title: Extracellular matrix biomarker, fibulin-1, is closely related to NT-proBNP and soluble urokinase plasminogen activator receptor in patients with aortic valve stenosis (the SEAS study).
abstract: BACKGROUND
  Fibulin-1, a circulating extracellular matrix glycoprotein, has been associated with arterial disease and elevated N-terminal prohormone B-type natriuretic peptide (NT-proBNP) in diabetes. Soluble urokinase plasminogen activator receptor (suPAR), a marker of inflammation, has been associated with subclinical atherosclerosis. Therefore, we aimed to explore the interplay between these biomarkers and mild to moderate aortic valve stenosis (AS).
  
  
  METHODS
  In 374 patients with mild to moderate AS, we investigated the relationship of fibulin-1 with NT-proBNP, levels of suPAR and the degree of AS at baseline and after one and four years of treatment with Simvastatin 40 mg and Ezetimibe 10 mg or placebo.
  
  
  RESULTS
  During treatment, fibulin-1 became more closely associated with NT-proBNP (βyear0 = 0.10, p = 0.08, βyear1 = 0.16, p = 0.005, βyear4 = 0.22, p<0.001) and suPAR (βyear0 = 0.05, p = 0.34, βyear1 = 0.16, p = 0.006, βyear4 = 0.13, p = 0.03) at the expense of the association to aortic valve area index (AVAI) (βyear0 = -0.14, p = 0.005, βyear1 = -0.08, p = 0.11, βyear4 = -0.06, p = 0.22) independently of age, gender, creatinine, and serum aspartate aminotransferase (Adj.Ryear02 = 0.19, Adj.Ryear12 = 0.22, Adj.Ryear42 = 0.27). Fibulin-1 was unrelated to aortic regurgitation, left ventricular mass, and ejection fraction. In patients with baseline AVAI<0.58 cm2/m2 (median value), fibulin-1 was more closely associated to NT-proBNP (βyear0 = 0.25, βyear1 = 0.21, βyear4 = 0.22, all p<0.01), and suPAR (βyear0 = 0.09, p = 0.26, βyear1 = 0.23, βyear4 = 0.21, both p<0.01) independently of age, gender, AST and treatment allocation.
  
  
  CONCLUSIONS
  Increased levels of fibulin-1 were independently associated with higher levels of suPAR and NT-proBNP especially in patients with lower AVAI, suggesting that fibulin-1 may be an early marker of AS as well as cardiac fibrosis secondarily to elevated left ventricular hemodynamic load.
authors.affiliation: Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa; The Cardiovascular and Metabolic Preventive Clinic, Department of Endocrinology, Centre for Individualized Medicine in Arterial Diseases (CIMA), Odense University Hospital, Odense, Denmark.
authors.forename: Ruan
authors.initials: R
authors.lastname: Kruger
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Centre for Individualized Medicine in Arterial Diseases (CIMA), Odense University Hospital, Odense, Denmark.
authors.forename: Lars M
authors.initials: LM
authors.lastname: Rasmussen
authors.affiliation: Medical University of South Carolina, Department of Cell Biology, Charleston, South Carolina, United States of America.
authors.forename: William S
authors.initials: WS
authors.lastname: Argraves
authors.affiliation: Clinical Research Centre 136, Hvidovre Hospital, Copenhagen, Denmark.
authors.forename: Jesper
authors.initials: J
authors.lastname: Eugen-Olsen
authors.affiliation: Department of Cardiology, Bispebjerg Hospital, Copenhagen, Denmark.
authors.forename: Olav W
authors.initials: OW
authors.lastname: Nielsen
authors.affiliation: Department of Cardiology, Glostrup Hospital, Copenhagen, Denmark.
authors.forename: Adam
authors.initials: A
authors.lastname: Blyme
authors.affiliation: Lund University and Heart Health Group, Malmö, Sweden.
authors.forename: Ronnie
authors.initials: R
authors.lastname: Willenheimer
authors.affiliation: Department of Medicine, Glostrup Hospital, Copenhagen, Denmark.
authors.forename: Kristian
authors.initials: K
authors.lastname: Wachtell
authors.affiliation: Hypertension in Africa Research Team (HART), North-West University, Potchefstroom, South Africa; The Cardiovascular and Metabolic Preventive Clinic, Department of Endocrinology, Centre for Individualized Medicine in Arterial Diseases (CIMA), Odense University Hospital, Odense, Denmark.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Olsen
mesh_terms: D000368:Aged; D001024:Aortic Valve Stenosis / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D004452:Echocardiography; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006439:Hemodynamics / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D011446:Prospective Studies; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D002135:Calcium-Binding Proteins; D010446:Peptide Fragments; D055293:Receptors, Urokinase Plasminogen Activator; C060820:fibulin; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain