Improvement in Echocardiographic and Diagnostic Biomarkers after Systemic Glucocorticoid Therapy in Infants with Pulmonary Hypertension.

OBJECTIVE: To assess the effect of treating pulmonary hypertension (PH) in infants younger than 1 year of age with systemic glucocorticoids while using echocardiographic and diagnostic biomarkers as measures of efficacy. STUDY DESIGN: A retrospective chart review was performed on 17 hospitalized infants younger than 1 year of age at St Louis Children's Hospital who received a 5- to 7-day course of systemic glucocorticoid treatment followed by a 3-week taper with no significant intracardiac shunts from January 1, 2017, to December 31, 2021. Quantitative echocardiographic indices for PH, N-terminal pro b-type natriuretic peptide, and/or b-type natriuretic peptide levels were collected before glucocorticoid treatment, after the glucocorticoid burst, and after the 21-day taper. RESULTS: Mean (±SD) gestational age was 32.1 (±5.8) weeks, 5 infants were (29%) concomitantly treated with sildenafil, and 8 were male. Twelve were classified as World Health Organization group 3 PH (71%) and 5 as World Health Organization group 1 PH. There were significant improvements 30 days after glucocorticoid initiation in b-type natriuretic peptide levels (P = .008), PCO2 (P = .03), eccentricity index (P = .005), right ventricular ejection time (P = .04), pulmonary artery acceleration time (P = .002), and pulmonary artery acceleration time-to-right ventricular ejection time ratio (P = .02). Tricuspid regurgitation velocity was not able to be assessed. There were no mortalities during the study timeline. CONCLUSIONS: In our retrospective study, systemic glucocorticoid therapy was well tolerated and appeared to be associated with significant improvement in cardiopulmonary function in infants with PH. Further prospective study in a larger sample is warranted.

Exercise-Induced Pulmonary Hypertension in Long-Term Survivors of Congenital Diaphragmatic Hernia.

OBJECTIVE: To determine the prevalence of exercise-induced pulmonary hypertension (PH) among long-survivors of congenital diaphragmatic hernia repair. STUDY DESIGN: This is a single-center, retrospective cohort study of CDH survivors who underwent exercise stress echocardiography (ESE) at Boston Children's Hospital from January 2006 to June 2020. PH severity was assessed by echocardiogram at baseline and after exercise. Patients were categorized by right ventricular systolic pressure (RVSP) after exercise: Group 1 - no or mild PH; and Group 2 - moderate or severe PH (RVSP ≥ 60 mmHg or ≥ ½ systemic blood pressure). RESULTS: Eighty-four patients with CDH underwent 173 ESE with median age 8.1 (4.8 - 19.1) years at first ESE. Sixty-four patients were classified as Group 1, 11 as Group 2, and 9 had indeterminate RVSP with ESE. Moderate to severe PH after exercise was found in 8 (10%) patients with no or mild PH at rest. Exercise-induced PH was associated with larger CDH defect size, patch repair, use of ECMO, supplemental oxygen at discharge, and higher WHO functional class. Higher VE/VCO2 slope, lower peak oxygen saturation, and lower percent predicted FEV1, and FEV1/FVC ratio were associated with Group 2 classification. ESE changed management in 9/11 Group 2 patients. PH was confirmed in all 5 Group 2 patients undergoing cardiac catheterization after ESE. CONCLUSIONS: Among long-term CDH survivors, 10% had moderate-severe exercise-induced PH on ESE, indicating ongoing pulmonary vascular abnormalities. Further studies are needed to optimally define PH screening and treatment for patients with repaired CDH.

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.

Pulmonary Hypertension in Infants and Children with Vein of Galen Malformation and Association with Clinical Outcomes.

