title: Plasma Biomarkers Reflecting Profibrotic Processes in Heart Failure With a Preserved Ejection Fraction: Data From the Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction Study.
abstract: BACKGROUND
  Heart failure with preserved ejection fraction is a clinical syndrome that has been associated with changes in the extracellular matrix. The purpose of this study was to determine whether profibrotic biomarkers accurately reflect the presence and severity of disease and underlying pathophysiology and modify response to therapy in patients with heart failure with preserved ejection fraction.
  
  
  RESULTS
  Four biomarkers, soluble form of ST2 (an interleukin-1 receptor family member), galectin-3, matrix metalloproteinase-2, and collagen III N-terminal propeptide were measured in the Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction (PARAMOUNT) trial at baseline, 12 and 36 weeks after randomization to valsartan or LCZ696. We examined the relationship between baseline biomarkers, demographic and echocardiographic characteristics, change in primary (change in N-terminal pro B-type natriuretic peptide) and secondary (change in left atrial volume) end points. The median (interquartile range) value for soluble form of ST2 (33 [24.6-48.1] ng/mL) and galectin 3 (17.8 [14.1-22.8] ng/mL) were higher, and for matrix metalloproteinase-2 (188 [155.5-230.6] ng/mL) lower, than in previously published referent controls; collagen III N-terminal propeptide (5.6 [4.3-6.9] ng/mL) was similar to referent control values. All 4 biomarkers correlated with severity of disease as indicated by N-terminal pro B-type natriuretic peptide, E/E', and left atrial volume. Baseline biomarkers did not modify the response to LCZ696 for lowering N-terminal pro B-type natriuretic peptide; however, left atrial volume reduction varied by baseline level of soluble form of ST2 and galectin 3; patients with values less than the observed median (<33 ng/mL soluble form of ST2 and <17.8 ng/mL galectin 3) had reduction in left atrial volume, those above median did not. Although LCZ696 reduced N-terminal pro B-type natriuretic peptide, levels of the other 4 biomarkers were not affected over time.
  
  
  CONCLUSIONS
  In patients with heart failure with preserved ejection fraction, biomarkers that reflect collagen homeostasis correlated with the presence and severity of disease and underlying pathophysiology, and may modify the structural response to treatment.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT00887588.
authors.affiliation: From the Department of Medicine, Medical University of South Carolina, Charleston (M.R.Z., C.F.B.); RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (P.S.J., B.L.C., S.D.S.); BHF Glasgow Cardiovascular Research Center, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (P.S.J., J.J.V.M.M.); Department of Cardiology, Medical University of Graz, Graz, Austria (B.P.); Department of Internal Medicine and Cardiology, Charité, Campus Virchow Klinikum, Berlin, Germany (B.P.); Department of Internal Medicine and Cardiology, German Heart Center, Berlin, Germany (B.P.); Department of Cardiology, University of Groningen, Groningen, The Netherlands (A.A.V.); and Novartis Pharmaceuticals, East Hanover, NJ (M.F.P., V.S., M.L.). zilem@musc.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zile
authors.affiliation: From the Department of Medicine, Medical University of South Carolina, Charleston (M.R.Z., C.F.B.); RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (P.S.J., B.L.C., S.D.S.); BHF Glasgow Cardiovascular Research Center, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (P.S.J., J.J.V.M.M.); Department of Cardiology, Medical University of Graz, Graz, Austria (B.P.); Department of Internal Medicine and Cardiology, Charité, Campus Virchow Klinikum, Berlin, Germany (B.P.); Department of Internal Medicine and Cardiology, German Heart Center, Berlin, Germany (B.P.); Department of Cardiology, University of Groningen, Groningen, The Netherlands (A.A.V.); and Novartis Pharmaceuticals, East Hanover, NJ (M.F.P., V.S., M.L.).
