title: Associations of Circulating Growth Differentiation Factor-15 and ST2 Concentrations With Subclinical Vascular Brain Injury and Incident Stroke.
abstract: OBJECTIVE
  Growth differentiation factor-15 (GDF-15) and soluble (s)ST2 are markers of cardiac and vascular stress. We investigated the associations between circulating concentrations of these biomarkers and incident stroke and subclinical vascular brain injury in a sample from the Framingham Offspring cohort.
  
  
  METHODS
  We followed 3374 stroke- and dementia-free individuals (mean age, 59.0±9.7 years; 53% women) attending the Framingham Offspring sixth examination cycle 11.8±3.0 years for incident stroke. A subsample of 2463 individuals underwent brain magnetic resonance imaging and neuropsychological testing ≈4.0±1.7 years after the sixth examination.
  
  
  RESULTS
  After adjustment for traditional cardiovascular risk factors, B-type natriuretic peptide, high-sensitivity C-reactive protein, and urine albumin levels, higher stress biomarker levels were associated cross-sectionally with lower brain volumes (β coefficients for intracranial volume comparing fourth [Q4] versus first biomarker [Q1] quartiles: -0.71% for GDF-15; P=0.002 and 0.47% for sST2; P=0.02) and worse performance on the visual reproduction test (β coefficients for Q4 versus Q1: -0.62 for GDF-15; P=0.009 and -0.40 for sST2; P=0.04). Higher GDF-15 concentrations were also associated with greater log-transformed white-matter hyperintensity volumes (β for Q4 versus Q1=0.19; P=0.01). Prospectively, a total of 203 (6%) individuals developed incident stroke/transient ischemic attack during follow-up. After multivariable adjustment, sST2 remained significantly associated with stroke/transient ischemic attack, hazard ratio for Q4 versus Q1 of 1.76, 95% confidence interval of 1.06 to 2.92, and P=0.03.
  
