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Background Endostatin, an angiogenic inhibitor, is associated with worse pulmonary arterial hypertension (PAH) outcomes in adults and poor lung growth in children. This study sought to assess whether endostatin is associated with disease severity and outcomes in pediatric PAH. Methods and Results Serum endostatin was measured in cross-sectional (N=160) and longitudinal cohorts (N=64) of pediatric subjects with PAH, healthy pediatric controls and pediatric controls with congenital heart disease (CHD) (N=54, N=15), and adults with CHD associated PAH (APAH-CHD, N=185). Outcomes, assessed by regression and Kaplan-Meier analysis, included hemodynamics, change in endostatin over time, and transplant-free survival. Endostatin secretion was evaluated in pulmonary artery endothelial and smooth muscle cells. Endostatin was higher in those with PAH compared with healthy controls and controls with CHD and was highest in those with APAH-CHD. In APAH-CHD, endostatin was associated with a shorter 6-minute walk distance and increased mean right atrial pressure. Over time, endostatin was associated with higher pulmonary artery pressure and pulmonary vascular resistance index, right ventricular dilation, and dysfunction. Endostatin decreased with improved hemodynamics over time. Endostatin was associated with worse transplant-free survival. Addition of endostatin to an NT-proBNP (N-terminal pro-B-type natriuretic peptide) based survival analysis improved risk stratification, reclassifying subjects with adverse outcomes. Endostatin was secreted primarily by pulmonary artery endothelial cells. Conclusions Endostatin is associated with disease severity, disease improvement, and worse survival in APAH-CHD. Endostatin with NT-proBNP improves risk stratification, better predicting adverse outcomes. The association of elevated endostatin with shunt lesions suggests that endostatin could be driven by both pulmonary artery flow and pressure. Endostatin could be studied as a noninvasive prognostic marker, particularly in APAH-CHD.

Rationale: Pulmonary arterial hypertension (PAH) is a fatal disease, and pulmonary microvascular remodeling is an important contributor to PAH development. Therefore, we hypothesized that a circulating angiogenic factor could predict disease severity and survival., Objectives: We sought to assess the relationship of serum hepatoma-derived growth factor (HDGF) with PAH disease severity and survival., Methods: Using a newly developed enzyme-linked immunosorbent assay, we evaluated circulating HDGF levels in two independent PAH cohorts and two different characterized control cohorts. Clinical and laboratory data were also used to assess the value of HDGF as a PAH prognostic biomarker., Measurements and Main Results: Serum HDGF levels were significantly elevated in two independent PAH cohorts. Importantly, serum HDGF levels were not elevated in a noncardiac chronic disease cohort. Further, patients with elevated HDGF had significantly lower exercise tolerance, worse New York Heart Association functional class, and higher levels of N-terminal pro-brain natriuretic peptide. HDGF was a strong predictor of mortality, with an unadjusted hazard ratio of 4.5 (95% confidence interval, 1.9-10.3; P = 0.003 by log-rank test). In multivariable Cox proportional hazards models, elevated HDGF levels predicted decreased survival after being adjusted for age, PAH subtype, invasive hemodynamics, and N-terminal pro-brain natriuretic peptide., Conclusions: Elevated HDGF was associated with worse functional class, exertional intolerance, and increased mortality in PAH, suggesting HDGF as a potential biomarker for predicting mortality and as having possible diagnostic value for distinguishing PAH from non-PAH. HDGF may add additional value in PAH risk stratification in clinical trials and may represent a potential target for future PAH drug development.

Background: Pulmonary hypertension (PH) is a significant cause of morbidity in preterm infants, but no screening guidelines exist. We sought to identify risk factors and clinical outcomes associated with PH in preterm infants to develop a PH risk score., Methods: Retrospective analysis of two separate populations of preterm infants (NICU cohort n = 230; Clinic registry n = 580)., Results: 8.3% of the NICU cohort had PH after 4 weeks of age, while 14.8% of the clinic registry had PH after 2 months of age. Lower birth weights and longer initial hospitalizations were associated with PH in both populations (p<0.001 for all tests). Using adjusted logistic regression, patent ductus arteriosus (PDA) requiring ligation was associated with PH in both the NICU cohort (OR: 3.19; p = 0.024) and the clinic registry (OR: 2.67; p<0.001). Risk factors (birth weight ≤780 grams, home supplemental oxygen use, and PDA ligation) identified in the clinic registry (training dataset) were validated in the NICU cohort with 0-1 factors present were associated with ≤1.5% probability of having PH, any 2 factors with a 25% probability, and all 3 factors with a 40% probability., Conclusions: Lower birth weight, PDA ligation, and respiratory support were associated with PH in both populations. A PH risk score based on clinical indicators from the training dataset predicted PH in the validation set. This risk score could help focus resources to preterm infants at higher risk for PH. Further work is needed to determine whether earlier or more aggressive management of ductal lesions could alter PH outcomes., Competing Interests: The authors have declared that no competing interests exist.

