Megan Griffiths1, Jun Yang1, Catherine E Simpson2, Dhananjay Vaidya3, Melanie Nies1, Stephanie Brandal1, Rachel Damico2, D Dunbar Ivy4, Eric D Austin5, Michael W Pauciulo6, Katie A Lutz6, Erika B Rosenzweig7, Russel Hirsch8, Delphine Yung9, William C Nichols6, Allen D Everett10. 1. Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD. 2. Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD. 3. Department of Internal Medicine, Johns Hopkins University, Baltimore, MD. 4. Division of Pediatric Cardiology, Children's Hospital Colorado, Denver, CO. 5. Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN. 6. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH. 7. Division of Pediatric Cardiology, Department of Pediatrics, Columbia University, New York, NY. 8. Division of Pediatric Cardiology, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH. 9. Division of Pediatric Cardiology, Department of Pediatrics, University of Washington, Seattle, WA. 10. Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD. Electronic address: aeveret3@jhmi.edu.
Abstract
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.
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.
Authors: Catherine E Simpson; Rachel L Damico; Paul M Hassoun; Lisa J Martin; Jun Yang; Melanie K Nies; R Dhananjay Vaidya; Stephanie Brandal; Michael W Pauciulo; Eric D Austin; D Dunbar Ivy; William C Nichols; Allen D Everett Journal: Chest Date: 2020-01-25 Impact factor: 9.410
Authors: Raymond L Benza; Mardi Gomberg-Maitland; Dave P Miller; Adaani Frost; Robert P Frantz; Aimee J Foreman; David B Badesch; Michael D McGoon Journal: Chest Date: 2011-06-16 Impact factor: 9.410
Authors: Dale A Burkett; Cameron Slorach; Sonali S Patel; Andrew N Redington; D Dunbar Ivy; Luc Mertens; Adel K Younoszai; Mark K Friedberg Journal: Circ Cardiovasc Imaging Date: 2016-09 Impact factor: 7.792
Authors: Raymond L Benza; Mardi Gomberg-Maitland; C Greg Elliott; Harrison W Farber; Aimee J Foreman; Adaani E Frost; Michael D McGoon; David J Pasta; Mona Selej; Charles D Burger; Robert P Frantz Journal: Chest Date: 2019-02-14 Impact factor: 9.410
Authors: Shoji Sanada; Daihiko Hakuno; Luke J Higgins; Eric R Schreiter; Andrew N J McKenzie; Richard T Lee Journal: J Clin Invest Date: 2007-05-10 Impact factor: 14.808
Authors: Laurie W Geenen; Vivan J M Baggen; Robert M Kauling; Thomas Koudstaal; Karin A Boomars; Eric Boersma; Jolien W Roos-Hesselink; Annemien E van den Bosch Journal: J Clin Med Date: 2019-09-20 Impact factor: 4.241