OBJECTIVE: To assess the extent and resolution of pulmonary hypertension (PH), cardiovascular factors, and echocardiographic findings associated with mortality in infants and children with vein of Galen malformation (VOGM). STUDY DESIGN: We performed a retrospective review of 49 consecutive children with VOGM admitted to Boston Children's Hospital from 2007 to 2020. Patient characteristics, echocardiographic data, and hospital course were analyzed for 2 cohorts based on age at presentation to Boston Children's Hospital: group 1 (age ≤60 days) or group 2 (age >60 days). RESULTS: Overall hospital survival was 35 of 49 (71.4%); 13 of 26 (50%) in group 1 and 22 of 23 (96%) in group 2 (P < .001). High-output PH (P = .01), cardiomegaly (P = .011), intubation (P = .019), and dopamine use (P = .01) were significantly more common in group 1 than group 2. Among patients in group 1, congestive heart failure (P = .015), intubation (P < .001), use of inhaled nitric oxide (P = .015) or prostaglandin E1 (P = .030), suprasystemic PH (P = .003), and right-sided dilation were significantly associated with mortality; in contrast, left ventricular volume and function, structural congenital heart disease, and supraventricular tachycardia were not associated. Inhaled nitric oxide achieved no clinical benefit in 9 of 11 treated patients. Resolution of PH was associated with overall survival (P < .001). CONCLUSIONS: VOGM remains associated with substantial mortality among infants presenting at ≤60 days of life owing to factors associated with high output PH. Resolution of PH is an indicator associated with survival and a surrogate end point for benchmarking outcomes.

Ventricular global function index is associated with clinical outcomes in pediatric pulmonary hypertension.

BACKGROUND: Multiple right ventricular (RV) metrics have prognostic value in pulmonary hypertension (PH). A cardiac magnetic resonance imaging (CMR) derived global ventricular function index (GFI) provided improved prediction of composite adverse outcome (CAO) in adults with atherosclerosis. GFI has not yet been explored in a PH population. We explored the feasibility of GFI as a predictor of CAO in a pediatric PH population. METHODS: Two center retrospective chart review identified pediatric PH patients undergoing CMR from Jan 2005-June 2021. GFI, defined as the ratio of the stroke volume to the sum of mean ventricular cavity and myocardial volume, was calculated for each patient. CAO was defined as death, lung transplant, Potts shunt, or parenteral prostacyclin initiation after CMR. Cox proportional hazards regression was used to estimate associations and assess model performance between CMR parameters and CAO. RESULTS: The cohort comprised 89 patients (54% female, 84% World Health Organization (WHO) Group 1; 70% WHO-FC ≤ 2; and 27% on parenteral prostacyclin). Median age at CMR was 12 years (IQR 8.1-17). Twenty-one (24%) patients experienced CAO during median follow up of 1.5 years. CAO cohort had higher indexed RV volumes (end systolic-145 vs 99 mL/m2, p = 0.003; end diastolic-89 vs 46 mL/m2, p = 0.004) and mass (37 vs 24 gm/m2, p = 0.003), but lower ejection fraction (EF) (42 vs 51%, p < 0.001) and GFI (40 vs 52%, p < 0.001). Higher indexed RV volumes (hazard ratios [HR] 1.01, CI 1.01-1.02), lower RV EF (HR 1.09, CI 1.05-1.12) and lower RV GFI (HR 1.09, CI 1.05-1.11) were associated with increased risk of CAO. In survival analysis, patients with RV GFI < 43% demonstrated decreased event-free survival and increased hazard of CAO compared to those with RV GFI ≥ 43%. In multivariable models, inclusion of GFI provided improved prediction of CAO compared to models incorporating ventricular volumes, mass or EF. CONCLUSIONS: RV GFI was associated with CAO in this cohort, and inclusion in multivariable models had increased predictive value compared to RVEF. GFI uses readily available CMR data without additional post-processing and may provide additional prognostic value in pediatric PH patients beyond traditional CMR markers.

Recovery of right ventricular function after bilateral lung transplantation for pediatric pulmonary hypertension.

