Catherine E Simpson1, Rachel L Damico1, Paul M Hassoun1, Lisa J Martin2, Jun Yang3, Melanie K Nies3, R Dhananjay Vaidya4, Stephanie Brandal3, Michael W Pauciulo2, Eric D Austin5, D Dunbar Ivy6, William C Nichols2, Allen D Everett7. 1. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD. 2. Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH. 3. Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD. 4. Division of General Internal Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD. 5. Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University, Nashville, TN. 6. Department of Pediatric Cardiology, Children's Hospital Colorado, Aurora, CO. 7. Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD. Electronic address: aeveret3@jhmi.edu.
Abstract
BACKGROUND: Three biomarkers, soluble suppression of tumorigenicity 2 (ST2), galectin 3 (Gal3), and N-terminal brain natriuretic peptide prohormone (NT-proBNP), are approved for noninvasive risk assessment in left-sided heart failure, and small observational studies have shown their prognostic usefulness in heterogeneous pulmonary hypertension cohorts. We examined associations between these biomarkers and disease severity and survival in a large cohort of patients with pulmonary arterial hypertension (PAH) (ie, group 1 pulmonary hypertension). We hypothesized that additive use of biomarkers in combination would improve the prognostic value of survival models. METHODS: Biomarker measurements and clinical data were obtained from 2,017 adults with group 1 PAH. Associations among biomarker levels and clinical variables, including survival times, were examined with multivariable regression models. Likelihood ratio tests and the Akaike information criterion were used to compare survival models. RESULTS: Higher ST2 and NT-proBNP were associated with higher pulmonary pressures and vascular resistance and lower 6-min walk distance. Higher ST2 and NT-proBNP levels were associated with increased risk of death (hazard ratios: 2.79; 95% CI, 2.21-3.53; P < .001 and 1.84; 95% CI, 1.62-2.10; P < .001, respectively). The addition of ST2 to survival models composed of other predictors of survival, including NT-proBNP, significantly improved model fit and predictive capacity. CONCLUSIONS: ST2 and NT-proBNP are strong, noninvasive prognostic biomarkers in PAH. Despite its prognostic value in left-sided heart failure, Gal3 was not predictive in PAH. Adding ST2 to survival models significantly improves model predictive capacity. Future studies are needed to develop multimarker assays that improve noninvasive risk stratification in PAH.
BACKGROUND: Three biomarkers, soluble suppression of tumorigenicity 2 (ST2), galectin 3 (Gal3), and N-terminal brain natriuretic peptide prohormone (NT-proBNP), are approved for noninvasive risk assessment in left-sided heart failure, and small observational studies have shown their prognostic usefulness in heterogeneous pulmonary hypertension cohorts. We examined associations between these biomarkers and disease severity and survival in a large cohort of patients with pulmonary arterial hypertension (PAH) (ie, group 1 pulmonary hypertension). We hypothesized that additive use of biomarkers in combination would improve the prognostic value of survival models. METHODS: Biomarker measurements and clinical data were obtained from 2,017 adults with group 1 PAH. Associations among biomarker levels and clinical variables, including survival times, were examined with multivariable regression models. Likelihood ratio tests and the Akaike information criterion were used to compare survival models. RESULTS: Higher ST2 and NT-proBNP were associated with higher pulmonary pressures and vascular resistance and lower 6-min walk distance. Higher ST2 and NT-proBNP levels were associated with increased risk of death (hazard ratios: 2.79; 95% CI, 2.21-3.53; P < .001 and 1.84; 95% CI, 1.62-2.10; P < .001, respectively). The addition of ST2 to survival models composed of other predictors of survival, including NT-proBNP, significantly improved model fit and predictive capacity. CONCLUSIONS:ST2 and NT-proBNP are strong, noninvasive prognostic biomarkers in PAH. Despite its prognostic value in left-sided heart failure, Gal3 was not predictive in PAH. Adding ST2 to survival models significantly improves model predictive capacity. Future studies are needed to develop multimarker assays that improve noninvasive risk stratification in PAH.
Authors: Mark H Williams; Clive E Handler; Raza Akram; Colette J Smith; Clare Das; Joanna Smee; Devaki Nair; Christopher P Denton; Carol M Black; John G Coghlan Journal: Eur Heart J Date: 2006-04-27 Impact factor: 29.983
Authors: Anna Fijalkowska; Marcin Kurzyna; Adam Torbicki; Grzegorz Szewczyk; Michal Florczyk; Piotr Pruszczyk; Monika Szturmowicz Journal: Chest Date: 2006-05 Impact factor: 9.410
Authors: Jeremy A Mazurek; Benjamin D Horne; Wajeeha Saeed; Muhammad R Sardar; Ronald Zolty Journal: Heart Lung Circ Date: 2017-02-08 Impact factor: 2.975
Authors: Robert P Frantz; Harrison W Farber; David B Badesch; C Greg Elliott; Adaani E Frost; Michael D McGoon; Carol Zhao; David R Mink; Mona Selej; Raymond L Benza Journal: Chest Date: 2018-01-31 Impact factor: 9.410
Authors: Rana Ghali; Raffaele Altara; William E Louch; Alessandro Cataliotti; Ziad Mallat; Abdullah Kaplan; Fouad A Zouein; George W Booz Journal: Hypertension Date: 2018-10 Impact factor: 10.190
Authors: Raymond L Benza; Harrison W Farber; Adaani Frost; Ekkehard Grünig; Marius M Hoeper; Dennis Busse; Christian Meier; Sylvia Nikkho; Hossein-Ardeschir Ghofrani Journal: J Heart Lung Transplant Date: 2018-03-01 Impact factor: 10.247
Authors: Sean Agbor-Enoh; Michael A Solomon; Samuel B Brusca; Jason M Elinoff; Yvette Zou; Moon Kyoo Jang; Hyesik Kong; Cumhur Y Demirkale; Junfeng Sun; Fayaz Seifuddin; Mehdi Pirooznia; Hannah A Valantine; Carl Tanba; Abhishek Chaturvedi; Grace M Graninger; Bonnie Harper; Li-Yuan Chen; Justine Cole; Manreet Kanwar; Raymond L Benza; Ioana R Preston Journal: Circulation Date: 2022-08-25 Impact factor: 39.918
Authors: Catherine E Simpson; Megan Griffiths; Jun Yang; Melanie K Nies; Dhananjay Vaidya; Stephanie Brandal; Lisa J Martin; Michael W Pauciulo; Katie A Lutz; Anna W Coleman; Eric D Austin; D Dunbar Ivy; William C Nichols; Allen D Everett; Paul M Hassoun; Rachel L Damico Journal: ERJ Open Res Date: 2022-06-27
Authors: Megan Griffiths; Jun Yang; Catherine E Simpson; Dhananjay Vaidya; Melanie Nies; Stephanie Brandal; Rachel Damico; D Dunbar Ivy; Eric D Austin; Michael W Pauciulo; Katie A Lutz; Erika B Rosenzweig; Russel Hirsch; Delphine Yung; William C Nichols; Allen D Everett Journal: Chest Date: 2021-02-18 Impact factor: 10.262
Authors: Catherine E Simpson; Megan Griffiths; Jun Yang; Melanie K Nies; R Dhananjay Vaidya; Stephanie Brandal; Lisa J Martin; Michael W Pauciulo; Katie A Lutz; Anna W Coleman; Eric D Austin; D Dunbar Ivy; William C Nichols; Allen D Everett; Paul M Hassoun; Rachel L Damico Journal: ERJ Open Res Date: 2021-10-11