Congenital Diaphragmatic Hernia Patients with Left Heart Hypoplasia and Left Ventricular Dysfunction Have Highest Odds of Mortality.

OBJECTIVES: To describe the scope of left ventricular (LV) dysfunction and left heart hypoplasia (LHH) in infants with congenital diaphragmatic hernia (CDH), to determine associations with CDH severity, and to evaluate the odds of extracorporeal membrane oxygenation (ECMO) and death with categories of left heart disease. STUDY DESIGN: Demographic and clinical variables were collected from a single-center, retrospective cohort of patients with CDH from January 2017 through May 2022. Quantitative measures of LV function and LHH were prospectively performed on initial echocardiograms. LHH was defined as ≥2 of the following: z score ≤ -2 of any left heart structure or LV end-diastolic volume <3 mL. LV dysfunction was defined as shortening fraction <28%, ejection fraction <60%, or global longitudinal strain <20%. The exposure was operationalized as a 4-group categorical variable (LV dysfunction +/-, LHH +/-). Logistic regression models evaluated associations with ECMO and death, adjusting for CDH severity. RESULTS: One hundred eight-two patients (80.8% left CDH, 63.2% liver herniation, 23.6% ECMO, 12.1% mortality) were included. Twenty percent demonstrated normal LV function and no LHH (LV dysfunction-/LHH-), 37% normal LV function with LHH (LV dysfunction-/LHH+), 14% LV dysfunction without LHH (LV dysfunction+/LHH-), and 28% both LV dysfunction and LHH (LV dysfunction+/LHH+). There was a dose-response effect between increasing severity of left heart disease, ECMO use, and mortality. LV dysfunction+/LHH + infants had the highest odds of ECMO use and death, after adjustment for CDH severity [OR (95% CI); 1.76 (1.20, 2.62) for ECMO, 2.76 (1.63, 5.17) for death]. CONCLUSIONS: In our large single-center cohort, patients with CDH with LV dysfunction+/LHH + had the highest risk of ECMO use and death.

Paediatric dominant and non-dominant handgrip reference curves and the association with body composition.

BACKGROUND: Lack of paediatric reference data limits the utility of handgrip strength as a measure of fitness and well-being. AIM: To develop paediatric handgrip reference curves and evaluate associations with body size and composition and race/ethnicity group. SUBJECTS AND METHODS: Handgrip, body size and composition data were obtained from National Health and Nutrition Examination Survey 2011-2014 participants aged 6-20 years. Densitometry-derived fat and appendicular lean soft tissue mass index Z-scores (FMIZ, ALSTMIZ) were generated in participants >8 years. Dominant and non-dominant handgrip reference curves were created using the LMS method. Analyses included sample weights to produce nationally representative estimates. RESULTS: Differences in handgrip strength according to hand dominance increased with age. Handgrip strength was associated with height and arm length Z-scores (R = 0.42 to 0.47) and ALSTMIZ (R = 0.54). Handgrip strength was higher in the non-Hispanic Black group and lower in the Mexican American compared to non-Hispanic White group. Group differences were attenuated when adjusted for height, arm length or ALSTMIZ. CONCLUSION: Paediatric handgrip reference curves were generated from which individual Z-scores can be calculated separately for dominant versus non-dominant hand and adjusted for body size. Association with ALSTMIZ suggests handgrip Z-score may be used as a measure of functional body composition.

Treprostinil in Neonates with Congenital Diaphragmatic Hernia-Related Pulmonary Hypertension.

OBJECTIVE: To describe our experience with treprostinil, evaluate correlations with cardiac function, and assess for adverse effects in neonates with congenital diaphragmatic hernia-related pulmonary hypertension (CDH-PH). STUDY DESIGN: A retrospective review of a single-center prospective registry at a quaternary care children's hospital. Patients included in the study had CDH-PH treated with treprostinil between April 2013 and September 2021. Assessed outcomes were brain-type natriuretic peptide levels and quantitative echocardiographic parameters collected at baseline, 1 week, 2 weeks, and 1 month after treprostinil initiation. Right ventricular (RV) function was assessed by tricuspid annular plane systolic excursion Z-score and speckle tracking echocardiography (global longitudinal and free wall strain). Septal position and left ventricular (LV) compression were assessed by eccentricity index and M-mode Z-scores. RESULTS: Fifty-one patients were included, with an average expected/observed lung-to-head ratio of 28.4 ± 9.0%. Most patients required extra-corporeal membrane oxygenation (n = 45, 88%). Survival to hospital discharge was 31/49 (63%). Treprostinil was initiated at a median age of 19 days with a median effective dose of 34 ng/kg/minute. Median baseline brain-type natriuretic peptide level decreased from 416.9 pg/mL to 120.5 pg/mL after 1 month. Treprostinil was associated with improved tricuspid annular plane systolic excursion Z-score, RV global longitudinal strain, RV free wall strain, LV eccentricity index, and LV diastolic and systolic dimensions, reflecting less compression by the RV, regardless of ultimate patient survival. No serious adverse effects were recorded. CONCLUSIONS: In neonates with CDH-PH, treprostinil administration is well tolerated and is associated with improved RV size and function.

