title: Fibrosis-related biomarkers and incident cardiovascular disease in older adults: the cardiovascular health study.
abstract: BACKGROUND
  Fibrotic changes in the heart and arteries have been implicated in a diverse range of cardiovascular diseases (CVD), but whether circulating biomarkers that reflect fibrosis are associated with CVD is unknown.
  
  
  RESULTS
  We determined the associations of 2 biomarkers of fibrosis, transforming growth factor- β (TGF-β), and procollagen type III N-terminal propeptide (PIIINP), with incident heart failure, myocardial infarction, and stroke among community-living older adults in the Cardiovascular Health Study. We measured circulating TGF-β (n=1371) and PIIINP (n=2568) from plasma samples collected in 1996 and ascertained events through 2010. Given TGF-β's pleiotropic effects on inflammation and fibrogenesis, we investigated potential effect modification by C-reactive protein in secondary analyses. After adjustment for sociodemographic, clinical, and biochemical risk factors, PIIINP was associated with total CVD (hazard ratio [HR] per SD=1.07; 95% confidence interval [CI], 1.01-1.14) and heart failure (HR per SD=1.08; CI, 1.01-1.16) but not myocardial infarction or stroke. TGF-β was not associated with any CVD outcomes in the full cohort but was associated with total CVD (HR per SD=1.16; CI, 1.02-1.31), heart failure (HR per SD=1.16; CI, 1.01-1.34), and stroke (HR per SD=1.20; CI, 1.01-1.42) among individuals with C-reactive protein above the median, 2.3 mg/L (P interaction <0.05).
  
  
  CONCLUSIONS
  Our findings provide large-scale, prospective evidence that circulating biomarkers of fibrosis, measured in community-living individuals late in life, are associated with CVD. Further research on whether TGF-β has a stronger fibrogenic effect in the setting of inflammation is warranted.
authors: From the Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, MA (I.A., E.B.R.); Department of Medicine, Boston University, MA (N.L.G.); Department of Research and Education, St. Francis Hospital/SUNY at Stony Brook, NY (E.B.); Department of Biostatistics (M.L.B.), Department of Epidemiology (A.L.F.), and Cardiovascular Health Research Unit, Department of Medicine (D.S.S.), University of Washington, Seattle; Department of Medicine (L.D.) and Channing Division of Network Medicine (E.B.R.), Brigham and Women's Hospital, Boston, MA; Department of Medicine, University of Maryland Medical School, Baltimore (J.S.G.); Department of Medicine, University of California San Diego and Veterans Affairs San Diego Healthcare System (J.H.I.); Departments of Medicine, Epidemiology, and Population Health, Albert Einstein College of Medicine, Bronx, NY (J.R.K.); Department of Biochemistry, University of Vermont, Burlington (R.P.T.); and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (K.J.M.). Isha_Agarwal@hms.harvard.edu.
authors: Isha
authors: I
authors: Agarwal
authors: From the Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, MA (I.A., E.B.R.); Department of Medicine, Boston University, MA (N.L.G.); Department of Research and Education, St. Francis Hospital/SUNY at Stony Brook, NY (E.B.); Department of Biostatistics (M.L.B.), Department of Epidemiology (A.L.F.), and Cardiovascular Health Research Unit, Department of Medicine (D.S.S.), University of Washington, Seattle; Department of Medicine (L.D.) and Channing Division of Network Medicine (E.B.R.), Brigham and Women's Hospital, Boston, MA; Department of Medicine, University of Maryland Medical School, Baltimore (J.S.G.); Department of Medicine, University of California San Diego and Veterans Affairs San Diego Healthcare System (J.H.I.); Departments of Medicine, Epidemiology, and Population Health, Albert Einstein College of Medicine, Bronx, NY (J.R.K.); Department of Biochemistry, University of Vermont, Burlington (R.P.T.); and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (K.J.M.).
