adult rates declined from 2021 through 2023.

10010 Background: Dexrazoxane (DRZ) has been associated with reduced adverse left ventricular (LV) remodeling shortly after doxorubicin (DOX) treatment (<5y) and preserved LV function in long-term (>15y) survivors of childhood cancer. What remains less clear are longitudinal changes in echocardiographic (echo) measures in this population. Methods: ALTE11C2 analyzed participants who received DOX treatment and were enrolled on COG protocols P9404, P9425, P9426, P9754, and Dana Farber Cancer Institute 95-01. Except for P9754, all other protocols featured upfront 1:1 randomization with DRZ (10:1mg/m 2 DRZ:DOX dose). Central echo remeasurements were used when possible, otherwise we used data from abstracted echo reports. Echo values were converted to age- or BSA-specific z-scores. Differences in z-scores by ±DRZ were estimated as a function of time using generalized estimating equations, adjusting for age, sex, DOX dose, chest radiotherapy, and data type (directly remeasured vs report). Results: 895 patients (67% male; 67% white non-Hispanic; mean age at diagnosis 11.4y; median DOX dose 360 mg/m 2 ; 32% chest radiotherapy) had evaluable echo data (n=2279 echos; 1581 centrally remeasured; 698 report only; mean of 1.0-1.7 echos per patient per time period, with an average of 1.4 echos per patient ≥15y). In multivariable analysis, DRZ was overall associated with more normal LV fractional shortening and less LV end-diastolic and end-systolic dilation, a pattern consistent with less subclinical dilated cardiomyopathy directionality. These cardioprotective changes associated with DRZ were seen most clearly in patients treated with DOX ≥250 mg/m 2 with this length of follow-up. Conclusions: DRZ exerts significant DOX cardioprotective effects on cardiac function and remodeling, detectable within 5y and persisting beyond 10y of follow-up. Z-score difference by ±DRZ as a function of time, adjusted for sex, age, echo type, DOX dose, chest radiotherapy. LV measure Overall Pre-treatment <2y 2-4y 5-9y ≥10y Fractional shortening 0.4 (0.2, 0.5) * 0.1 (-0.2, 0.5) 0.1 (-0.2, 0.5) 0.7 (0.4, 0.9) * 0.5 (0.2, 0.9) * 0.4 (0.2, 0.7) * End-diastolic dimension -0.2 (-0.4, -0.1) * -0.2 (-0.4, 0.0) -0.0 (-0.3, 0.2) -0.4 (-0.6, -0.2) * -0.2 (-0.5, 0.1) -0.3 (-0.6, 0.0) * End-systolic dimension -0.3 (-0.5, -0.2) * -0.2 (-0.5, 0.0) -0.1 (-0.3, 0.1) -0.5 (-0.7, -0.3) * -0.4 (-0.7, -0.1) * -0.4 (-0.7, -0.2) * End-diastolic posterior wall thickness 0.0 (-0.1, 0.2) -0.4 (-0.7, -0.2) * -0.1 (-0.3, 0.2) 0.4 (0.2, 0.6) * 0.1 (-0.3, 0.5) 0.0 (-0.2, 0.3) End-diastolic septal wall thickness 0.1 (-0.1, 0.2) -0.2 (-0.5, 0.1) -0.1 (-0.3, 0.2) 0.3 (0.1, 0.5) * 0.2 (-0.1, 0.5) 0.2 (-0.1, 0.4) Thickness-to-dimension ratio (adverse remodeling=negative) 0.1 (-0.1, 0.2) -0.3 (-0.5, 0.0) -0.1 (-0.3, 0.2) 0.4 (0.2, 0.7) * 0.1 (-0.3, 0.6) 0.1 (-0.2, 0.4) Mass -0.1 (-0.2, 0.1) -0.4 (-0.6, -0.1) * -0.0 (-0.3, 0.2) 0.1 (-0.2, 0.3) -0.3 (-0.9, 0.3) 0.2 (-0.1, 0.6) *p<0.05.

Background:Energy drinks (EDs) may contain caffeine, amino acids, vitamins, and other ingredients that have been associated with serious adverse effects primarily in children and young adults. Objectives:We sought to understand ED exposures including demographic trends, clinical effects, and outcomes in the US Poison Centers' National Poison Data System (NPDS) and compared similar reports of caffeinated beverages. Methods:We analyzed all NPDS closed, human exposures to single-use EDs reported to NPDS between October 1, 2010, and September 30, 2013. Results:NPDS recorded 10,588 cases of ED exposure. Active ingredients were identified in 5,139 (49%) cases. Of the 4,803 (93%) exposures to alcohol-free EDs, 51% were in children 5 years old or younger, 10% were in children 6 to 12 years old, 16% were in adolescents 13 to 19 years old, and 23% were adults at least 20 years old. Unintentional exposures were highest in children 5 years old or younger (75%). Intentional exposures were highest in adolescents (45%). Moderate or major adverse outcomes from EDs containing multiple caffeine ingredients were more common than single ingredient caffeine products (23% vs. 15%; P<0.001). Exposures associated with ethanol EDs had worse outcomes than those without (42% vs. 19%, respectively; P<0.001). The most common clinical effects associated with ED exposures were neurologic (N=1,042, 22%), gastrointestinal (N=792, 17%), and cardiovascular (N=567, 12%); 14 cases were life-threatening, and 1 adolescent girl with vascular Ehlers Danlos syndrome died. Recent follow up from January 1, 2020 to December 31, 2021 shows consistent trends in use and a clear difference between EDs and caffeinated beverage case numbers and medical outcomes. The number of cases was similar in each year except for a notable increase mid-2020 believed related to the pandemic with our query returning 4,367 reported ED cases between 2020 and 2021. Conclusion:A substantial proportion of ED calls to poison centers involve children, some of whom experience severe neurologic and cardiac toxicity, among other symptoms. ED exposure calls are more common and have more medical severity than exposures to caffeine or coffee beans alone. The number and severity of adverse ED events warrant efforts to educate the public about the risks, especially in children.

Objective: To compare arterial stiffness between young adults with perinatally acquired HIV (YAPHIV) and young adults perinatally HIV exposed but uninfected (YAPHEU). Design: Cross-sectional analysis of pulse wave velocity (PWV) measures among participants with echocardiography in the PHACS Cardiac Toxicity Substudy. Methods: A total of 150 participants (95 YAPHIV, 55 YAPHEU, mean 23.4 years, 60% female, 72% Black, 24% Hispanic) had echocardiography and PWV measured. We compared PWV between groups. Among YAPHIV, we fit linear regression models to evaluate the association of measures of HIV disease severity and antiretroviral treatment (ART) with PWV. We computed correlations between PWV and measures of left ventricular structure and function. Results: Mean PWV did not differ by group (YAPHIV 5.63 vs YAPHEU 5.39 m/s; P = 0.50). HIV control was good (82% with viral load <400 copies/ml); 91% used combination ART. Mean PWV was normal, but 3 of 95 YAPHIV (3%) had values above 11.8 m/s (level associated with cardiovascular events in adults). Weak correlations (<0.20) were observed between PWV and echocardiographic measures. Among YAPHIV, current and historical HIV severity measures were not associated with PWV. YAPHIV on protease inhibitor (PI)-based ART had higher mean PWV than those on integrase strand inhibitors (1.68 m/s higher, 95% CI -0.36, 3.72) or nonnucleoside transcriptase inhibitors (1.58 m/s higher, 95% CI −0.94, 4.11). Conclusions: Our data shows no difference in PWV between those perinatally exposed to and perinatally infected with HIV. Therefore, CV risk reduction guidelines should be followed to prevent CV disease in all young adults.