Article

Plasma proteomics of differential outcome to long-term therapy in children with idiopathic pulmonary arterial hypertension

Department of Pediatric Critical Care, University of Colorado Denver, Denver, CO 80045, USA.
PROTEOMICS - CLINICAL APPLICATIONS (Impact Factor: 2.68). 06/2012; 6(5-6):257-67. DOI: 10.1002/prca.201100078
Source: PubMed

ABSTRACT The prognosis for children with IPAH unresponsive to therapy is poor. We investigated the plasma proteome for a molecular basis of good versus poor outcome to long-term vasodilator therapy.
Plasma was collected at baseline or shortly after therapy initiation and following chronic vasodilator therapy, then divided into those with good outcome (n = 8), and those with a poor outcome (n = 7). To identify proteins unique to either outcome, we used differential gel electrophoresis and mass spectrometry. Results were confirmed by commercial enzyme-linked immunosorbent assay.
Before and after therapy, SAA-4 was 4-fold lower in those with good outcome compared to those with poor outcome, while serum paraoxonase/arylesterase-1 was increased 2-fold in those with good outcome versus poor outcome. After therapy, haptoglobin and hemopexin were 1.45- and 1.8-fold lower, respectively, in those with a good versus poor outcome. Among those with a good outcome, SAP was 1.3-fold lower prior to therapy.
SAP and SAA-4 regulate circulating mononuclear phagocytes. As such, they may contribute to the differential response to chronic vasodilator therapy in the context of inflammation in IPAH.

Download full-text

Full-text

Available from: David Dunbar Ivy, Aug 25, 2015
0 Followers
 · 
117 Views
  • Source
    • "Second, this study supports the idea that iron plays a role in the development of PH, perhaps through increased iron-mediated protein carbonylation. Finally, we sought to investigate the plasma proteome of children with PH as a basis to predict outcome in response to vasodilator therapy[90]. Interestingly, we found correlations between serum amyloid A and serum amyloid P to outcome. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pulmonary hypertension (PH) is a fatal syndrome that arises from a multifactorial and complex background, is characterized by increased pulmonary vascular resistance and right heart afterload, and often leads to cor pulmonale. Over the past decades, remarkable progress has been made in reducing patient symptoms and delaying the progression of the disease. Unfortunately, PH remains a disease with no cure. The substantial heterogeneity of PH continues to be a major limitation to the development of newer and more efficacious therapies. New advances in our understanding of the biological pathways leading to such a complex pathogenesis will require the identification of the important proteins and protein networks that differ between a healthy lung (or right ventricle) and a remodeled lung in an individual with PH. In this article, we present the case for the increased use of proteomics-the study of proteins and protein networks- as a discovery tool for key proteins and protein networks operational in the PH lung. We review recent applications of proteomics in PH, and summarize the biological pathways identified. Finally, we attempt to presage what the future will bring with regard to proteomics in PH and offer our perspectives on the prospects of developing personalized proteomics and custom-tailored therapies.
    PROTEOMICS - CLINICAL APPLICATIONS 02/2015; 9(1-2). DOI:10.1002/prca.201400157 · 2.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Drug trials in neonates and children with pulmonary hypertensive vascular disease pose unique but not insurmountable challenges. Childhood is defined by growth and development. Both may influence disease and outcomes of drug trials. The developing pulmonary vascular bed and airways may be subjected to maldevelopment, maladaptation, growth arrest, or dysregulation that influence the disease phenotype. Drug therapy is influenced by developmental changes in renal and hepatic blood flow, as well as in metabolic systems such as cytochrome P450. Drugs may affect children differently from adults, with different clearance, therapeutic levels and toxicities. Toxicity may not be manifested until the child reaches physical, endocrine and neurodevelopmental maturity. Adverse effects may be revealed in the next generation, should the development of ova or spermatozoa be affected. Consideration of safe, age-appropriate tablets and liquid formulations is an obvious but often neglected prerequisite to any pediatric drug trial. In designing a clinical trial, precise phenotyping and genotyping of disease is required to ensure appropriate and accurate inclusion and exclusion criteria. We need to explore physiologically based pharmacokinetic modeling and simulations together with statistical techniques to reduce sample size requirements. Clinical endpoints such as exercise capacity, using traditional classifications and testing cannot be applied routinely to children. Many lack the necessary neurodevelopmental skills and equipment may not be appropriate for use in children. Selection of endpoints appropriate to encompass the developmental spectrum from neonate to adolescent is particularly challenging. One possible solution is the development of composite outcome scores that include age and a developmentally specific functional classification, growth and development scores, exercise data, biomarkers and hemodynamics with repeated evaluation throughout the period of growth and development. In addition, although potentially costly, we recommend long-term continuation of blinded dose ranging after completion of the short-term, double-blind, placebo-controlled trial for side-effect surveillance, which should include neurodevelopmental and peripubertal monitoring. The search for robust evidence to guide safe therapy of children and neonates with pulmonary hypertensive vascular disease is a crucial and necessary goal.
    01/2013; 3(1):252-66. DOI:10.4103/2045-8932.109931
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pulmonary arterial hypertension (PAH) in the pediatric population is associated with a variety of underlying diseases and causes, significantly morbidity and mortality. In the majority of patients, PAH in children is idiopathic or associated with congenital heart disease (CHD), with pulmonary hypertension (PH) associated with connective tissue disease, a rare cause in children. Classification of pediatric PH has generally followed the WHO classification, but recognition of the importance of fetal origins of PH and developmental abnormalities have led to the formation of a new pediatric-specific classification. Incidence data from the Netherlands has revealed an annual incidence and point prevalence of 0.7 and 4.4 for idiopathic PAH and 2.2 and 15.6 for associated pulmonary arterial hypertension-CHD cases per million children. Although the treatment with new selective pulmonary vasodilators offers hemodynamic and functional improvement in pediatric populations, the treatments in children largely depend on results from evidence-based adult studies and experience of clinicians treating children. A recent randomized clinical trial of sildenafil and its long-term extension has led to disparate recommendations in the United States and Europe.
    Seminars in Respiratory and Critical Care Medicine 10/2013; 34(5):627-44. DOI:10.1055/s-0033-1356461 · 3.02 Impact Factor
Show more