title: Serum endostatin is a genetically determined predictor of survival in pulmonary arterial hypertension.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) is a medically incurable disease resulting in death from right ventricular (RV) failure. Both pulmonary vascular and RV remodeling are linked to dynamic changes in the microvasculature. Therefore, we hypothesized that circulating angiostatic factors could be linked to outcomes and represent novel biomarkers of disease severity in PAH.
  
  
  OBJECTIVE
  We sought to determine the relationship of a potent angiostatic factor, endostatin (ES), with disease severity and mortality in PAH. Furthermore, we assessed genetic predictors of ES expression and/or function and their association with outcomes in PAH.
  
  
  METHODS
  We measured levels of serum ES in two independent cohorts of patients with PAH. Contemporaneous clinical data included New York Heart Association functional class, 6-minute-walk distance, invasive hemodynamics, and laboratory chemistries.
  
  
  RESULTS
  Serum ES correlated with poor functional status, decreased exercise tolerance, and invasive hemodynamics variables. Furthermore, serum ES was a strong predictor of mortality. A loss-of-function, missense variant in the gene encoding ES, Col18a1, was linked to lower circulating protein and was independently associated with reduced mortality.
  
  
  CONCLUSIONS
  Our data link increased expression of ES to disease severity in PAH and demonstrate a significant relationship with adverse outcomes. Circulating ES levels can be genetically influenced, implicating ES as a genetically determined modifier of disease severity impacting on survival. These observations support serum ES as a potential biomarker in PAH with the capacity to predict poor outcomes. More importantly, this study implicates Col18a1/ES as a potential new therapeutic target in PAH.
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine.
authors.forename: Rachel
authors.initials: R
authors.lastname: Damico
authors.forename: Todd M
authors.initials: TM
authors.lastname: Kolb
authors.forename: Lidenys
authors.initials: L
authors.lastname: Valera
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.forename: Traci
authors.initials: T
authors.lastname: Housten
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Tedford
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.forename: Nicholas
authors.initials: N
authors.lastname: Rafaels
authors.forename: Li
authors.initials: L
authors.lastname: Gao
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Barnes
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Benza
authors.forename: James L
authors.initials: JL
authors.lastname: Rand
authors.forename: Rizwan
authors.initials: R
authors.lastname: Hamid
authors.forename: James E
authors.initials: JE
authors.lastname: Loyd
authors.forename: Ivan M
authors.initials: IM
authors.lastname: Robbins
authors.forename: Anna R
authors.initials: AR
authors.lastname: Hemnes
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.forename: Eric D
authors.initials: ED
authors.lastname: Austin
authors.forename: M Bradley
authors.initials: MB
authors.lastname: Drummond
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Mathai
authors.forename: Paul M
authors.initials: PM
authors.lastname: Hassoun
mesh_terms: D015415:Biomarkers / Q000097:blood; D043170:Collagen Type XVIII / Q000097:blood* / Q000235:genetics; D043169:Endostatins / Q000097:blood* / Q000235:genetics; D005080:Exercise Test; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood* / Q000145:classification / Q000235:genetics / Q000401:mortality; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D012372:ROC Curve; D012720:Severity of Illness Index; D018497:Ventricular Dysfunction, Right / Q000503:physiopathology*
chemical_list: D015415:Biomarkers; D043170:Collagen Type XVIII; D043169:Endostatins
keywords: collagen 18a1; endostatin; genetics; pulmonary arterial hypertension; survival