BACKGROUND: Lung transplantation is a therapeutic option for end-stage pediatric pulmonary hypertension (PH). Right ventricular (RV) recovery post-lung transplant in children with PH has not been well-described, and questions persist about the peri-operative course and post-transplant cardiac function after lung transplantation in medically refractory PH patients with baseline RV dysfunction. METHODS: A single-center chart review identified patients with childhood PH who subsequently underwent bilateral orthotopic lung transplantation between 2000 and 2020. Twenty-six patients met criteria; three were excluded due to echocardiograms not available for digital review. RV fractional area change (FAC) and left ventricular eccentricity index (LVEI) were determined prior to transplantation, and at 1, 3, 6, and 12-month post-transplantation. RESULTS: Fourteen of 23 patients had baseline RV dysfunction. The median age at transplantation was 16.5 years and 13.9 years for those with and without baseline RV dysfunction, respectively. Of the 14 with baseline RV dysfunction, 12 (86%) were alive 1-year post-transplantation. All patients with baseline RV dysfunction had increased RV-FAC post-transplantation with normalization of RV-FAC in 70% at 3 months and 100% of patients by 12-month post-transplantation. Duration of ventilation (p = .4), intensive care unit (p = .5), or hospital stay (p = .9) was not associated with pre-transplant RV function. CONCLUSIONS: Among pediatric patients with PH and RV dysfunction, pre-transplantation RV function was not associated with short-term outcomes. All patients with baseline RV dysfunction had improvement in RV function, justifying consideration of lung transplantation among pediatric patients with end-stage PH and RV dysfunction.

Clinical Implications of the Genetic Background in Pediatric Pulmonary Arterial Hypertension: Data from the Spanish REHIPED Registry.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a severe and rare disease with an important genetic background. The influence of genetic testing in the clinical classification of pediatric PAH is not well known and genetics could influence management and prognosis. OBJECTIVES: The aim of this work was to identify the molecular fingerprint of PH children in the REgistro de pacientes con HIpertensión Pulmonar PEDiátrica (REHIPED), and to investigate if genetics could have an impact in clinical reclassification and prognosis. METHODS: We included pediatric patients with a genetic analysis from REHIPED. From 2011 onward, successive genetic techniques have been carried out. Before genetic diagnosis, patients were classified according to their clinical and hemodynamic data in five groups. After genetic analysis, the patients were reclassified. The impact of genetics in survival free of lung transplantation was estimated by Kaplan-Meier curves. RESULTS: Ninety-eight patients were included for the analysis. Before the genetic diagnoses, there were idiopathic PAH forms in 53.1%, PAH associated with congenital heart disease in 30.6%, pulmonary veno-occlusive disease-PVOD-in 6.1%, familial PAH in 5.1%, and associated forms with multisystemic disorders-MSD-in 5.1% of the patients. Pathogenic or likely pathogenic variants were found in 44 patients (44.9%). After a genetic analysis, 28.6% of the cohort was "reclassified", with the groups of heritable PAH, heritable PVOD, TBX4, and MSD increasing up to 18.4%, 8.2%, 4.1%, and 12.2%, respectively. The MSD forms had the worst survival rates, followed by PVOD. CONCLUSIONS: Genetic testing changed the clinical classification of a significant proportion of patients. This reclassification showed relevant prognostic implications.

The Genetic Epidemiology of Pediatric Pulmonary Arterial Hypertension.

OBJECTIVE: To describe the prevalence of pulmonary arterial hypertension (PAH)-associated gene mutations, and other genetic characteristics in a national cohort of children with PAH from the Dutch National registry and to explore genotype-phenotype associations and outcomes. STUDY DESIGN: Children (n = 70) diagnosed with idiopathic PAH, heritable PAH, PAH associated with congenital heart disease with coincidental shunt (PAH-congenital heart disease group 3), PAH after closure of a cardiac shunt (PAH-congenital heart disease group 4), or PAH associated with other noncardiac conditions were enrolled. Targeted next-generation sequencing was performed on PAH-associated genes (BMPR2, ACVRL1, EIF2AK4, CAV1, ENG, KCNK3, SMAD9, and TBX4). Also, children were tested for specific genetic disorders in case of clinical suspicion. Additionally, children were tested for copy number variations. RESULTS: Nineteen children (27%) had a PAH-associated gene mutation/variant: BMPR2 n = 7, TBX4 n = 8, ACVRL1 n = 1, KCNK3 n = 1, and EIF2AK4 n = 2. Twelve children (17%) had a genetic disorder with an established association with PAH (including trisomy 21 and cobalamin C deficiency). In another 16 children (23%), genetic disorders without an established association with PAH were identified (including Noonan syndrome, Beals syndrome, and various copy number variations). Survival rates differed between groups and was most favorable in TBX4 variant carriers. CONCLUSIONS: Children with PAH show a high prevalence of genetic disorders, not restricted to established PAH-associated genes. Genetic architecture could play a role in risk-stratified care management in pediatric PAH.

Interventional Cardiovascular Magnetic Resonance Imaging (iCMR) in an Adolescent with Pulmonary Hypertension.

The interventional cardiac magnetic resonance imaging (iCMR) catheterization procedure is feasible and safe for children and adults with pulmonary hypertension and congenital heart defects (CHD). With iCMR, the calculation of pulmonary vascular resistance (PVR) in children with complex CHD with multilevel shunt lesions is accurate. In this paper, we describe the role of the MRI-guided right-sided cardiac catheterization procedure to accurately estimate PVR in the setting of multiple shunt lesions (ventricular septal defect and patent ductus arteriosus) and to address the clinical question of operability in an adolescent with trisomy 21 and severe pulmonary hypertension.

COVID-19 and Pulmonary Hypertension in Children: What Do We Know So Far?

The interplay between coronavirus disease 2019 (COVID-19) and pulmonary hypertension (PH) in children is unknown. Adults with PH are at potential risk for severe complications and high mortality due to associated comorbidities. It is difficult to extrapolate the outcomes of COVID-19 in adults to pediatric PH patients. Overall, a small number of COVID-19 cases is reported in patients with preexisting PH. Several factors may be responsible for the low incidence of COVID-19 in children with PH. Pulmonary hypertension is a rare disease, testing is not universal, and patients may have followed more rigorously the Center for Disease Control's guidelines recommended for personal protection with mask-wearing, social distancing, and hand sanitization through ongoing health education. The small number of COVID-19 cases in patients with preexisting PH does not support that PH is protective for COVID-19. However, medications used to treat PH may have some protection against COVID-19. This review discusses the pathophysiology of PH occurring with COVID-19, differences between children and adults with COVID-19, strategies for management of preexisting PH in children during the ongoing pandemic, and its impact within the field of PH.

Diagnostics in Children and Adolescents with Suspected or Confirmed Pulmonary Hypertension.

We provide a practical approach on the initial assessment and diagnostic work-up of children and adolescents with pulmonary hypertension (PH). Transthoracic echocardiography (TTE) often serves as initial study tool before invasive cardiac catheterization. Misinterpretation of TTE variables may lead to missed or delayed diagnosis with devastating consequences, or unnecessary invasive diagnostics that have inherited risks. In addition to clinical and biochemical markers, serial examination of patients with PH using a standardized TTE approach, determining conventional and novel echocardiographic variables, may allow early diagnosis and treatment in paediatric PH. Cardiac magnetic resonance imaging and computed tomography represent important non-invasive imaging modalities, that together with TTE may enable comprehensive assessment of ventricular function and pulmonary hemodynamics. Invasive assessment of haemodynamics (ventricular, pulmonary) and testing of acute vasoreactivity in the catheterization laboratory is still the gold standard for the diagnosis of PH and pulmonary hypertensive vascular disease (PHVD) in children and for the initiation of specific PH therapy. We suggest the regular assessment of prognostic TTE variables as part of a standardized approach for initial diagnosis of children with PH. Overreliance on any single TTE variable should be avoided as it detracts from the overall diagnostic potential of a standardized TTE examination for PH.

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.

Prognostic Value of Serial Risk Stratification in Adult and Pediatric Pulmonary Arterial Hypertension: A Systematic Review.