Quantitative Measures of Right Ventricular Size and Function by Echocardiogram Correlate with Cardiac Catheterization Hemodynamics in Congenital Diaphragmatic Hernia.

OBJECTIVE: To evaluate associations between cardiac catheterization (cath) hemodynamics, quantitative measures of right ventricular (RV) function by echocardiogram, and survival in patients with congenital diaphragmatic hernia (CDH). STUDY DESIGN: This single-center retrospective cohort study enrolled patients with CDH who underwent index cath from 2003 to 2022. Tricuspid annular plane systolic excursion z score, RV fractional area change, RV free wall and global longitudinal strain, left ventricular (LV) eccentricity index, RV/LV ratio, and pulmonary artery acceleration time were measured from preprocedure echocardiograms. Associations between hemodynamic values, echocardiographic measures, and survival were evaluated by Spearman correlation and Wilcoxon rank sum test, respectively. RESULTS: Fifty-three patients (68% left-sided, 74% liver herniation, 57% extracorporeal membrane oxygenation, 93% survival) underwent cath (39 during index hospitalization, 14 later) including device closure of a patent ductus arteriosus in 5. Most patients (n = 31, 58%) were on pulmonary hypertension treatment at cath, most commonly sildenafil (n = 24, 45%) and/or intravenous treprostinil (n = 16, 30%). Overall, hemodynamics were consistent with precapillary pulmonary hypertension. Pulmonary capillary wedge pressure was >15 mm Hg in 2 patients (4%). Lower fractional area change and worse ventricular strain were associated with higher pulmonary artery pressure while higher LV eccentricity index and higher RV/LV ratio were associated with both higher pulmonary artery pressure and higher pulmonary vascular resistance. Hemodynamics did not differ based on survival status. CONCLUSIONS: Worse RV dilation and dysfunction by echocardiogram correlate with higher pulmonary artery pressure and pulmonary vascular resistance on cath in this CDH cohort. These measures may represent novel, noninvasive clinical trial targets in this population.

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.

Pulmonary Hypertension in Children with Down Syndrome: Results from the Pediatric Pulmonary Hypertension Network Registry.

OBJECTIVE: To characterize distinct comorbidities, outcomes, and treatment patterns in children with Down syndrome and pulmonary hypertension in a large, multicenter pediatric pulmonary hypertension registry. STUDY DESIGN: We analyzed data from the Pediatric Pulmonary Hypertension Network (PPHNet) Registry, comparing demographic and clinical characteristics of children with Down syndrome and children without Down syndrome. We examined factors associated with pulmonary hypertension resolution and a composite outcome of pulmonary hypertension severity in the cohort with Down syndrome. RESULTS: Of 1475 pediatric patients with pulmonary hypertension, 158 (11%) had Down syndrome. The median age at diagnosis of pulmonary hypertension in patients with Down syndrome was 0.49 year (IQR, 0.21-1.77 years), similar to that in patients without Down syndrome. There was no difference in rates of cardiac catheterization and prescribed pulmonary hypertension medications in children with Down syndrome and those without Down syndrome. Comorbidities in Down syndrome included congenital heart disease (95%; repaired in 68%), sleep apnea (56%), prematurity (49%), recurrent respiratory exacerbations (35%), gastroesophageal reflux (38%), and aspiration (31%). Pulmonary hypertension resolved in 43% after 3 years, associated with a diagnosis of pulmonary hypertension at age <6 months (54% vs 29%; P = .002) and a pretricuspid shunt (65% vs 38%; P = .02). Five-year transplantation-free survival was 88% (95% CI, 80%-97%). Tracheostomy (hazard ratio [HR], 3.29; 95% CI, 1.61-6.69) and reflux medication use (HR, 2.08; 95% CI, 1.11-3.90) were independently associated with a composite outcome of severe pulmonary hypertension. CONCLUSIONS: Despite high rates of cardiac and respiratory comorbidities that influence the severity of pulmonary hypertension, children with Down syndrome-associated pulmonary hypertension generally have a survival rate similar to that of children with non-Down syndrome-associated pulmonary hypertension. Resolution of pulmonary hypertension is common but reduced in children with complicated respiratory comorbidities.

Update on Management and Outcomes of Congenital Diaphragmatic Hernia.

Infants with congenital diaphragmatic hernia (CDH) benefit from comprehensive multidisciplinary teams that have experience in caring for the unique and complex issues associated with CDH. Despite prenatal referral to specialized high-volume centers, advanced ventilation strategies and pulmonary hypertension management, and extracorporeal membrane oxygenation, mortality and morbidity remain high. These infants have unique and complex issues that begin in fetal and infant life, but persist through adulthood. Here we will review the literature and share our clinical care pathway for neonatal care and follow up. While many advances have occurred in the past few decades, our work is just beginning to continue to improve the mortality, but also importantly the morbidity of CDH.

Prevalent pharmacotherapy of US Fontan survivors: A study utilizing data from the MarketScan Commercial and Medicaid claims databases.

BACKGROUND: 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. METHODS: 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. RESULTS: A cohort of 4,056 subjects (median age 12 years [interquartile range: 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 = .008), antiarrhythmic agents, digoxin, ACEi/ARB, and beta blockers (each P < .0001), but also lower likelihood of filled prescriptions for pulmonary vasodilators, conventional diuretics (both P < .0001), and mineralocorticoid receptor antagonists (P = .02). CONCLUSIONS: 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.

Deficits in the Functional Muscle-Bone Unit in Youths with Fontan Physiology.

OBJECTIVE: 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. STUDY DESIGN: 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 = 46; aged 5-20 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). RESULTS: Fontan BMD z-scores were significantly lower than reference at all sites-whole body, -0.34 ± 0.85 (P = .01); spine, -0.41 ± 0.96 (P = .008); hip, -0.75 ± 1.1 (P < .001); femoral neck, -0.73 ± 1.0 (P < .001); distal one-third radius, -0.87 ± 1.1 (P < .001); and ultradistal radius. -0.92 ± 1.03 (P < .001)-as was LLMZ (-0.93 ± 1.1; P < .001). Lower LLMZ was associated with lower BMD of the whole body (R2 = 0.40; P < .001), lumbar spine (R2 = 0.16; P = .005), total hip (R2 = 0.32; P < .001), femoral neck (R2 = 0.47; P < .001), and ultradistal radius (R2 = 0.35; P < .001). CONCLUSIONS: 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.

Marked skeletal muscle deficits are associated with 6-minute walk distance in paediatric pulmonary hypertension.

BACKGROUND: Poor growth is common in children with pulmonary hypertension; however, skeletal muscle deficits have not been described and the association between muscle deficits and functional status is unknown. METHODS: Patients aged 8-18 years with pulmonary hypertension (diagnostic Groups 1, 2, or 3) and World Health Organization functional class I or II underwent dual-energy absorptiometry to measure leg lean mass Z-score (a surrogate for skeletal muscle). Muscle strength was assessed using dynamometry. Physical activity questionnaires were administered. Clinical data, including 6-minute walk distance, were reviewed. Relationships between skeletal muscle, physical activity score, and 6-minute walk distance were assessed by correlations and linear regression. RESULTS: Sixteen patients (12.1 ± 3.2 years, 50% female, 56% Group 1, 56% functional class II) were enrolled. Leg lean mass Z-score was significantly less than reference data (-1.40 ± 1.12 versus 0.0 ± 0.9, p < 0.001) and worse in those with functional class II versus I (-2.10 ± 0.83 versus -0.50 ± 0.73, p < 0.01). Leg lean mass Z-score was positively associated with right ventricular systolic function by tricuspid annular plane systolic Z-score (r = 0.54, p = 0.03) and negatively associated with indexed pulmonary vascular resistance (r = -0.78, p < 0.001). Leg lean mass Z-score and forearm strength were positively associated with physical activity score. When physical activity score was held constant, leg lean mass Z-score independently predicted 6-minute walk distance (R2 = 0.39, p = 0.03). CONCLUSIONS: Youth with pulmonary hypertension demonstrate marked skeletal muscle deficits in association with exercise intolerance. Future studies should investigate whether low leg lean mass is a marker of disease severity or an independent target that can be improved.