authors: Nicole L
authors: NL
authors: Glazer
authors: From the Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, MA (I.A., E.B.R.); Department of Medicine, Boston University, MA (N.L.G.); Department of Research and Education, St. Francis Hospital/SUNY at Stony Brook, NY (E.B.); Department of Biostatistics (M.L.B.), Department of Epidemiology (A.L.F.), and Cardiovascular Health Research Unit, Department of Medicine (D.S.S.), University of Washington, Seattle; Department of Medicine (L.D.) and Channing Division of Network Medicine (E.B.R.), Brigham and Women's Hospital, Boston, MA; Department of Medicine, University of Maryland Medical School, Baltimore (J.S.G.); Department of Medicine, University of California San Diego and Veterans Affairs San Diego Healthcare System (J.H.I.); Departments of Medicine, Epidemiology, and Population Health, Albert Einstein College of Medicine, Bronx, NY (J.R.K.); Department of Biochemistry, University of Vermont, Burlington (R.P.T.); and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (K.J.M.).
authors: Eddy
authors: E
authors: Barasch
authors: From the Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, MA (I.A., E.B.R.); Department of Medicine, Boston University, MA (N.L.G.); Department of Research and Education, St. Francis Hospital/SUNY at Stony Brook, NY (E.B.); Department of Biostatistics (M.L.B.), Department of Epidemiology (A.L.F.), and Cardiovascular Health Research Unit, Department of Medicine (D.S.S.), University of Washington, Seattle; Department of Medicine (L.D.) and Channing Division of Network Medicine (E.B.R.), Brigham and Women's Hospital, Boston, MA; Department of Medicine, University of Maryland Medical School, Baltimore (J.S.G.); Department of Medicine, University of California San Diego and Veterans Affairs San Diego Healthcare System (J.H.I.); Departments of Medicine, Epidemiology, and Population Health, Albert Einstein College of Medicine, Bronx, NY (J.R.K.); Department of Biochemistry, University of Vermont, Burlington (R.P.T.); and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (K.J.M.).
authors: Mary L
authors: ML
authors: Biggs
authors: From the Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, MA (I.A., E.B.R.); Department of Medicine, Boston University, MA (N.L.G.); Department of Research and Education, St. Francis Hospital/SUNY at Stony Brook, NY (E.B.); Department of Biostatistics (M.L.B.), Department of Epidemiology (A.L.F.), and Cardiovascular Health Research Unit, Department of Medicine (D.S.S.), University of Washington, Seattle; Department of Medicine (L.D.) and Channing Division of Network Medicine (E.B.R.), Brigham and Women's Hospital, Boston, MA; Department of Medicine, University of Maryland Medical School, Baltimore (J.S.G.); Department of Medicine, University of California San Diego and Veterans Affairs San Diego Healthcare System (J.H.I.); Departments of Medicine, Epidemiology, and Population Health, Albert Einstein College of Medicine, Bronx, NY (J.R.K.); Department of Biochemistry, University of Vermont, Burlington (R.P.T.); and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (K.J.M.).
authors: Luc
authors: L
authors: Djousse
authors: From the Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, MA (I.A., E.B.R.); Department of Medicine, Boston University, MA (N.L.G.); Department of Research and Education, St. Francis Hospital/SUNY at Stony Brook, NY (E.B.); Department of Biostatistics (M.L.B.), Department of Epidemiology (A.L.F.), and Cardiovascular Health Research Unit, Department of Medicine (D.S.S.), University of Washington, Seattle; Department of Medicine (L.D.) and Channing Division of Network Medicine (E.B.R.), Brigham and Women's Hospital, Boston, MA; Department of Medicine, University of Maryland Medical School, Baltimore (J.S.G.); Department of Medicine, University of California San Diego and Veterans Affairs San Diego Healthcare System (J.H.I.); Departments of Medicine, Epidemiology, and Population Health, Albert Einstein College of Medicine, Bronx, NY (J.R.K.); Department of Biochemistry, University of Vermont, Burlington (R.P.T.); and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (K.J.M.).