BACKGROUND: In pulmonary arterial hypertension, it is recommended to base therapeutic decisions on risk stratification. This systematic review aims to report the prognostic value of serial risk stratification in adult and pediatric pulmonary arterial hypertension and to explore the usability of serial risk stratification as treatment target. METHODS AND RESULTS: Electronic databases PubMed, Embase, and Web of Science were searched up to January 30, 2023, using terms associated with pulmonary arterial hypertension, pediatric pulmonary hypertension, and risk stratification. Observational studies and clinical trials describing risk stratification at both baseline and follow-up were included. Sixty five studies were eligible for inclusion, including only 2 studies in a pediatric population. C-statistic range at baseline was 0.31 to 0.77 and improved to 0.30 to 0.91 at follow-up. In 53% of patients, risk status changed (42% improved, 12% worsened) over 168 days (interquartile range, 137-327 days; n=22 studies). The average proportion of low-risk patients increased from 18% at baseline to 36% at a median follow-up of 244 days (interquartile range, 140-365 days; n=40 studies). In placebo-controlled drug studies, risk statuses of the intervention groups improved more and worsened less compared with the placebo groups. Furthermore, a low-risk status, but also an improved risk status, at follow-up was associated with a better outcome. Similar results were found in the 2 pediatric studies. CONCLUSIONS: Follow-up risk stratification has improved prognostic value compared with baseline risk stratification, and change in risk status between baseline and follow-up corresponded to a change in survival. These data support the use of serial risk stratification as treatment target in pulmonary arterial hypertension.

The evolution of clinical trials for pediatric pulmonary hypertension: are the needs of patients and their caregivers being met?

INTRODUCTION: Pediatric pulmonary hypertension is a rare condition. Survival remains poor in the current management era. There is a lack of data regarding the medical management of pediatric pulmonary hypertension and most pulmonary vasodilators are used off-label in children. AREAS COVERED: Pediatric pulmonary hypertension clinical trials' design and realization face many hurdles, including poor recruitment, limited available pharmacologic and physiologic data in children of various ages, ethical issues, and the lack of validated trial endpoint. Innovative clinical trial designs have emerged and may allow us to overcome some of these issues. Extrapolation of adult data to children, with additional pharmacokinetic and safety data, remains extremely important and valid in etiologies where the pediatric and the adult pathophysiologies are believed to be similar. EXPERT OPINION: Close collaboration between sponsors, regulators, patients, caregivers, physicians and researchers is necessary to develop efficacious and safe drugs for pediatric pulmonary hypertension. The increasing involvement of patients' and caregivers' participation in the development of clinical trials should help shape future research that is feasible and meaningful to the patients.

Successful Atrial Septal Defect Closure Subsequent to Medical Pulmonary Preconditioning in an Infant With Severe Pulmonary Hypertension Associated With Bronchopulmonary Dysplasia.