Inhaled Nitric Oxide Is Associated with Improved Oxygenation in a Subpopulation of Infants with Congenital Diaphragmatic Hernia and Pulmonary Hypertension.

OBJECTIVES: To determine which patients with congenital diaphragmatic hernia (CDH) and pulmonary hypertension (PH) benefit from inhaled nitric oxide (iNO) treatment by comparing characteristics and outcomes of iNO responders to nonresponders. STUDY DESIGN: We performed a retrospective chart review of infants with CDH treated at our center between 2011 and 2016. In a subset of patients, iNO was initiated for hypoxemia or echocardiographic evidence of extrapulmonary right to left shunting. Initial post-treatment blood gases were reviewed, and patients were classified as responders (increased PaO2 >20 mm Hg) or nonresponders. Baseline characteristics, echocardiograms and outcomes were compared between groups with Fisher exact tests and Mann-Whitney t tests, as appropriate. RESULTS: During the study period, 95 of 131 patients with CDH (73%) were treated with iNO. All patients with pretreatment echocardiograms (n = 90) had echocardiographic evidence of PH. Thirty-eight (40%) patients met treatment response criteria. Responders had significant improvements in PaO2 (51 ± 3 vs 123 ± 7 mm Hg, P < .01), alveolar-arterial gradient (422 ± 30 vs 327 ± 27 mm Hg, P < .01), and PaO2 to FiO2 ratio (82 ± 10 vs 199 ± 15 mm Hg, P < .01). Nonresponders were more likely to have left ventricular systolic dysfunction (27% vs 8%, P = .03) on echocardiogram. Responders were less likely to require extracorporeal membrane support (50 vs 24%, P = .02). CONCLUSIONS: iNO treatment is associated with improved oxygenation and reduced need for ECMO in a subpopulation of patients with CDH with PH and normal left ventricular systolic function.

Holodiastolic Flow Reversal at the Descending Aorta on Cardiac Magnetic Resonance is Neither Sensitive Nor Specific for Significant Aortic Regurgitation in Patients with Congenital Heart Disease.

Holodiastolic flow reversal in the descending aorta on echocardiogram suggests significant aortic regurgitation. The study aim was to determine whether the presence of holodiastolic flow reversal on cardiac magnetic resonance imaging (MRI) correlates with aortic valve regurgitant fraction. We retrospectively reviewed 166 cardiac MRIs (64 % male, age 14.1 ± 9.5 years) from January 2011 to May 2012 where velocity mapping was acquired at both the aortic valve and the descending aorta at the level of the diaphragm. Descending aorta velocity maps were checked for baseline offset using a static reference region. Holodiastolic flow reversal was defined as flow reversal throughout diastole both before and after baseline correction. Significant aortic regurgitation was defined as regurgitant fraction >10 %. Aortic valve regurgitant fraction was <10 % in 144 patients (Group A), 10-20 % inclusive in 7 patients (Group B), and >20 % in 15 patients (Group C). Though the aortic valve regurgitant fraction was significantly higher for patients with holodiastolic flow reversal versus those without (8.5 ± 14.2 vs. 3.8 ± 6.6 %, p = 0.02), holodiastolic flow reversal was present in 32 Group A patients (22 %). In comparison, 4 Group B patients (57 %) and 7 Group C patients (47 %) had holodiastolic flow reversal. The sensitivity (Groups B and C) was 0.5, and the specificity (Group A) was 0.78. Holodiastolic flow reversal in the descending aorta on cardiac MRI was neither sensitive nor specific for predicting significant aortic regurgitation in this study population. Holodiastolic flow reversal in the absence of significant aortic regurgitation may be a relatively common finding in patients with congenital heart disease.

Tricuspid annular plane systolic excursion does not correlate with right ventricular ejection fraction in patients with hypoplastic left heart syndrome after Fontan palliation.

