title: Fibroblast growth factor-23, cardiovascular prognosis, and benefit of angiotensin-converting enzyme inhibition in stable ischemic heart disease.
abstract: OBJECTIVE
  This study sought to test 2 hypotheses: 1) fibroblast growth factor (FGF)-23 identifies patients with stable ischemic heart disease (SIHD) at high risk of cardiovascular events independent of clinical factors, renal function, and established cardiovascular biomarkers; and 2) FGF-23 identifies patients who derive greater clinical benefit from angiotensin-converting enzyme inhibitor therapy.
  
  
  BACKGROUND
  FGF-23 is an endocrine regulator of mineral metabolism and markedly elevated levels are associated with cardiovascular events in patients with chronic kidney disease. Data in patients with SIHD are more sparse.
  
  
  METHODS
  FGF-23 levels were measured in 3,627 patients with SIHD randomly assigned to trandolapril or placebo within the PEACE (Prevention of Events With Angiotensin-Converting Enzyme) trial and followed up for a median of 5.1 years.
  
  
  RESULTS
  After adjustment for clinical risk predictors, left ventricular ejection fraction, markers of renal function, and established cardiovascular biomarkers, FGF-23 concentration was independently associated with an increased risk of cardiovascular death or heart failure among patients allocated to placebo (quartile 4 hazard ratio: 1.73; 95% confidence interval, 1.09 to 2.74; p = 0.02) and significantly improved metrics of discrimination. Furthermore, among patients in the top quartile of FGF-23 levels, trandolapril significantly reduced cardiovascular death or incident heart failure (hazard ratio: 0.45; 95% confidence interval: 0.28 to 0.72), whereas there was no clinical benefit in the remaining patients (hazard ratio: 1.07; 95% confidence interval: 0.75 to 1.52; p interaction = 0.0039). This interaction was independent of and additive to stratification based on renal function.
  