While atrial septal defect (ASD) may contribute to right ventricular decompression in patients with severe pulmonary hypertension (PH), the pulmonary vasculature might be compromised by increased pulmonary blood flow, even though pulmonary vasodilators successfully reduce resistance. ASD closure is a treatment option that may ameliorate PH symptoms associated with bronchopulmonary dysplasia (BPD) in infants. However, the feasibility of ASD closure is obscure in patients with BPD-PH causing right-to-left shunting. Here, we present an eight-month-old girl with ASD complicated by BPD-PH, in which the pulmonary pressure exceeded the systemic pressure; the ASD was successfully closed after pulmonary preconditioning with dexamethasone and high-dose diuretics. Our patient was delivered as the third baby in triplets at a gestational age of 25 weeks, with a birth weight of 344 g. She was diagnosed with BPD at three months of age (37 weeks of postmenstrual age) with a body weight of 1.4 kg. Mild pulmonary hypertension was identified at the age of five months, and oral sildenafil was initiated. While her atrial septal defect was small at the time of PH diagnosis, it became hemodynamically significant when she grew up to 3.4 kg of body weight, at seven months after birth. Her estimated right ventricular pressure was apparently more than the systemic pressure, and oxygen saturation fluctuated between 82% and 97% under oxygen supplementation due to bidirectional interatrial shunt with predominant right-to-left shunting. Pulmonary preconditioning lowered the estimated right ventricular pressure to almost equal the systemic pressure and elevated arterial oxygen saturation while also suppressing right-to-left shunting. Cardiac catheterization after preconditioning revealed a ratio of pulmonary blood pressure to systemic blood pressure ratio (Pp/Ps) of 0.9, pulmonary resistance of 7.3 WU-m2, and a pulmonary to systemic blood flow ratio (Qp/Qs) of 1.3 (approximately 1.0 in the normal circulation without significant shunt), with the cardiac index of 2.8 L/min/m2. The acute pulmonary vasoreactivity test against the combination of 20 ppm nitric oxide and 100% oxygen was negative, although the patient had consistently high pulmonary flow with makeshift improvements after preconditioning. Despite the high pulmonary resistance even after preconditioning, aggressive ASD closure was performed so that pulmonary flow could be consistently suppressed regardless of the pulmonary condition. Her Pp/Ps under 100% oxygen with 20 ppm nitric oxide was 0.7 immediately after closure. After two years of follow-up, her estimated right ventricular pressure was less than half of the systemic pressure with the use of three pulmonary vasodilators, including sildenafil, macitentan, and beraprost. A strategy to temporarily improve PH and respiratory status aimed at ASD closure could be a treatment option for the effective use of multiple pulmonary vasodilators, by which intensive treatment of BPD can be achieved.

Corrigendum: Case report: Selexipag in pediatric pulmonary hypertension: initiation, transition, and titration.

[This corrects the article DOI: 10.3389/fped.2023.1050508.].

Cardiac Magnetic Resonance Derived Left Ventricular Eccentricity Index and Right Ventricular Mass Measurements Predict Outcome in Children with Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is associated with increased right ventricular (RV) afterload, affecting RV remodeling and RV performance, a major determinant of outcome in PAH-patients. In children with PAH, treatment strategy is guided by risk stratification where noninvasive prognosticators are highly needed. The prognostic value of RV characteristics derived by cardiac magnetic resonance (CMR) has been scarcely studied in pediatric PAH. We aimed to identify CMR-derived morphometric and functional RV characteristics prognostic for outcome in children with PAH. From the Dutch National cohort, thirty-eight children with either idiopathic/heritable PAH (IPAH/HPAH) or PAH associated with congenital heart disease (PAH-CHD), who underwent CMR, were included (median (interquartile range) [IQR] age 13.0 years (10.8-15.0), 66% females). Patients had severe PAH, characterized by their World Health Organization Functional Class, increased N-terminal pro-B-type natriuretic peptide and high pulmonary arterial pressure and pulmonary vascular resistance index at time of CMR. RV-ejection fraction (RVEF), indexed RV-mass (RVMi), the ratio between RV and LV mass (RVM/LVM-ratio) and left ventricular eccentricity index (LVEI) all correlated with transplant-free survival from time of CMR. These correlations could not be confirmed in the PAH-CHD group. This study shows that CMR-derived measures reflecting RV function and remodeling (LVEI, RVMi, RVM/LVM-ratio, RVEF) predict transplant-free survival in children with IPAH/HPAH and may be included in risk stratification scores in pediatric PAH.

Case Report: Selexipag in pediatric pulmonary hypertension: Initiation, transition, and titration.

Selexipag, a selective prostacyclin receptor agonist, is approved for treating pulmonary arterial hypertension in WHO Group 1 adult patients. Compared to parenteral prostacyclin formulations, selexipag offers a significant improvement in patient's and caregiver's quality of life because of its oral formulation, frequency of administration, and mechanism of action. Although experience in the pediatric population is limited to case reports in older adolescent patients and selexipag is not approved for use in the pediatric pulmonary hypertension population, many pediatric centers are expanding the use of this therapy to this population. We report our institution's experience in the use of selexipag to treat pulmonary hypertension in children under 10 years of age, between 10 and 30 kg. Seven patients were initiated on selexipag therapy including de novo initiation and transition from intravenous treprostinil to oral selexipag. All patients were on stable background therapy with phosphodiesterase-5 inhibitor and endothelin receptor antagonist therapies at baseline. All patients reached their planned goal selexipag dose during admission without the need for changes to the titration schedule and without hemodynamic deterioration. In our experience, oral selexipag is safe and well-tolerated in young pediatric patients with pulmonary hypertension. Based on our favorable experience, we developed an institution-specific selexipag process algorithm for continued successful use in the pediatric population.

Impact of Asthma Phenotypes on Myocardial Performance and Pulmonary Hypertension in Children and Adolescents With Moderate to Severe Persistent Asthma.

BACKGROUND: Asthma is characterized by chronic inflammation and remodeling of pulmonary vessels and airway wall resulting in pulmonary hypertension (PH). Increased afterload on right ventricle (RV) myocardium leads to RV diastolic dysfunction (RVDD). Echocardiography is an excellent tool to detect these changes early. Using echocardiography, we assessed the impact of clinical asthma phenotypes on myocardial performance and PH in children with asthma. MATERIALS AND METHODS: Sixty children with moderate or severe persistent asthma and 60 age and gender-matched healthy controls were enrolled. As per clinical phenotypes, children with asthma were classified into early wheezers (n = 30) and late wheezers (n = 30). Pulmonary function tests (PFT) and echocardiography, both conventional and pulse wave (PW), were performed. RESULTS: Children with asthma had significant RVDD and higher incidence (33%) of PH. Myocardial performance index (MPI) was poor in asthmatics, 0.41 (0.04) compared to controls, 0.38 (0.03). Measures for PH such as tricuspid regurgitation (TR) gradient, TR velocity, and pulmonary artery pressure (PAP) were significantly higher in cases. Among clinical asthma phenotypes, there was no difference in left ventricular ejection fraction (LVEF) between early 64.3% (4.6) and late wheezers 65.6% (4.4). MPI was better in late wheezers at 0.41 (0.05) than in early wheezers at 0.40 (0.03). TR gradient, TR velocity, and PAP were significantly higher in early wheezers. The odds ratio for the development of PH was 0.74 (CI 0.25 - 2.17), and for the development of RVDD was 3.2 (CI 0.77 - 13.8), both in favor of early wheezers. CONCLUSION: Children with asthma, particularly early-onset wheezers are at increased risk of developing PH and RVDD. We suggest annual screening by conventional echocardiography and pulse wave Doppler imaging for early diagnosis and timely initiation of management.

Factors leading to supranormal cardiac index in pediatric pulmonary hypertension patients treated with parenteral prostanoid therapy.

Parenteral prostanoid therapy (PPT) can result in supranormal cardiac index (SCI; >4 L/min/m2) in pediatric pulmonary hypertension (PPH) patients. We evaluated the incidence, hemodynamic factors, and outcomes associated with SCI in PPH. This retrospective cohort study included 22 PPH patients on PPT from 2005 to 2020. Hemodynamic profiles were compared between the baseline and 3-6 month follow-up catheterization in the SCI and non-SCI cohorts. Cox regression analysis examined time to composite adverse outcome (CAO; Potts shunt, lung transplant, or death) controlling for initial disease severity. SCI developed in 17 (77%) patients, of whom 11 (65%) developed SCI within 6 months. The SCI cohort was characterized by significant augmentation of cardiac index (CI) and stroke volume (SV) as well as reductions in systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR). Conversely, the non-SCI cohort had unchanged SV despite a modest rise in CI as well as persistent vasoconstriction. After median follow-up of 4.3 years (range 0.2-13 years), non-SCI patients were at significantly increased risk for the CAO (5/5: three deaths, two Potts shunts) compared with SCI patients (5/17: two deaths, three lung transplants; adjusted hazard ratio 14.0 [95% confidence interval: 2.1-91.3], p < 0.001). A majority of PPH patients developed SCI within 6-12 months of starting PPT and demonstrated lower risk of adverse outcomes compared with non-SCI patients. These data suggest that change in SVR and SV after 3-6 months of PPT may be early markers of therapeutic response and prognosis.