Tricuspid annular plane systolic excursion (TAPSE) reflects longitudinal myocardial shortening, the main component of right ventricular (RV) contraction in normal hearts. To date, TAPSE has not been extensively studied in patients with hypoplastic left heart syndrome (HLHS) and systemic RVs after Fontan palliation. This retrospective study investigated HLHS patients after Fontan with cardiac magnetic resonance (CMR) performed between 1 January 2010 and 1 August 2012 and transthoracic echocardiogram (TTE) performed within 6 months of CMR. The maximal apical displacement of the lateral tricuspid valve annulus was measured on CMR (using four-chamber cine images) and on TTE (using two-dimensional apical views). To create TTE-TAPSE z-scores, published reference data were used. Intra- and interobserver variability was tested with analysis of variance. Inter-technique agreement of TTE and CMR was tested with Bland-Altman analysis. In this study, 30 CMRs and TTEs from 29 patients were analyzed. The age at CMR was 14.1 ± 7.1 years, performed 11.9 ± 7.8 years after Fontan. For CMR-TAPSE, the intraclass correlation coefficients for inter- and intraobserver variability were 0.89 and 0.91, respectively. The TAPSE measurements were 0.57 ± 0.2 cm on CMR and 0.70 ± 0.2 cm on TTE (TTE-TAPSE z score, -8.7 ± 1.0). The mean difference in TAPSE between CMR and TTE was -0.13 cm [95 % confidence interval (CI) -0.21 to -0.05], with 95 % limits of agreement (-0.55 to 0.29 cm). The study showed no association between CMR-TAPSE and RVEF (R = 0.08; p = 0.67). In patients with HLHS after Fontan, TAPSE is reproducible on CMR and TTE, with good agreement between the two imaging methods. Diminished TAPSE suggests impaired longitudinal shortening in the systemic RV. However, TAPSE is not a surrogate for RVEF in this study population.

Elevated pulmonary capillary wedge pressure, higher blood pressure, and lower cardiac index in infants with bronchopulmonary dysplasia.

BACKGROUND: Left ventricular diastolic dysfunction indicated by elevated pulmonary capillary wedge pressure (ePCWP) may worsen cardiorespiratory status in bronchopulmonary dysplasia (BPD), but the scope of ePCWP by cardiac catheterization is not well described. METHODS: This single-center retrospective cohort study included infants with BPD without congenital heart disease, significant intracardiac shunts, or pulmonary vein stenosis who underwent cardiac catheterization from 2010 to 2021. ePCWP was defined as >10 mmHg. Quantitative measures of ventricular systolic and diastolic function were performed on existing echocardiograms. Patients with and without ePCWP were compared using the Chi-squared or Wilcoxon rank-sum tests. Associations between catheterization hemodynamics and echocardiographic parameters were assessed by simple linear regression. RESULTS: Seventy-one infants (93% Grade 2 or 3 BPD) met inclusion criteria, and 30 (42%) had ePCWP. Patients with ePCWP were older at catheterization (6.7 vs. 4.5 months, p < 0.001), more commonly underwent tracheostomy (66.7% vs. 29.3%, p = 0.003), and had higher mean systemic blood pressure [64.5 (56.0, 75.0) vs. 47.0 (43.0, 55.0) mm Hg, p < 0.001], higher systemic vascular resistance [11.9 (10.4, 15.6) vs. 8.7 (6.7, 11.2) WU*m2, p < 0.001), and lower cardiac index [3.9 (3.8, 4.9) vs. 4.7 (4.0, 6.3) L/min/m2, p = 0.03] at catheterization. Mean pulmonary artery pressure, pulmonary vascular resistance, and mortality were similar between the groups. Echocardiographic indices of left ventricular diastolic dysfunction did not correlate with PCWP. CONCLUSIONS: ePCWP was common in infants with severe BPD who underwent cardiac catheterization in this cohort. The association between ePCWP and higher systemic blood pressure supports further study of afterload reduction in this population.

Creating a digital approach for promoting physical activity in pediatric pulmonary hypertension: A framework for future interventions.

Children with pulmonary hypertension (PH) often demonstrate limited exercise capacity. Data support exercise as an effective nonpharmacologic intervention among adults with PH. However, data on exercise training in children and adolescents are limited, and characteristics of the optimal exercise program in pediatric PH have not been identified. Exercise programs may have multiple targets, including muscle deficits which are associated with exercise limitations in both adult and pediatric PH. Wearable accelerometer sensors measure physical activity volume and intensity in the naturalistic setting and can facilitate near continuous data transfer and bidirectional communication between patients and the study team when paired with informatics tools during exercise interventions. To address the knowledge gaps in exercise training in pediatric PH, we designed a prospective, single arm, nonrandomized pilot study to determine feasibility and preliminary estimates of efficacy of a 16-week home exercise intervention, targeting lower extremity muscle mass and enriched by wearable mobile health technology. The exercIse Training in pulmONary hypertEnsion (iTONE) trial includes (1) semistructured exercise prescriptions tailored to the participant's baseline level of activity and access to resources; (2) interval goal setting fostering self-efficacy; (3) real time monitoring of activity via wearable devices; (4) a digital platform enabling communication and feedback between participant and study team; (5) multiple avenues to assess participant safety. This pilot intervention will provide information on the digital infrastructure needed to conduct home-based exercise interventions in PH and will generate important preliminary data on the effect of exercise interventions in youth with chronic cardiorespiratory conditions to power larger studies in the future.

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.

Exercise capacity in the Fontan circulation.

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.

Kids Mod PAH trial: A multicenter trial comparing mono- versus duo-therapy for initial treatment of pediatric pulmonary hypertension.

Pulmonary hypertension (PH) is a significant health problem that contributes to high morbidity and mortality in diverse cardiac, pulmonary, and systemic diseases in children. Evidence-based advances in PH care have been challenged by a paucity of quality endpoints for assessing clinical course and the lack of robust clinical trial data to guide pharmacologic therapies in children. While the landmark adult AMBITION trial demonstrated the benefit of up-front combination PH therapy with ambrisentan and tadalafil, it remains unknown whether upfront combination therapy leads to more rapid and sustained clinical benefits in children with various categories of PH. In this article, we describe the inception of the Kids Mod PAH Trial, a multicenter Phase III trial, to address whether upfront combination therapy (sildenafil and bosentan vs. sildenafil alone) improves PH outcomes in children, recognizing that marked differences between the etiology and therapeutic response between adults and children exist. The primary endpoint of this study is WHO functional class (FC) 12 months after initiation of study drug therapy. In addition to the primary outcome, secondary endpoints are being assessed, including a composite measure of time to clinical worsening, WHO FC at 24 months, echocardiographic assessment of PH and quantitative assessment of right ventricular function, 6-min walk distance, and NT-proBNP levels. Exploratory endpoints include selected biomarkers, actigraphy, and assessments of quality of life. This study is designed to pave the way for additional clinical trials by establishing a robust infrastructure through the development of a PPHNet Clinical Trials Network.

Skeletal muscle deficits are associated with worse exercise performance in pediatric pulmonary hypertension.

Background: Skeletal muscle deficits are associated with worse exercise performance in adults with pulmonary hypertension (PH) but the impact is poorly understood in pediatric PH. Objective: To study muscle deficits, physical inactivity, and performance on cardiopulmonary exercise test (CPET) and exercise cardiac magnetic resonance (eCMR) in pediatric PH. Methods: Youth 8-18 years participated in a prospective, cross-sectional study including densitometry (DXA) for measurement of leg lean mass Z-score (LLMZ), handheld dynamometer with generation of dominant and non-dominant handgrip Z-scores, Physical Activity Questionnaire (PAQ), CPET, and optional eCMR. CPET parameters were expressed relative to published reference values. CMR protocol included ventricular volumes and indexed systemic flow at rest and just after supine ergometer exercise. Relationships between LLMZ, PAQ score, and exercise performance were assessed by Pearson correlation and multiple linear regression. Results: There were 25 participants (13.7 ± 2.8 years, 56% female, 64% PH Group 1, 60% functional class I); 12 (48%) performed both CPET and eCMR. Mean LLMZ (-0.96 ± 1.14) was associated with PAQ score (r = 50, p = 0.01) and with peak oxygen consumption (VO2) (r = 0.74, p = < 0.001), VO2 at anaerobic threshold (r = 0.65, p < 0.001), and peak work rate (r = 0.64, p < 0.01). Higher handgrip Z-scores were associated with better CPET and eCMR performance. On regression analysis, LLMZ and PAQ score were positively associated with peak VO2, while handgrip Z-score and PAQ score were positively associated with peak work rate. Conclusion: Muscle mass and strength are positively associated with exercise performance in pediatric PH. Future studies should determine the effect of rehabilitation programs on muscle properties and exercise performance.