Background and Objectives: Pulmonary hypertension (PH) has been associated with substantial morbidity and mortality in children, but existing analyses of inpatient care are limited to small single-institution series or focused registries representative of selected patient subgroups. We examined US national data on pediatric PH hospitalizations to determine trends in volume, demographics, procedures performed during admission, and resource utilization., Methods: Retrospective cohort study using a national administrative database of pediatric hospital discharges: the Kids' Inpatient Database., Results: Children with PH accounted for 0.13% of the 43 million pediatric hospitalizations in the United States between 1997 and 2012, and discharges demonstrated an increasing trend over the study period (P < .0001). Cumulative, inflation-adjusted national hospital charges for PH hospitalizations rose (P = .0003) from $926 million in 1997 to $3.12 billion in 2012. Patients with PH without associated congenital heart disease (CHD) comprised an increasing and majority (56.4%) proportion over the study period (P < .0001), children without associated CHD admitted at urban teaching hospitals comprised the fastest-growing subgroup. In-hospital, all-cause mortality was high (5.9%) in children with PH, but demonstrated a decreasing trend (P < .0001)., Conclusions: Morbidity and mortality of pediatric PH continue to represent substantial and growing health care burdens. Shifts in case mix toward PH not associated with CHD, toward noncardiac procedures, and toward care in urban teaching hospitals will increase pressure to manage resource utilization in this small but growing patient group and to improve expertise and define excellence in PH care across a wide range of clinical settings., (Copyright © 2015 by the American Academy of Pediatrics.)

Analysis of the human proteome has become increasingly sophisticated, and offers invaluable potential insight into the pathophysiology of human disease. The increasing standardization of methods, speed, and sophistication of mass spectrometric analysis, availability of reliable antibodies, and dissemination of information among the scientific community has allowed for exponential growth of our knowledge base. The continued effort to provide a molecular explanation for future medical applications based on biomarker discovery is epitomized by the outstanding efforts of the human proteome project, whose goal is to generate a map of the human proteome. However, proteomic analysis is underrepresented in pediatric illness; given the unique challenges of research in the pediatric population, proteomic analysis represents enormous untapped potential, especially in the further elucidation of the pathophysiology of rare diseases such as pulmonary hypertension (PH). In this article, we will describe the unique challenge of pediatric research, the importance of alternative avenues such as proteomics for in-depth analysis of pediatric pathobiology at the cellular level, the specific need for proteomic investigation of pediatric PH, the current status of PH proteomics, and future directions., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Pulmonary hypertension (PH) is an increasingly recognized complication of premature birth and bronchopulmonary dysplasia (BPD), and is associated with increased morbidity and mortality. Extreme phenotypic variability exists among preterm infants of similar gestational ages, making it difficult to predict which infants are at increased risk for developing PH. Intrauterine growth retardation or drug exposures, postnatal therapy with prolonged positive pressure ventilation, cardiovascular shunts, poor postnatal lung and somatic growth, and genetic or epigenetic factors may all contribute to the development of PH in preterm infants with BPD. In addition to the variability of severity of PH, there is also qualitative variability seen in PH, such as the variable responses to vasoactive medications. To reduce the morbidity and mortality associated with PH, a multi-pronged approach is needed. First, improved screening for and increased recognition of PH may allow for earlier treatment and better clinical outcomes. Second, identification of both prenatal and postnatal risk factors for the development of PH may allow targeting of therapy and resources for those at highest risk. Third, understanding the pathophysiology of the preterm pulmonary vascular bed may help improve outcomes through recognizing pathways that are dysregulated in PH, identifying novel biomarkers, and testing novel treatments. Finally, the recognition of conditions and exposures that may exacerbate or lead to recurrent PH is needed to help with developing treatment guidelines and preventative strategies that can be used to reduce the burden of disease., (Copyright © 2012 Wiley Periodicals, Inc.)