title: Prognostic utility of novel biomarkers of cardiovascular stress in patients with aortic stenosis undergoing valve replacement.
abstract: OBJECTIVE
  In heart failure populations without aortic stenosis (AS), the prognostic utility of multiple biomarkers in addition to clinical factors has been demonstrated. We aimed to determine whether multiple biomarkers of cardiovascular stress are associated with mortality in patients with AS undergoing aortic valve replacement (AVR) independent of clinical factors.
  
  
  METHODS
  From a prospective registry of patients with AS, 345 participants who were referred for and treated with AVR (transcatheter (n=183) or surgical (n=162)) were included. Eight biomarkers were measured on blood samples obtained prior to AVR: growth differentiation factor 15 (GDF15), soluble ST2 (sST2), amino-terminal pro-B-type natriuretic peptide (NTproBNP), galectin-3, high-sensitivity cardiac troponin T, myeloperoxidase, high-sensitivity C reactive protein and monocyte chemotactic protein-1. Biomarkers were evaluated based on median value (high vs low) in a Cox proportional hazards model for all-cause mortality and a parsimonious group of biomarkers selected. Mean follow-up was 1.9±1.2 years; 91 patients died.
  
  
  RESULTS
  Three biomarkers (GDF15, sST2 and NTproBNP) were retained in the model. One-year mortality was 5%, 12%, 18% and 33% for patients with 0 (n=79), 1 (n=96), 2 (n=87) and 3 (n=83) biomarkers elevated, respectively (p<0.001). After adjustment for the Society of Thoracic Surgeons (STS) risk score, a greater number of elevated biomarkers was associated with increased mortality (referent: 0 elevated): 1 elevated (HR 1.47, 95% CI 0.60 to 3.63, p=0.40), 2 elevated (HR 2.89, 95% CI 1.24 to 6.74, p=0.014) and 3 elevated (HR 4.59, 95% CI 1.97 to 10.71, p<0.001). Among patients at intermediate or high surgical risk (STS score ≥4), 1-year and 2-year mortality rates were 34% and 43% for patients with three biomarkers elevated versus 4% and 4% for patients with 0 biomarkers elevated. When added to the STS score, the number of biomarkers elevated provided a category-free net reclassification improvement of 64% at 1 year (p<0.001). The association between a greater number of elevated biomarkers and increased mortality after valve replacement was similar in the transcatheter and surgical AVR populations.
  
  
  CONCLUSIONS
  These findings demonstrate the potential utility of multiple biomarkers to aid in risk stratification of patients with AS. Further studies are needed to evaluate their utility in clinical decision-making in specific AS populations.
authors.affiliation: Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Brian R
authors.identifier: http://orcid.org/0000-0002-6879-5343
authors.initials: BR
authors.lastname: Lindman
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Jared G
authors.initials: JG
authors.lastname: Breyley
authors.affiliation: Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Joel D
authors.initials: JD
authors.lastname: Schilling
authors.affiliation: Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Vatterott
authors.affiliation: Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Zajarias
authors.affiliation: Department of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Hersh S
authors.initials: HS
authors.lastname: Maniar
authors.affiliation: Department of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: Damiano
authors.affiliation: Department of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Moon
authors.affiliation: Department of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Lawton
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Gage
authors.affiliation: Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Sintek
authors.affiliation: Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Aquino
authors.affiliation: Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Holley
authors.affiliation: Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Neil M
authors.initials: NM
authors.lastname: Patel
authors.affiliation: Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Lawler
authors.affiliation: Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Lasala
authors.affiliation: Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Novak
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001024:Aortic Valve Stenosis / Q000097:blood / Q000175:diagnosis / Q000401:mortality / Q000503:physiopathology / Q000601:surgery / Q000628:therapy*; D015415:Biomarkers / Q000097:blood; D006328:Cardiac Catheterization / Q000009:adverse effects / Q000401:mortality; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000097:blood*; D019918:Heart Valve Prosthesis Implantation / Q000009:adverse effects / Q000401:mortality; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood*; D010446:Peptide Fragments / Q000097:blood*; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011956:Receptors, Cell Surface / Q000097:blood*; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D013312:Stress, Physiological; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; C079241:IL1RL1 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain