Abstract
Background
Insulin-like growth factors (IGFs), and their binding proteins (IGFBPs), play a significant role in cardiovascular function and may influence the pathobiology of PAH. We determined the diagnostic and prognostic value of IGF1 and IGFBP2 in pediatric PAH.
Methods
Serum was analyzed by ELISA for IGF1 and IGFBP2 in pediatric PAH subjects from the NHLBI PAH Biobank (PAHB, n = 175) and a cohort of asthmatic subjects (n = 46, age 0–21 years) as a chronic pediatric pulmonary disease control. Biomarkers were analyzed with demographic and clinical variables for PAH severity.
Results
Serum IGF1 was significantly lower in PAH compared to controls, while IGFBP2 was elevated in PAH subjects compared to controls. In the PAHB, IGF1 was negatively associated with mPAP and PVR, while IGFBP2 was positively associated with PVR and negatively associated with cardiac output and 6-min walk distance. Higher IGFBP2 levels were associated with use of prostacyclin therapy. IGFBP2 was associated with death, transplant, or palliative shunt with a Cox proportional hazard ratio of 8.8 (p < 0.001) but not IGF1 (p = 0.13).
Conclusions
Circulating IGFBP2 is a novel marker for pediatric PAH, which is associated with worse functional status, and survival. IGF axis dysregulation may be an important mechanistic target in pediatric pulmonary arterial hypertension.
Impact
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Pediatric pulmonary hypertension is a severe disease, with poorly understood pathobiology.
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There are few studies looking at the pathobiology of pulmonary hypertension only in children.
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The IGF axis is dysregulated in pediatric pulmonary arterial hypertension.
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IGF axis dysregulation, with increased IGFBP2, is associated with worse clinical outcomes in pediatric pulmonary artery hypertension.
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IGF axis dysregulation gives new insight into the disease process and may be a mechanistic or therapeutic target.
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Acknowledgements
This study was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute awards R01HL135114 and R01 HL150070 (to A.D.E., M.N., J.Y., R.D., D.V., W.C.N., D.I., and E.D.A.), R24 HL105333 (to W.C.N., M.W.P., D.I., and E.D.A.). Serum/tissue samples were provided by PHBI under the Pulmonary Hypertension Breakthrough Initiative (PHBI). Funding for the PHBI is provided under an NHLBI R24 grant, #R24HL123767 (to A.D.E.). M.G. was supported by the Pediatric Scientist Development Program. The Pediatric Scientist Development Program is supported by Award Number K12-HD000850 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. M.N was supported by The Matthew and Michael Wojciechowski Pulmonary Hypertension Pediatric Proof-of-Concept Grant (Dr. Robyn J. Barst Pediatric PH Research and Mentoring Fund Grant).
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M.G., J.Y., M.N., and A.D.E. planned the project, analyzed the data, and wrote the manuscript; M.G., S.B., and J.Y. performed the experiments and interpreted the results; M.G., R.D., and J.Y. performed statistical analysis; M.N., M.W., E.C.M., T.G., R.D., D.I., E.D.A., W.C.N., M.W.P., K.L., E.B.R., R.H., D.Y., and A.D.E. recruited subjects and performed research; all authors reviewed, revised, and approved the manuscript for submission.
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All samples and clinical data have been collected with informed consent and assent where appropriate. All cohorts have been approved by the Institutional Review Board at their respective institution and by the Johns Hopkins University Institutional Review Board.
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Griffiths, M., Yang, J., Nies, M. et al. Pediatric pulmonary hypertension: insulin-like growth factor-binding protein 2 is a novel marker associated with disease severity and survival. Pediatr Res 88, 850–856 (2020). https://doi.org/10.1038/s41390-020-01113-x
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DOI: https://doi.org/10.1038/s41390-020-01113-x
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