Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other structural anomalies and/or neurobehavioral manifestations. Rare de novo protein-coding variants and copy-number variations contribute to CDH in the population. However, most individuals with CDH remain genetically undiagnosed. Here, we perform integrated de novo and common-variant analyses using 1,469 CDH individuals, including 1,064 child-parent trios and 6,133 ancestry-matched, unaffected controls for the genome-wide association study. We identify candidate CDH variants in 15 genes, including eight novel genes, through deleterious de novo variants. We further identify two genomic loci contributing to CDH risk through common variants with similar effect sizes among Europeans and Latinx. Both loci are in putative transcriptional regulatory regions of developmental patterning genes. Estimated heritability in common variants is ∼19%. Strikingly, there is no significant difference in estimated polygenic risk scores between isolated and complex CDH or between individuals harboring deleterious de novo variants and individuals without these variants. The data support a polygenic model as part of the CDH genetic architecture.

Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.

An interdisciplinary consensus approach to pulmonary hypertension in developmental lung disease.

It is increasingly recognised that diverse genetic respiratory disorders present as severe pulmonary hypertension (PH) in the neonate and young infant, but many controversies and uncertainties persist regarding optimal strategies for diagnosis and management to maximise long-term outcomes. To better define the nature of PH in the setting of developmental lung disease (DEVLD), in addition to the common diagnoses of bronchopulmonary dysplasia and congenital diaphragmatic hernia, we established a multidisciplinary group of expert clinicians from stakeholder paediatric specialties to highlight current challenges and recommendations for clinical approaches, as well as counselling and support of families. In this review, we characterise clinical features of infants with DEVLD/DEVLD-PH and identify decision-making challenges including genetic evaluations, the role of lung biopsies, the use of imaging modalities and treatment approaches. The importance of working with team members from multiple disciplines, enhancing communication and providing sufficient counselling services for families is emphasised to create an interdisciplinary consensus.

Safety and Effectiveness of Selexipag in Pediatric Pulmonary Hypertension: A Retrospective Multicenter Cohort Study.

OBJECTIVE: To describe the safety and effectiveness of treating pediatric patients who have pulmonary arterial hypertension (PAH) with selexipag in a real-world, multicenter cohort, given that data supporting its use in pediatric PAH are sparse. STUDY DESIGN: We report a multicenter, retrospective, cohort study of children with PAH treated with selexipag. Demographic and clinical variables were extracted from the medical records. Clinical parameters were analyzed at 3 timepoints: before selexipag, 3-12 months after selexipag, and >12 months follow-up. RESULTS: Eighty-seven patients were included, 32 received selexipag as add-on to background therapy, and 55 transitioned from another prostanoid. The median starting and final doses were 4.7 and 28.5 µg/kg/dose twice daily, respectively. Add-on patients demonstrated improved indexed pulmonary to systemic vascular resistance ratio after selexipag initiation (PVRi/SVRi, 0.62v0.53; P = .034) with a lower average mean pulmonary artery pressure (46 vs 39 mm Hg; P = NS), and oxygen consumption (maximal oxygen consumption during cardiopulmonary exercise testing [VO2 max] 27.8 mL/kg/min vs 30.9 mL/kg/min; P = NS). Transition patients demonstrated stable mean pulmonary artery pressure (47 mm Hg vs 45 mm Hg; P = NS) and a lower mean indexed pulmonary vascular resistance (10.9 Wood units∗m2 vs 8.2 Wood units∗m2; P = NS) but late functional worsening in some with VO2 max decreased at follow-up (26.0 mL/kg/min vs 19.5 mL/kg/min). Side effects were noted in 40% of the cohort, but prompted discontinuation in only 2%. CONCLUSIONS: In a large, multicenter cohort, the oral prostacyclin agonist selexipag demonstrates favorable tolerability and effectiveness. Add-on patients demonstrated early hemodynamic improvement. Transition patients demonstrated early stability with risk of late functional worsening, highlighting the importance of ongoing monitoring.

Assessment of Biventricular Systolic and Diastolic Function Using Conventional and Strain Echocardiography in Children with Sickle Cell Disease Surviving 1-year After Hematopoietic Stem Cell Transplant.

Hematopoietic stem cell transplant (HSCT) is a potentially curative therapy for children with sickle cell disease (SCD). The effects of HSCT on ventricular function are not well characterized in children with SCD. Echocardiograms from children with SCD who underwent HSCT between 2007 and 2017 were retrospectively analyzed before and 1-year after HSCT. Left ventricular (LV) volumes, mass, and ejection fraction were calculated by the 5/6 area*length method. LV end-diastolic and systolic dimensions, septal, and posterior wall thickness, and fractional shortening were measured by M-mode. Mitral and tricuspid inflow Dopplers (E and A waves) as well as mitral, tricuspid, and septal tissue Dopplers (E', A') were assessed. E/A, E'/A' and E/E' ratios were calculated. Biventricular strain imaging was performed using speckle-tracking echocardiography. Peak global systolic longitudinal and circumferential LV strain, and global longitudinal right ventricular strain, as well as early and late diastolic strain rate, were measured on LV apical 4-chamber, LV short-axis mid-papillary, and RV apical views, respectively. Forty-seven children (9.7 ± 5.5 years, 60% male) met inclusion criteria. Pre-HSCT, subjects had mild LV dilation with normal LV systolic function by conventional measure of ejection fraction and fractional shortening. There was a significant reduction in LV volume, mass, and ejection fraction after HSCT, but measurements remained within normal range. LV longitudinal and circumferential strain were normal pre-HSCT and showed no significant change post-HSCT. RV strain decreased after HSCT, but the absolute change was small, and mean values were normal both pre- and post-HSCT. Conventional measures of diastolic function were all normal pre-HSCT. Post-HSCT there was a reduction in select parameters, but all parameters remained within normal range. Early and late diastolic strain rate parameters showed no significant change from pre- to post-HSCT. At one-year after HSCT in children with SCD conventional measures of systolic and diastolic function are within normal limits. Except for a small decrease in RV systolic strain with values remaining within normal limits, systolic strain and diastolic strain rate values did not significantly change 1-year after HSCT.

Disparities in resource utilisation by families of children with cardiac conditions.

OBJECTIVES: There are limited data documenting sources of medical information that families use to learn about paediatric cardiac conditions. Our study aims to characterise these resources and to identify any disparities in resource utilisation. We hypothesise there are significant variations in the resources utilised by families from different educational and socio-economic backgrounds. METHODS: A survey evaluating what resources families use (websites, healthcare professionals, social media, etc.) to better understand paediatric cardiac conditions was administered to caretakers and paediatric patients at Morgan Stanley Children's Hospital. Patients with a prior diagnosis of CHD, cardiac arrhythmia, and/or heart failure were included. Caretakers' levels of education (fewer than 16 years vs. 16 years or more) and patients' medical insurance types (public vs. private) were compared with regard to the utilisation of resources. RESULTS: Surveys completed by 137 (91%) caretakers and 27 (90%) patients were analysed. Websites were utilised by 72% of caretakers and 56% of patients. Both private insurance and higher education were associated with greater reported utilisation of websites, healthcare professionals, and personal networks (by insurance p = 0.009, p = 0.001, p = 0.006; by education p = 0.022, p < 0.001, p = 0.018). They were also more likely to report use of electronic devices (such as a computer) compared to those with public medical insurance and fewer than 16 years of education (p < 0.001, p < 0.001, respectively). CONCLUSION: Both levels of education and insurance status are associated with the utilisation of informative resources and digital devices by families seeking to learn more about cardiac conditions in children.

Congenital Heart Disease with Congenital Diaphragmatic Hernia: Surgical Decision Making and Outcomes.

OBJECTIVE: To describe the types of congenital heart disease (CHD) in a congenital diaphragmatic hernia (CDH) cohort in a large volume center and evaluate surgical decision making and outcomes based on complexity of CHD and associated conditions. STUDY DESIGN: A retrospective review of patients with CHD and CDH diagnosed by echocardiogram between 01/01/2005 and 07/31/2021. The cohort was divided into 2 groups based on survival at discharge. RESULTS: Clinically important CHD was diagnosed in 19% (62/326) of CDH patients. There was 90% (18/20) survival in children undergoing surgery for both CHD and CDH as neonates, and 87.5 (22/24) in those undergoing repair initially for CDH alone. A genetic anomaly identified on clinical testing was noted in 16% with no significant association with survival. A higher frequency of other organ system anomalies was noted in nonsurvivors compared with survivors. Nonsurvivors were more likely to have unrepaired CDH (69% vs 0%, P < .001) and unrepaired CHD (88% vs 54%, P < .05), reflecting a decision not to offer surgery. CONCLUSIONS: Survival was excellent in patients who underwent repair of both CHD and CDH. Patients with univentricular physiology have poor survival and this finding should be incorporated into pre and postnatal counseling about eligibility for surgery. In contrast, patients with other complex lesions including transposition of the great arteries have excellent outcomes and survival at 5 years follow-up at a large pediatric and cardiothoracic surgical center.

Measurement of Physical Activity by Actigraphy in Infants and Young Children with Pulmonary Arterial Hypertension.

OBJECTIVE: To evaluate the feasibility, tolerability, and adherence with wearable actigraphy devices among infants and children with pulmonary arterial hypertension (PAH). STUDY DESIGN: This multicenter, prospective, observational study included children ages 0-6 years with and without PAH. Participants wore the ActiGraph wGT3X-BT on the hip and FitBit Inspire on the wrist during waking hours for 14 days. Steps, vector magnitude counts per minute, activity intensity, heart rate, and heart rate variability were compared between groups. RESULTS: Forty-seven participants (18 PAH, 29 control) were enrolled from 10 North American sites. PAH patients were mostly functional class II (n = 16, 89%) and treated with oral medications at the time of enrollment. The number of wear days was not significantly different between the groups (ActiGraph: 10 [95% CI: 5.5, 12.2] in PAH vs 8 [4, 12] in control, P = .20; FitBit 13 [10, 13.8] in PAH vs 12 [8, 14] in control, P = .87). Complete data were obtained in 81% of eligible ActiGraph participants and 72% of FitBit participants. PAH participants demonstrated fewer steps, lower vector magnitude counts per minute, more sedentary activity, and less intense physical activity at all levels compared with control participants. No statistically significant differences in heart rate variability were demonstrated between the 2 groups. CONCLUSIONS: Measurement of physical activity and other end points using wearable actigraphy devices was feasible in young children with PAH. Larger studies should determine associations between physical activity and disease severity in young patients with PAH to identify relevant end points for pediatric clinical trials.

Ventricular function and tissue characterization by cardiac magnetic resonance imaging following hospitalization for multisystem inflammatory syndrome in children: a prospective study.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a severe life-threatening manifestation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that often presents with acute cardiac dysfunction and cardiogenic shock. While recovery from acute illness is excellent, the long-term myocardial impact is unknown. OBJECTIVE: To compare cardiac MRI findings in children 6-9 months after their hospitalization with MIS-C against MRI findings in healthy controls to assess for residual myocardial disease. MATERIALS AND METHODS: We prospectively performed cardiac MRI on 13 children 6-9 months following their hospitalization with MIS-C: eight of these children had a history of left ventricle ejection fraction (LVEF) < 50%, persistent symptoms, or electrocardiogram (ECG) abnormalities and underwent clinical MRI; five of these children without cardiac abnormalities during their hospitalization underwent research MRIs. We compared their native T1 and T2 mapping values with those of 20 normal controls. RESULTS: Cardiac MRI was performed at 13.6 years of age (interquartile range [IQR] 11.9-16.4 years) and 8.2 months (IQR 6.8-9.6 months) following hospitalization. Twelve children displayed normal ejection fraction: left ventricle (LV) 57.2%, IQR 56.1-58.4; right ventricle (RV) 53.1%, IQR 52.0-55.7. One had low-normal LVEF (52%). They had normal extracellular volume (ECV) and normal T2 and native T1 times compared to controls. There was no qualitative evidence of edema. One child had late gadolinium enhancement (LGE) with normal ejection fraction, no edema, and normal T1 and T2 times. When stratifying children who had MIS-C according to history of LVEF <55% on echocardiography, there was no difference in MRI values. CONCLUSION: Although many children with MIS-C present acutely with cardiac dysfunction, residual myocardial damage 6-9 months afterward appears minimal. Long-term implications warrant further study.

Outcomes and Risk Factors of Interventions for Pediatric Post-operative Pulmonary Vein Stenosis.

Pulmonary vein stenosis (PVS) in children is a challenging condition with poor outcomes. Post-operative stenosis can occur after repair of anomalous pulmonary venous return (APVR) or stenosis within native veins. There is limited data on the outcomes of post-operative PVS. Our objective was to review our experience and assess surgical and transcatheter outcomes. Single-center retrospective study was performed including patients < 18 years who developed restenosis after baseline pulmonary vein surgery that required additional intervention(s) from 1/2005 to 1/2020. Non-invasive imaging, catheterization and surgical data were reviewed. We identified 46 patients with post-operative PVS with 11 (23.9%) patient deaths. Median age at index procedure was 7.2 months (range 1 month-10 years), and median follow-up was 10.8 months (range 1 day-13 years). Index procedure was surgical in 36 (78.3%) and transcatheter in 10 (21.7%). Twenty-three (50%) patients developed vein atresia. Mortality was not associated with number of affected veins, vein atresia, or procedure type. Single ventricle physiology, complex congenital heart disease (CCHD), and genetic disorders were associated with mortality. Survival rate was higher in APVR patients (p = 0.03). Patients with three or more interventions had a higher survival rate compared to patients with 1-2 interventions (p = 0.02). Male gender, necrotizing enterocolitis, and diffuse hypoplasia were associated with vein atresia. In post-operative PVS, mortality is associated with CCHD, single ventricle physiology, and genetic disorders. Vein atresia is associated with male gender, necrotizing enterocolitis, and diffuse hypoplasia. Multiple repeated interventions may offer a patient survival benefit; however, larger prospective studies are necessary to elucidate this relationship further.

Likely damaging de novo variants in congenital diaphragmatic hernia patients are associated with worse clinical outcomes.

PURPOSE: Congenital diaphragmatic hernia (CDH) is associated with significant mortality and long-term morbidity in some but not all individuals. We hypothesize monogenic factors that cause CDH are likely to have pleiotropic effects and be associated with worse clinical outcomes. METHODS: We enrolled and prospectively followed 647 newborns with CDH and performed genomic sequencing on 462 trios to identify de novo variants. We grouped cases into those with and without likely damaging (LD) variants and systematically assessed CDH clinical outcomes between the genetic groups. RESULTS: Complex cases with additional congenital anomalies had higher mortality than isolated cases (P = 8 × 10-6). Isolated cases with LD variants had similar mortality to complex cases and much higher mortality than isolated cases without LD (P = 3 × 10-3). The trend was similar with pulmonary hypertension at 1 month. Cases with LD variants had an estimated 12-17 points lower scores on neurodevelopmental assessments at 2 years compared with cases without LD variants, and this difference is similar in isolated and complex cases. CONCLUSION: We found that the LD genetic variants are associated with higher mortality, worse pulmonary hypertension, and worse neurodevelopment outcomes compared with non-LD variants. Our results have important implications for prognosis, potential intervention and long-term follow up for children with CDH.

SARS-CoV-2 Infection in Patients with Down Syndrome, Congenital Heart Disease, and Pulmonary Hypertension: Is Down Syndrome a Risk Factor?

With increasing information available about the epidemiology, pathophysiology, and management of patients affected with severe acute respiratory syndrome corona virus-2 infection, patients with Down syndrome, congenital heart disease, airway obstruction, and pulmonary hypertension present a unique challenge. This case series describes 3 patients with Down syndrome and respiratory failure secondary to coronavirus infection.

Sildenafil Use in Children with Pulmonary Hypertension.