authors.forename: Pardeep S
authors.initials: PS
authors.lastname: Jhund
authors.affiliation: From the Department of Medicine, Medical University of South Carolina, Charleston (M.R.Z., C.F.B.); RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (P.S.J., B.L.C., S.D.S.); BHF Glasgow Cardiovascular Research Center, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (P.S.J., J.J.V.M.M.); Department of Cardiology, Medical University of Graz, Graz, Austria (B.P.); Department of Internal Medicine and Cardiology, Charité, Campus Virchow Klinikum, Berlin, Germany (B.P.); Department of Internal Medicine and Cardiology, German Heart Center, Berlin, Germany (B.P.); Department of Cardiology, University of Groningen, Groningen, The Netherlands (A.A.V.); and Novartis Pharmaceuticals, East Hanover, NJ (M.F.P., V.S., M.L.).
authors.forename: Catalin F
authors.initials: CF
authors.lastname: Baicu
authors.affiliation: From the Department of Medicine, Medical University of South Carolina, Charleston (M.R.Z., C.F.B.); RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (P.S.J., B.L.C., S.D.S.); BHF Glasgow Cardiovascular Research Center, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (P.S.J., J.J.V.M.M.); Department of Cardiology, Medical University of Graz, Graz, Austria (B.P.); Department of Internal Medicine and Cardiology, Charité, Campus Virchow Klinikum, Berlin, Germany (B.P.); Department of Internal Medicine and Cardiology, German Heart Center, Berlin, Germany (B.P.); Department of Cardiology, University of Groningen, Groningen, The Netherlands (A.A.V.); and Novartis Pharmaceuticals, East Hanover, NJ (M.F.P., V.S., M.L.).
authors.forename: Brian L
authors.initials: BL
authors.lastname: Claggett
authors.affiliation: From the Department of Medicine, Medical University of South Carolina, Charleston (M.R.Z., C.F.B.); RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (P.S.J., B.L.C., S.D.S.); BHF Glasgow Cardiovascular Research Center, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (P.S.J., J.J.V.M.M.); Department of Cardiology, Medical University of Graz, Graz, Austria (B.P.); Department of Internal Medicine and Cardiology, Charité, Campus Virchow Klinikum, Berlin, Germany (B.P.); Department of Internal Medicine and Cardiology, German Heart Center, Berlin, Germany (B.P.); Department of Cardiology, University of Groningen, Groningen, The Netherlands (A.A.V.); and Novartis Pharmaceuticals, East Hanover, NJ (M.F.P., V.S., M.L.).
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
authors.affiliation: From the Department of Medicine, Medical University of South Carolina, Charleston (M.R.Z., C.F.B.); RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (P.S.J., B.L.C., S.D.S.); BHF Glasgow Cardiovascular Research Center, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (P.S.J., J.J.V.M.M.); Department of Cardiology, Medical University of Graz, Graz, Austria (B.P.); Department of Internal Medicine and Cardiology, Charité, Campus Virchow Klinikum, Berlin, Germany (B.P.); Department of Internal Medicine and Cardiology, German Heart Center, Berlin, Germany (B.P.); Department of Cardiology, University of Groningen, Groningen, The Netherlands (A.A.V.); and Novartis Pharmaceuticals, East Hanover, NJ (M.F.P., V.S., M.L.).
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Voors
authors.affiliation: From the Department of Medicine, Medical University of South Carolina, Charleston (M.R.Z., C.F.B.); RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (P.S.J., B.L.C., S.D.S.); BHF Glasgow Cardiovascular Research Center, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (P.S.J., J.J.V.M.M.); Department of Cardiology, Medical University of Graz, Graz, Austria (B.P.); Department of Internal Medicine and Cardiology, Charité, Campus Virchow Klinikum, Berlin, Germany (B.P.); Department of Internal Medicine and Cardiology, German Heart Center, Berlin, Germany (B.P.); Department of Cardiology, University of Groningen, Groningen, The Netherlands (A.A.V.); and Novartis Pharmaceuticals, East Hanover, NJ (M.F.P., V.S., M.L.).
authors.forename: Margaret F
authors.initials: MF
authors.lastname: Prescott
authors.affiliation: From the Department of Medicine, Medical University of South Carolina, Charleston (M.R.Z., C.F.B.); RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (P.S.J., B.L.C., S.D.S.); BHF Glasgow Cardiovascular Research Center, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (P.S.J., J.J.V.M.M.); Department of Cardiology, Medical University of Graz, Graz, Austria (B.P.); Department of Internal Medicine and Cardiology, Charité, Campus Virchow Klinikum, Berlin, Germany (B.P.); Department of Internal Medicine and Cardiology, German Heart Center, Berlin, Germany (B.P.); Department of Cardiology, University of Groningen, Groningen, The Netherlands (A.A.V.); and Novartis Pharmaceuticals, East Hanover, NJ (M.F.P., V.S., M.L.).
authors.forename: Victor
authors.initials: V
authors.lastname: Shi
authors.affiliation: From the Department of Medicine, Medical University of South Carolina, Charleston (M.R.Z., C.F.B.); RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (P.S.J., B.L.C., S.D.S.); BHF Glasgow Cardiovascular Research Center, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (P.S.J., J.J.V.M.M.); Department of Cardiology, Medical University of Graz, Graz, Austria (B.P.); Department of Internal Medicine and Cardiology, Charité, Campus Virchow Klinikum, Berlin, Germany (B.P.); Department of Internal Medicine and Cardiology, German Heart Center, Berlin, Germany (B.P.); Department of Cardiology, University of Groningen, Groningen, The Netherlands (A.A.V.); and Novartis Pharmaceuticals, East Hanover, NJ (M.F.P., V.S., M.L.).
authors.forename: Martin
authors.initials: M
authors.lastname: Lefkowitz
authors.affiliation: From the Department of Medicine, Medical University of South Carolina, Charleston (M.R.Z., C.F.B.); RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (P.S.J., B.L.C., S.D.S.); BHF Glasgow Cardiovascular Research Center, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (P.S.J., J.J.V.M.M.); Department of Cardiology, Medical University of Graz, Graz, Austria (B.P.); Department of Internal Medicine and Cardiology, Charité, Campus Virchow Klinikum, Berlin, Germany (B.P.); Department of Internal Medicine and Cardiology, German Heart Center, Berlin, Germany (B.P.); Department of Cardiology, University of Groningen, Groningen, The Netherlands (A.A.V.); and Novartis Pharmaceuticals, East Hanover, NJ (M.F.P., V.S., M.L.).
authors.forename: John J V
authors.initials: JJ
authors.lastname: McMurray
authors.affiliation: From the Department of Medicine, Medical University of South Carolina, Charleston (M.R.Z., C.F.B.); RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (P.S.J., B.L.C., S.D.S.); BHF Glasgow Cardiovascular Research Center, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (P.S.J., J.J.V.M.M.); Department of Cardiology, Medical University of Graz, Graz, Austria (B.P.); Department of Internal Medicine and Cardiology, Charité, Campus Virchow Klinikum, Berlin, Germany (B.P.); Department of Internal Medicine and Cardiology, German Heart Center, Berlin, Germany (B.P.); Department of Cardiology, University of Groningen, Groningen, The Netherlands (A.A.V.); and Novartis Pharmaceuticals, East Hanover, NJ (M.F.P., V.S., M.L.).
authors.forename: Scott D
authors.initials: SD
authors.lastname: Solomon
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000613:Aminobutyrates / Q000627:therapeutic use*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood*; D001713:Biphenyl Compounds; D001798:Blood Proteins; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D005355:Fibrosis; D037502:Galectin 3 / Q000097:blood; D037161:Galectins; D006333:Heart Failure / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000097:blood; D011347:Procollagen / Q000097:blood; D011446:Prospective Studies; D011956:Receptors, Cell Surface / Q000097:blood; D012720:Severity of Illness Index; D013318:Stroke Volume; D013777:Tetrazoles / Q000627:therapeutic use*; D016896:Treatment Outcome; D000068756:Valsartan / Q000627:therapeutic use*; D016277:Ventricular Function, Left
chemical_list: D000613:Aminobutyrates; D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D015415:Biomarkers; D001713:Biphenyl Compounds; D001798:Blood Proteins; D004338:Drug Combinations; D037502:Galectin 3; D037161:Galectins; C079241:IL1RL1 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; C428445:LGALS3 protein, human; D010446:Peptide Fragments; D011347:Procollagen; D011956:Receptors, Cell Surface; D013777:Tetrazoles; C041876:procollagen Type III-N-terminal peptide; D000068756:Valsartan; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: biomarkers; extracellular matrix; heart failure; homeostasis; pathophysiology