authors: Annette L
authors: AL
authors: Fitzpatrick
authors: From the Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, MA (I.A., E.B.R.); Department of Medicine, Boston University, MA (N.L.G.); Department of Research and Education, St. Francis Hospital/SUNY at Stony Brook, NY (E.B.); Department of Biostatistics (M.L.B.), Department of Epidemiology (A.L.F.), and Cardiovascular Health Research Unit, Department of Medicine (D.S.S.), University of Washington, Seattle; Department of Medicine (L.D.) and Channing Division of Network Medicine (E.B.R.), Brigham and Women's Hospital, Boston, MA; Department of Medicine, University of Maryland Medical School, Baltimore (J.S.G.); Department of Medicine, University of California San Diego and Veterans Affairs San Diego Healthcare System (J.H.I.); Departments of Medicine, Epidemiology, and Population Health, Albert Einstein College of Medicine, Bronx, NY (J.R.K.); Department of Biochemistry, University of Vermont, Burlington (R.P.T.); and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (K.J.M.).
authors: John S
authors: JS
authors: Gottdiener
authors: From the Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, MA (I.A., E.B.R.); Department of Medicine, Boston University, MA (N.L.G.); Department of Research and Education, St. Francis Hospital/SUNY at Stony Brook, NY (E.B.); Department of Biostatistics (M.L.B.), Department of Epidemiology (A.L.F.), and Cardiovascular Health Research Unit, Department of Medicine (D.S.S.), University of Washington, Seattle; Department of Medicine (L.D.) and Channing Division of Network Medicine (E.B.R.), Brigham and Women's Hospital, Boston, MA; Department of Medicine, University of Maryland Medical School, Baltimore (J.S.G.); Department of Medicine, University of California San Diego and Veterans Affairs San Diego Healthcare System (J.H.I.); Departments of Medicine, Epidemiology, and Population Health, Albert Einstein College of Medicine, Bronx, NY (J.R.K.); Department of Biochemistry, University of Vermont, Burlington (R.P.T.); and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (K.J.M.).
authors: Joachim H
authors: JH
authors: Ix
authors: From the Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, MA (I.A., E.B.R.); Department of Medicine, Boston University, MA (N.L.G.); Department of Research and Education, St. Francis Hospital/SUNY at Stony Brook, NY (E.B.); Department of Biostatistics (M.L.B.), Department of Epidemiology (A.L.F.), and Cardiovascular Health Research Unit, Department of Medicine (D.S.S.), University of Washington, Seattle; Department of Medicine (L.D.) and Channing Division of Network Medicine (E.B.R.), Brigham and Women's Hospital, Boston, MA; Department of Medicine, University of Maryland Medical School, Baltimore (J.S.G.); Department of Medicine, University of California San Diego and Veterans Affairs San Diego Healthcare System (J.H.I.); Departments of Medicine, Epidemiology, and Population Health, Albert Einstein College of Medicine, Bronx, NY (J.R.K.); Department of Biochemistry, University of Vermont, Burlington (R.P.T.); and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (K.J.M.).
authors: Jorge R
authors: JR
authors: Kizer
authors: From the Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, MA (I.A., E.B.R.); Department of Medicine, Boston University, MA (N.L.G.); Department of Research and Education, St. Francis Hospital/SUNY at Stony Brook, NY (E.B.); Department of Biostatistics (M.L.B.), Department of Epidemiology (A.L.F.), and Cardiovascular Health Research Unit, Department of Medicine (D.S.S.), University of Washington, Seattle; Department of Medicine (L.D.) and Channing Division of Network Medicine (E.B.R.), Brigham and Women's Hospital, Boston, MA; Department of Medicine, University of Maryland Medical School, Baltimore (J.S.G.); Department of Medicine, University of California San Diego and Veterans Affairs San Diego Healthcare System (J.H.I.); Departments of Medicine, Epidemiology, and Population Health, Albert Einstein College of Medicine, Bronx, NY (J.R.K.); Department of Biochemistry, University of Vermont, Burlington (R.P.T.); and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (K.J.M.).
authors: Eric B
authors: EB
authors: Rimm
authors: From the Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, MA (I.A., E.B.R.); Department of Medicine, Boston University, MA (N.L.G.); Department of Research and Education, St. Francis Hospital/SUNY at Stony Brook, NY (E.B.); Department of Biostatistics (M.L.B.), Department of Epidemiology (A.L.F.), and Cardiovascular Health Research Unit, Department of Medicine (D.S.S.), University of Washington, Seattle; Department of Medicine (L.D.) and Channing Division of Network Medicine (E.B.R.), Brigham and Women's Hospital, Boston, MA; Department of Medicine, University of Maryland Medical School, Baltimore (J.S.G.); Department of Medicine, University of California San Diego and Veterans Affairs San Diego Healthcare System (J.H.I.); Departments of Medicine, Epidemiology, and Population Health, Albert Einstein College of Medicine, Bronx, NY (J.R.K.); Department of Biochemistry, University of Vermont, Burlington (R.P.T.); and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (K.J.M.).
authors: David S
authors: DS
authors: Sicovick
authors: From the Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, MA (I.A., E.B.R.); Department of Medicine, Boston University, MA (N.L.G.); Department of Research and Education, St. Francis Hospital/SUNY at Stony Brook, NY (E.B.); Department of Biostatistics (M.L.B.), Department of Epidemiology (A.L.F.), and Cardiovascular Health Research Unit, Department of Medicine (D.S.S.), University of Washington, Seattle; Department of Medicine (L.D.) and Channing Division of Network Medicine (E.B.R.), Brigham and Women's Hospital, Boston, MA; Department of Medicine, University of Maryland Medical School, Baltimore (J.S.G.); Department of Medicine, University of California San Diego and Veterans Affairs San Diego Healthcare System (J.H.I.); Departments of Medicine, Epidemiology, and Population Health, Albert Einstein College of Medicine, Bronx, NY (J.R.K.); Department of Biochemistry, University of Vermont, Burlington (R.P.T.); and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (K.J.M.).
authors: Russell P
authors: RP
authors: Tracy
authors: From the Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, MA (I.A., E.B.R.); Department of Medicine, Boston University, MA (N.L.G.); Department of Research and Education, St. Francis Hospital/SUNY at Stony Brook, NY (E.B.); Department of Biostatistics (M.L.B.), Department of Epidemiology (A.L.F.), and Cardiovascular Health Research Unit, Department of Medicine (D.S.S.), University of Washington, Seattle; Department of Medicine (L.D.) and Channing Division of Network Medicine (E.B.R.), Brigham and Women's Hospital, Boston, MA; Department of Medicine, University of Maryland Medical School, Baltimore (J.S.G.); Department of Medicine, University of California San Diego and Veterans Affairs San Diego Healthcare System (J.H.I.); Departments of Medicine, Epidemiology, and Population Health, Albert Einstein College of Medicine, Bronx, NY (J.R.K.); Department of Biochemistry, University of Vermont, Burlington (R.P.T.); and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (K.J.M.).
authors: Kenneth J
authors: KJ
authors: Mukamal
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis; D002318:Cardiovascular Diseases / Q000097:blood* / Q000453:epidemiology* / Q000473:pathology; D005260:Female; D005355:Fibrosis; D006333:Heart Failure / Q000097:blood / Q000453:epidemiology / Q000473:pathology; D006801:Humans; D015994:Incidence; D008297:Male; D009203:Myocardial Infarction / Q000097:blood / Q000453:epidemiology / Q000473:pathology; D010446:Peptide Fragments / Q000097:blood*; D011347:Procollagen / Q000097:blood*; D011379:Prognosis; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D020521:Stroke / Q000097:blood / Q000453:epidemiology / Q000473:pathology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000097:blood*; D014481:United States / Q000453:epidemiology
chemical_list: D015415:Biomarkers; D010446:Peptide Fragments; D011347:Procollagen; D016212:Transforming Growth Factor beta; C041876:procollagen Type III-N-terminal peptide; D002097:C-Reactive Protein
keywords: cardiovascular diseases; collagen; epidemiology; heart failure