OBJECTIVE: To assess the demographics, treatment algorithm, and outcomes in a large cohort of children treated with sildenafil. STUDY DESIGN: A retrospective cohort study of children with pulmonary hypertension (PH) treated with sildenafil at a single institution between 2004 and 2015. Baseline and follow-up data collected by chart review. RESULTS: There were 269 children included in this study: 47 with idiopathic pulmonary arterial hypertension, 53 with congenital heart disease, 135 with bronchopulmonary dysplasia, 24 with congenital diaphragmatic hernia, and 7 with other causes. Sildenafil was initial monotherapy in 84.8% and add-on therapy in 15.2%. Median follow-up time was 3.1 years (2 weeks-12.4 years). On follow-up, 99 (37%) remained on sildenafil or transitioned to tadalafil, 93 (35%) stopped sildenafil for improvement in PH, 54 (20%) died, and 20 (7%) were lost to follow-up. PH was most likely to improve in those with bronchopulmonary dysplasia, allowing for the discontinuation of sildenafil in 45%. Eighteen deaths were related to PH and 36 from other systemic causes. Two patients stopped sildenafil owing to airway spasm with desaturation. Overall survival was significantly lower in World Health Organization group 3 PH (bronchopulmonary dysplasia and congenital diaphragmatic hernia) vs group 1 (idiopathic pulmonary arterial hypertension and congenital heart disease), P = .02. CONCLUSIONS: In this retrospective experience in children with mainly World Health Organization groups 1 and 3 PH, low-dose sildenafil was well-tolerated, safe, and had an acceptable side effect profile. Although patients with group 3 PH have high mortality, survivors have a high likelihood of PH improving.

Racial and Ethnic Differences in Pediatric Pulmonary Hypertension: An Analysis of the Pediatric Pulmonary Hypertension Network Registry.

OBJECTIVE: To investigate racial and ethnic differences in pulmonary hypertension subtypes and survival differences in a pediatric population. STUDY DESIGN: This was a retrospective analysis of a cohort of patients with pulmonary hypertension (aged ≤18 years) enrolled in the Pediatric Pulmonary Hypertension Network registry between 2014 and 2018, comprising patients at eight Pediatric Centers throughout North America (n = 1417). RESULTS: Among children diagnosed after the neonatal period, pulmonary arterial hypertension was more prevalent among Asians (OR, 1.83; 95% CI, 1.21-2.79; P = .0045), lung disease-associated pulmonary hypertension among blacks (OR, 2.09; 95% CI, 1.48-2.95; P < .0001), idiopathic pulmonary arterial hypertension among whites (OR, 1.58; 95% CI, 1.06-2.41; P = .0289), and pulmonary veno-occlusive disease among Hispanics (OR, 6.11; 95% CI, 1.34-31.3; P = .0184). Among neonates, persistent pulmonary hypertension of the newborn (OR, 4.07; 95% CI, 1.54-10.0; P = .0029) and bronchopulmonary dysplasia (OR, 8.11; 95% CI, 3.28-19.8; P < .0001) were more prevalent among blacks, and congenital diaphragmatic hernia was more prevalent among whites (OR, 2.29; 95% CI, 1.25-4.18; P = .0070). An increased mortality risk was observed among blacks (HR, 1.99; 95% CI, 1.03-3.84; P = .0396), driven primarily by the heightened mortality risk among those with lung disease-associated pulmonary hypertension (HR, 2.84; 95% CI, 1.15-7.04; P = .0241). CONCLUSIONS: We found significant racial variability in the prevalence of pulmonary hypertension subtypes and survival outcomes among children with pulmonary hypertension. Given the substantial burden of this disease, further studies to validate phenotypic differences and to understand the underlying causes of survival disparities between racial and ethnic groups are warranted.

Breast Milk and Necrotizing Enterocolitis in Congenital Heart Disease: A Case-Control Study.

Background: Necrotizing enterocolitis (NEC) is a complication that can affect infants with congenital heart disease (CHD). The objective of this study is to determine whether breast milk, which is associated with decreased incidence of NEC in preterm infants, is protective in infants with CHD. Methods: Retrospective case-control study of infants ≥ 33 weeks gestational age with CHD who underwent cardiac surgery during their admission to the Infant Cardiac Unit from 2008 to 2017. Cases were defined as infants with modified Bell's stage ≥ II NEC. Controls were matched by date of birth, gestational age, and pre- or postcardiac surgery feed initiation. Results: A total of 926 infants with gestational age ≥ 33 weeks and CHD were admitted; 18 cases of NEC were identified and compared with 84 controls. Breast milk intake was higher in controls, but this difference was not statistically significant. Single ventricle (SV) physiology was identified as an independent risk factor for NEC by multivariable analysis. Analysis of infants with SV physiology demonstrated that median age at time of surgery was 9 days (interquartile range [IQR], 7-12) in NEC cases and 5 days (IQR, 4-9) in controls (P = .02). Conclusions: While this study is inconclusive with regard to feeding composition and risk of NEC in infants with CHD, the trend toward greater intake of breast milk in the control group suggests that breast milk may be protective for these infants. Infants with SV physiology are at high risk for NEC. Earlier time to stage I palliation may be a modifiable risk factor for NEC.

Safety and Tolerability of Continuous Inhaled Iloprost Therapy for Severe Pulmonary Hypertension in Neonates and Infants.

This is a single-center retrospective study to assess the safety and tolerability of continuous inhaled iloprost use as rescue therapy for refractory pulmonary hypertension (PH) in critically ill neonates and infants. A retrospective chart review was performed on 58 infants and data were collected at baseline, 1, 6, 12, 24, 48 and 72 h of iloprost initiation. Primary outcomes were change in heart rate (HR), fraction of inspired oxygen (FiO2), mean airway pressures (MAP), blood pressure (BP) and oxygenation index (OI). Secondary outcomes were need for extracorporeal membrane oxygenation (ECMO) and death. 51 patients treated for >6 h were analyzed in 2 age groups, neonate (≤28 days: n = 32) and infant (29-365 days: n = 19). FiO2 (p < 0.001) and OI (p = 0.01) decreased, while there were no significant changes in MAP, BP and HR. Of the fifteen patients placed on ECMO, seven were bridged off ECMO on iloprost and eight died. Twenty-four out of fifty-one patients (47%) recovered without requiring ECMO, while twelve (23%) died. Iloprost as add-on therapy for refractory PH in critically ill infants in the NICU has an acceptable tolerability and safety profile. Large prospective multicenter studies using iloprost in the neonatal ICU are necessary to validate these results.

Actigraphy methodology in the Kids Mod PAH trial: Physical activity as a functional endpoint in pediatric clinical trials.

Pulmonary vasodilator treatment can improve hemodynamics, right ventricular function, symptoms, and survival in pediatric pulmonary hypertension (PH). However, clinical trial data are lacking due to many constraints. One major limitation is the lack of relevant trial endpoints reflective of hemodynamics or functional status in patients in whom standard exercise testing is impractical, unreliable, or not reproducible. The Kids Mod PAH trial (Mono- vs. Duo Therapy for Pediatric Pulmonary Arterial Hypertension) is an ongoing multicenter, Phase III, randomized, open-label, pragmatic trial to compare the safety and efficacy of first-line combination therapy (sildenafil and bosentan) to first-line monotherapy (sildenafil alone) in 100 pediatric patients with PH across North America. Investigators will measure participants' physical activity with a research-grade, wrist-worn actigraphy device at multiple time points as an exploratory secondary outcome. Vector magnitude counts per minute and activity intensity will be compared between the treatment arms. By directly and noninvasively measuring physical activity in the ambulatory setting, we aim to identify a novel, simple, inexpensive, and highly reproducible approach for quantitative assessment of exercise tolerance in pediatric PH. These data will increase the field's understanding of the effect of pulmonary vasodilator treatment on daily activity - a quantitative measure of functional status and wellbeing in pediatric PH and a potential primary outcome for future clinical trials in children with cardiopulmonary disorders.