TY - JOUR
T1 - ST2 Is a Biomarker of Pediatric Pulmonary Arterial Hypertension Severity and Clinical Worsening
AU - Griffiths, Megan
AU - Yang, Jun
AU - Simpson, Catherine E.
AU - Vaidya, Dhananjay
AU - Nies, Melanie
AU - Brandal, Stephanie
AU - Damico, Rachel
AU - Ivy, D. Dunbar
AU - Austin, Eric D.
AU - Pauciulo, Michael W.
AU - Lutz, Katie A.
AU - Rosenzweig, Erika B.
AU - Hirsch, Russel
AU - Yung, Delphine
AU - Nichols, William C.
AU - Everett, Allen D.
N1 - Funding Information:
Other contributions: Serum/tissue samples were provided by the Pulmonary Hypertension Breakthrough Initiative (PHBI). Funding for the PHBI is provided under a National Heart, Lung, and Blood Institute R24 Grant [R24HL123767]. Samples and/or data from the PAHB, which receives government support under an investigator-initiated grant [R24 HL105333] awarded by the National Heart, Lung, and Blood Institute, were used in this study. The authors thank contributors, including the Pulmonary Hypertension Centers who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible.
Funding Information:
FUNDING/SUPPORT: This study was supported by National Institutes of Health / National Heart, Lung, and Blood Institute [ R01HL135114 and R01 HL150070 , A. D. E., M. N., J. Y., R. D., D. V., W. C. N., D. D. I., and E. D. A.; R24 HL105333, W. C. N. and M. W. P.; and F32 HL143835-01A1, C. E. S.]. M. G. was supported by the Pediatric Scientist Development Program , which is supported by K12-HD000850 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development . D. D. I. was supported by a National Institutes of Health/ National Center for Advancing Translational Sciences Colorado CTSA Grant UL1 TR002535 . M. N. was supported by a Matthew and Michael Wojciechowski Pulmonary Hypertension Pediatric Proof-of-Concept Grant [Dr. Robyn J. Barst Pediatric PH Research and Mentoring Fund Grant].
Publisher Copyright:
© 2021 American College of Chest Physicians
PY - 2021/7
Y1 - 2021/7
N2 - Background: Pediatric pulmonary hypertension is a severe disease defined by sustained elevation of pulmonary artery pressures and pulmonary vascular resistance (PVR). Noninvasive diagnostic and prognostic markers that are more pulmonary vascular specific have been elusive because of disease heterogeneity and patient growth. Research Question: Is soluble suppressor of tumorigenicity (ST2) associated with pulmonary hemodynamic and functional changes in pediatric pulmonary hypertension? Does ST2 improve mortality risk models in pediatric pulmonary hypertension? Study Design and Methods: Two pediatric cohorts (age < 21 years) were assayed for ST2 and N-terminal prohormone B-natriuretic peptide: a cross-sectional cohort from the National Heart Lung and Blood Institute-funded National Biological Sample and Data Repository for PAH (PAHB) (N = 182), and a second longitudinal cohort from Children's Hospital of Colorado (N = 61). Adjusted linear regression was used for association with clinical variables. Clinical mortality models (the Registry to Evaluate Early and Long-Term PAH Disease Management [REVEAL] score) with and without ST2 were used to predict worsening outcomes and compared. Pulmonary artery endothelial and smooth muscle cell ST2 expression and secretion were assayed in vitro. Results: In an adjusted (age and sex) analysis in the PAHB, ST2 was significantly associated with shorter 6-min walk distance (P = .03) and increased PVR index (P = .02). In adjusted longitudinal regression in the Children's Hospital of Colorado cohort, ST2 was significantly associated with higher PVR index (P < .001), shorter 6-min walk distance (P = .01), and higher mean pulmonary artery pressure (P < .001). Although the REVEAL Risk Score Calculator 2.0 was predictive of clinical worsening in the PAHB (hazard ratio, 1.88), addition of ST2 significantly improved the model (hazard ratio, 2.05). In cell culture, ST2 was produced and secreted predominately by endothelial cells as opposed to smooth muscle cells (P < .0001). Interpretation: In two pediatric PAH cohorts, elevated ST2 was associated with unfavorable pulmonary hemodynamics and functional measures, clinical worsening, and significantly improved prediction of clinical worsening. Pulmonary artery endothelial cellular expression of ST2 suggests that ST2 is a more pulmonary vascular-specific marker for pulmonary hypertension.
AB - Background: Pediatric pulmonary hypertension is a severe disease defined by sustained elevation of pulmonary artery pressures and pulmonary vascular resistance (PVR). Noninvasive diagnostic and prognostic markers that are more pulmonary vascular specific have been elusive because of disease heterogeneity and patient growth. Research Question: Is soluble suppressor of tumorigenicity (ST2) associated with pulmonary hemodynamic and functional changes in pediatric pulmonary hypertension? Does ST2 improve mortality risk models in pediatric pulmonary hypertension? Study Design and Methods: Two pediatric cohorts (age < 21 years) were assayed for ST2 and N-terminal prohormone B-natriuretic peptide: a cross-sectional cohort from the National Heart Lung and Blood Institute-funded National Biological Sample and Data Repository for PAH (PAHB) (N = 182), and a second longitudinal cohort from Children's Hospital of Colorado (N = 61). Adjusted linear regression was used for association with clinical variables. Clinical mortality models (the Registry to Evaluate Early and Long-Term PAH Disease Management [REVEAL] score) with and without ST2 were used to predict worsening outcomes and compared. Pulmonary artery endothelial and smooth muscle cell ST2 expression and secretion were assayed in vitro. Results: In an adjusted (age and sex) analysis in the PAHB, ST2 was significantly associated with shorter 6-min walk distance (P = .03) and increased PVR index (P = .02). In adjusted longitudinal regression in the Children's Hospital of Colorado cohort, ST2 was significantly associated with higher PVR index (P < .001), shorter 6-min walk distance (P = .01), and higher mean pulmonary artery pressure (P < .001). Although the REVEAL Risk Score Calculator 2.0 was predictive of clinical worsening in the PAHB (hazard ratio, 1.88), addition of ST2 significantly improved the model (hazard ratio, 2.05). In cell culture, ST2 was produced and secreted predominately by endothelial cells as opposed to smooth muscle cells (P < .0001). Interpretation: In two pediatric PAH cohorts, elevated ST2 was associated with unfavorable pulmonary hemodynamics and functional measures, clinical worsening, and significantly improved prediction of clinical worsening. Pulmonary artery endothelial cellular expression of ST2 suggests that ST2 is a more pulmonary vascular-specific marker for pulmonary hypertension.
KW - ST2
KW - biomarkers
KW - pediatric cardiology
KW - pediatric pulmonary hypertension
KW - pulmonary hypertension
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U2 - 10.1016/j.chest.2021.01.085
DO - 10.1016/j.chest.2021.01.085
M3 - Article
C2 - 33609516
AN - SCOPUS:85109198707
SN - 0012-3692
VL - 160
SP - 297
EP - 306
JO - Diseases of the chest
JF - Diseases of the chest
IS - 1
ER -