  
  CONCLUSIONS
  Elevated levels of FGF-23 are associated with cardiovascular death and incident heart failure in patients with SIHD and identify patients who derive significant clinical benefit from angiotensin-converting enzyme inhibitor therapy regardless of renal function. (Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy [PEACE]: NCT00000558).
authors.affiliation: Women's College Research Institute and Division of Cardiology, Department of Medicine, Women's College Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Udell
authors.affiliation: TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: David A
authors.initials: DA
authors.lastname: Morrow
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Petr
authors.initials: P
authors.lastname: Jarolim
authors.affiliation: TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Sarah
authors.initials: S
authors.lastname: Sloan
authors.affiliation: TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Elaine B
authors.initials: EB
authors.lastname: Hoffman
authors.affiliation: Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: O'Donnell
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Amit N
authors.initials: AN
authors.lastname: Vora
authors.affiliation: Department of Cardiology, Division of Medicine, Akershus University Hospital, and Center for Heart Failure Research and KG Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway.
authors.forename: Torbjørn
authors.initials: T
authors.lastname: Omland
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Solomon
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Pfeffer
authors.affiliation: TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Eugene
authors.initials: E
authors.lastname: Braunwald
authors.affiliation: TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: msabatine@partners.org.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Sabatine
mesh_terms: D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000209:etiology; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood*; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000097:blood* / Q000150:complications / Q000188:drug therapy*; D011379:Prognosis; D012306:Risk
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D015415:Biomarkers; C000717427:FGF23 protein, human; D007211:Indoles; C052035:trandolapril; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23
keywords: angiotensin-converting enzyme inhibitors; biomarkers; coronary artery disease; fibroblast growth factor-23; kidney
references.citation: J Am Soc Nephrol. 2014 Feb;25(2):349-60
references.pmid: 24158986
references.citation: JAMA. 2011 Jun 15;305(23):2432-9
references.pmid: 21673295
references.citation: Nephrol Dial Transplant. 2010 Mar;25(3):993-7
references.pmid: 20037168
references.citation: J Am Soc Nephrol. 2007 Sep;18(9):2600-8
references.pmid: 17656479
references.citation: Eur Heart J Acute Cardiovasc Care. 2013 Sep;2(3):211-8
references.pmid: 24222832
references.citation: Atherosclerosis. 2009 Dec;207(2):546-51
references.pmid: 19524924
references.citation: Nephrol Dial Transplant. 2010 May;25(5):1376-81
references.pmid: 20124546
references.citation: Am J Physiol. 1995 May;268(5 Pt 2):H1927-38
references.pmid: 7771542
references.citation: Eur J Clin Invest. 2012 Jun;42(6):649-56
references.pmid: 22150123
references.citation: J Am Coll Cardiol. 2007 Jul 17;50(3):205-14
references.pmid: 17631211
references.citation: Am J Physiol Endocrinol Metab. 2013 Apr 15;304(8):E863-73
references.pmid: 23443925
references.citation: Circulation. 2012 May 8;125(18):2181-3
references.pmid: 22492634
references.citation: J Am Soc Nephrol. 2011 Sep;22(9):1603-9
references.pmid: 21852584
references.citation: Circulation. 2012 May 8;125(18):2243-55
references.pmid: 22492635
references.citation: Ann Intern Med. 1999 Mar 16;130(6):461-70
references.pmid: 10075613
references.citation: Circulation. 2012 Jan 17;125(2):233-40
references.pmid: 22179538
references.citation: Circulation. 2007 Dec 4;116(23):2687-93
references.pmid: 18025537
references.citation: Am J Epidemiol. 2012 Sep 15;176(6):473-81
references.pmid: 22875755
references.citation: Eur Heart J. 2011 Nov;32(21):2688-96
references.pmid: 21733911
references.citation: N Engl J Med. 2008 Aug 7;359(6):584-92
references.pmid: 18687639
references.citation: N Engl J Med. 2009 Dec 24;361(26):2538-47
references.pmid: 19940289
references.citation: Circulation. 2007 Mar 27;115(12):1528-36
references.pmid: 17372173
references.citation: Kidney Int. 2013 Jan;83(1):160-6
references.pmid: 22951890
references.citation: PLoS One. 2012;7(9):e44161
references.pmid: 22970174
references.citation: Am J Cardiol. 1998 Aug 6;82(3A):25H-30H
references.pmid: 9719019
references.citation: Circulation. 2009 May 19;119(19):2545-52
references.pmid: 19414634
references.citation: Ann Intern Med. 2003 Jul 15;139(2):137-47
references.pmid: 12859163
references.citation: Circulation. 2004 Dec 14;110(24):3667-73
references.pmid: 15569840
references.citation: Ann Intern Med. 2010 May 18;152(10):640-8
references.pmid: 20479029
references.citation: N Engl J Med. 2003 Apr 24;348(17):1656-63
references.pmid: 12711740
references.citation: N Engl J Med. 2004 Nov 11;351(20):2058-68
references.pmid: 15531767
references.citation: Kidney Int. 2011 Jun;79(12):1370-8
references.pmid: 21389978
references.citation: N Engl J Med. 2002 Nov 28;347(22):1795-7
references.pmid: 12456857
references.citation: J Am Coll Cardiol. 2012 Jul 17;60(3):200-7
references.pmid: 22703926
references.citation: Nature. 2006 Dec 7;444(7120):770-4
references.pmid: 17086194
references.citation: JAMA. 2011 Mar 16;305(11):1119-27
references.pmid: 21406649
references.citation: J Clin Invest. 2011 Nov;121(11):4393-408
references.pmid: 21985788
references.citation: Curr Opin Nephrol Hypertens. 2010 Jul;19(4):335-42
references.pmid: 20583336
references.citation: N Engl J Med. 2002 Nov 14;347(20):1557-65
references.pmid: 12432042
references.citation: Kidney Int. 2003 Dec;64(6):2272-9
references.pmid: 14633152
references.citation: Nature. 1997 Nov 6;390(6655):45-51
references.pmid: 9363890
references.citation: Am Heart J. 2011 May;161(5):956-62
references.pmid: 21570529
references.citation: Circulation. 2006 Jul 4;114(1):26-31
references.pmid: 16801465
references.citation: Clin Chem. 2001 Nov;47(11):2031-3
references.pmid: 11673373