  
  CONCLUSIONS
  Circulating GDF-15 and sST2 are associated with subclinical brain injury and cognitive impairment. Higher sST2 concentrations are also associated with incident stroke, suggesting potential links between cardiac stress biomarkers and brain injury.
authors.affiliation: From the Framingham Heart Study, MA (C.A., A.B., T.J.W., R.S.V., S.S.); Department of Cardiology, Gentofte Hospital, University of Copenhagen, Denmark (C.A.); Department of Biostatistics, Boston University School of Public Health, MA (S.R.P., A.B.); Department of Neurology (A.B., S.S.) and Section of Preventive Medicine and Cardiology (R.S.V.), Boston University School of Medicine, MA; Department of Neurology, University of California at Davis, Sacramento (C.D.); Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany (K.C.W.); Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN (T.J.W.); and Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston (J.L.J.). ca@heart.dk.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Andersson
authors.affiliation: From the Framingham Heart Study, MA (C.A., A.B., T.J.W., R.S.V., S.S.); Department of Cardiology, Gentofte Hospital, University of Copenhagen, Denmark (C.A.); Department of Biostatistics, Boston University School of Public Health, MA (S.R.P., A.B.); Department of Neurology (A.B., S.S.) and Section of Preventive Medicine and Cardiology (R.S.V.), Boston University School of Medicine, MA; Department of Neurology, University of California at Davis, Sacramento (C.D.); Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany (K.C.W.); Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN (T.J.W.); and Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston (J.L.J.).
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Preis
authors.affiliation: From the Framingham Heart Study, MA (C.A., A.B., T.J.W., R.S.V., S.S.); Department of Cardiology, Gentofte Hospital, University of Copenhagen, Denmark (C.A.); Department of Biostatistics, Boston University School of Public Health, MA (S.R.P., A.B.); Department of Neurology (A.B., S.S.) and Section of Preventive Medicine and Cardiology (R.S.V.), Boston University School of Medicine, MA; Department of Neurology, University of California at Davis, Sacramento (C.D.); Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany (K.C.W.); Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN (T.J.W.); and Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston (J.L.J.).
authors.forename: Alexa
authors.initials: A
authors.lastname: Beiser
authors.affiliation: From the Framingham Heart Study, MA (C.A., A.B., T.J.W., R.S.V., S.S.); Department of Cardiology, Gentofte Hospital, University of Copenhagen, Denmark (C.A.); Department of Biostatistics, Boston University School of Public Health, MA (S.R.P., A.B.); Department of Neurology (A.B., S.S.) and Section of Preventive Medicine and Cardiology (R.S.V.), Boston University School of Medicine, MA; Department of Neurology, University of California at Davis, Sacramento (C.D.); Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany (K.C.W.); Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN (T.J.W.); and Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston (J.L.J.).
authors.forename: Charles
authors.initials: C
authors.lastname: DeCarli
authors.affiliation: From the Framingham Heart Study, MA (C.A., A.B., T.J.W., R.S.V., S.S.); Department of Cardiology, Gentofte Hospital, University of Copenhagen, Denmark (C.A.); Department of Biostatistics, Boston University School of Public Health, MA (S.R.P., A.B.); Department of Neurology (A.B., S.S.) and Section of Preventive Medicine and Cardiology (R.S.V.), Boston University School of Medicine, MA; Department of Neurology, University of California at Davis, Sacramento (C.D.); Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany (K.C.W.); Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN (T.J.W.); and Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston (J.L.J.).
authors.forename: Kai C
authors.initials: KC
authors.lastname: Wollert
authors.affiliation: From the Framingham Heart Study, MA (C.A., A.B., T.J.W., R.S.V., S.S.); Department of Cardiology, Gentofte Hospital, University of Copenhagen, Denmark (C.A.); Department of Biostatistics, Boston University School of Public Health, MA (S.R.P., A.B.); Department of Neurology (A.B., S.S.) and Section of Preventive Medicine and Cardiology (R.S.V.), Boston University School of Medicine, MA; Department of Neurology, University of California at Davis, Sacramento (C.D.); Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany (K.C.W.); Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN (T.J.W.); and Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston (J.L.J.).
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wang
authors.affiliation: From the Framingham Heart Study, MA (C.A., A.B., T.J.W., R.S.V., S.S.); Department of Cardiology, Gentofte Hospital, University of Copenhagen, Denmark (C.A.); Department of Biostatistics, Boston University School of Public Health, MA (S.R.P., A.B.); Department of Neurology (A.B., S.S.) and Section of Preventive Medicine and Cardiology (R.S.V.), Boston University School of Medicine, MA; Department of Neurology, University of California at Davis, Sacramento (C.D.); Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany (K.C.W.); Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN (T.J.W.); and Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston (J.L.J.).
authors.forename: James L
authors.initials: JL
authors.lastname: Januzzi
authors.affiliation: From the Framingham Heart Study, MA (C.A., A.B., T.J.W., R.S.V., S.S.); Department of Cardiology, Gentofte Hospital, University of Copenhagen, Denmark (C.A.); Department of Biostatistics, Boston University School of Public Health, MA (S.R.P., A.B.); Department of Neurology (A.B., S.S.) and Section of Preventive Medicine and Cardiology (R.S.V.), Boston University School of Medicine, MA; Department of Neurology, University of California at Davis, Sacramento (C.D.); Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany (K.C.W.); Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN (T.J.W.); and Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston (J.L.J.).
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.affiliation: From the Framingham Heart Study, MA (C.A., A.B., T.J.W., R.S.V., S.S.); Department of Cardiology, Gentofte Hospital, University of Copenhagen, Denmark (C.A.); Department of Biostatistics, Boston University School of Public Health, MA (S.R.P., A.B.); Department of Neurology (A.B., S.S.) and Section of Preventive Medicine and Cardiology (R.S.V.), Boston University School of Medicine, MA; Department of Neurology, University of California at Davis, Sacramento (C.D.); Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany (K.C.W.); Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN (T.J.W.); and Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston (J.L.J.).
authors.forename: Sudha
authors.initials: S
authors.lastname: Seshadri
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D020214:Cerebrovascular Trauma / Q000097:blood*; D003072:Cognition Disorders / Q000097:blood*; D003430:Cross-Sectional Studies; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000097:blood*; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D002546:Ischemic Attack, Transient / Q000097:blood*; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011956:Receptors, Cell Surface / Q000097:blood*; D020521:Stroke / Q000097:blood*
chemical_list: D015415:Biomarkers; D055436:Growth Differentiation Factor 15; C079241:IL1RL1 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D011956:Receptors, Cell Surface
keywords: follow-up studies; growth differentiation factor-15; magnetic resonance imaging; neuroimaging; stroke