TY - JOUR T1 - The angiostatic peptide endostatin enhances mortality risk prediction in pulmonary arterial hypertension JF - ERJ Open Research JO - erjor DO - 10.1183/23120541.00378-2021 SP - 00378-2021 AU - Catherine E. Simpson AU - Megan Griffiths AU - Jun Yang AU - Melanie K. Nies AU - R. Dhananjay Vaidya AU - Stephanie Brandal AU - Lisa J. Martin AU - Michael W. Pauciulo AU - Katie A. Lutz AU - Anna W. Coleman AU - Eric D. Austin AU - D. Dunbar Ivy AU - William C. Nichols AU - Allen D. Everett AU - Paul M. Hassoun AU - Rachel L. Damico Y1 - 2021/01/01 UR - http://openres.ersjournals.com/content/early/2021/07/15/23120541.00378-2021.abstract N2 - Currently available noninvasive markers for assessing disease severity and mortality risk in pulmonary arterial hypertension (PAH) are unrelated to fundamental disease biology. Endostatin, an angiostatic peptide known to inhibit pulmonary artery endothelial cell migration, proliferation, and survival in vitro, has been linked to adverse hemodynamics and shortened survival in small PAH cohorts. This observational cohort study sought to assess 1) the prognostic performance of circulating endostatin levels in a large, multicenter PAH cohort, and 2) the added value gained by incorporating endostatin into existing PAH risk prediction models.Endostatin ELISAs were performed on enrollment samples collected from 2017 PAH subjects with detailed clinical data, including survival times. Endostatin associations with clinical variables, including survival, were examined using multivariable regression and Cox proportional hazards models. Extended survival models including endostatin were compared to null models based on the REVEAL risk prediction tool and ESC/ERS low risk criteria using likelihood ratio tests, Akaike and Bayesian information criteria, and C-statistics.Higher endostatin was associated with higher right atrial pressure, mean pulmonary arterial pressure, and pulmonary vascular resistance and with shorter six-minute walk distance (p<0.01). Mortality risk doubled for each log-higher endostatin (hazard ratio 2.3, 95% confidence interval 1.6 to 3.4, p<0.001). Endostatin remained an independent predictor of survival when incorporated into existing risk prediction models. Adding endostatin to REVEAL-based and ESC/ERS criteria-based risk assessment strategies improved mortality risk prediction.Endostatin is a robust, independent predictor of mortality in PAH. Adding endostatin to existing PAH risk prediction strategies improves PAH risk assessment.FootnotesThis manuscript has recently been accepted for publication in the ERJ Open Research. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article.Conflict of interest: Dr. Simpson has nothing to disclose.Conflict of interest: Megan GriffithsConflict of interest: Dr. Yang has nothing to disclose.Conflict of interest: Dr. Nies has nothing to disclose.Conflict of interest: Dr. Vaidya has nothing to disclose.Conflict of interest: Dr. Brandal has nothing to disclose.Conflict of interest: Dr. Martin reports grants from NIH, during the conduct of the study.Conflict of interest: Dr. Pauciulo has nothing to disclose.Conflict of interest: Dr. Lutz has nothing to disclose.Conflict of interest: Dr. Coleman has nothing to disclose.Conflict of interest: Dr. Austin reports grants from NIH/NHLBI, during the conduct of the study; .Conflict of interest: The University of Colorado contracts with Actelion, Bayer, GSK, Lilly, Liquidia, and United Therapeutics for Dr Ivy to be a consultant and to perform clinical trials. Dr Ivy has received money for travel and lodging from Bayer and food and beverage from United Therapeutics.Conflict of interest: Dr. Nichols has nothing to disclose.Conflict of interest: Dr. Everett reports In addition, Dr. Everett has a patent Biomarkers of Pulmonary Hypertension pending.Conflict of interest: Paul M. Hassoun.Conflict of interest: Dr. Damico has nothing to disclose. ER -