title: Circulating GDF-15 levels predict future secondary manifestations of cardiovascular disease explicitly in women but not men with atherosclerosis.
abstract: BACKGROUND
  Elevated serum levels of growth differentiation factor-15 (GDF-15), is an established risk factor for a range of cardiovascular diseases. We aimed to evaluate the predictive value of plasma GDF-15 as a biomarker for secondary cardiovascular events (CVE) in patients with atherosclerosis undergoing carotid endarterectomy (CEA). Secondly, we determined whether plasma GDF-15 was associated with carotid plaque characteristics.
  
  
  METHODS
  Circulating GDF-15 levels were determined by Luminex assay in a cohort of 1056 patients from the Athero-Express biobank. Composite endpoint was defined as major CVE, death and peripheral vascular interventions. Findings were validated in 473 patients from the independent Carotid Plaque Imaging Project biobank.
  
  
  RESULTS
  GDF-15 levels did not associate with secondary CVE in the total cohort. However, following a significant interaction with sex, it was found to be strongly, independently predictive of secondary CVE in women but not men (quartile 4 vs. quartile 1: HR 3.04 [95% CI 1.35-6.86], p=0.007 in women vs. HR 0.96 [95% CI 0.66-1.40], p=0.845 in men). This was also observed in the validation cohort (women: HR 2.28 [95% CI 1.04-5.05], p=0.041), albeit dependent upon renal function. In addition, GDF-15 was associated with the presence of plaque smooth muscle cells and calcification.
  
  
  CONCLUSIONS
  High circulating GDF-15 levels are predictive of secondary CVE in women but not in men with carotid atherosclerotic disease undergoing CEA, suggesting a potential use for GDF-15 as a biomarker for secondary prevention in women. Sex differences in the role of GDF-15 in atherosclerotic disease deserve further interest.
authors.affiliation: Laboratory for Experimental Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Clinical Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands.
authors.forename: Aisha
authors.initials: A
authors.lastname: Gohar
authors.affiliation: Experimental Cardiovascular Research Unit, and Cardiology (coronary) Clinic, Department of Clinical Sciences, Malmö, Skåne University Hospital, Lund University, Sweden.
authors.forename: Isabel
authors.initials: I
authors.lastname: Gonçalves
authors.affiliation: Laboratory for Experimental Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Joyce
authors.initials: J
authors.lastname: Vrijenhoek
authors.affiliation: Laboratory for Experimental Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: Haitjema
authors.affiliation: Laboratory for Experimental Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Ian
authors.initials: I
authors.lastname: van Koeverden
authors.affiliation: Experimental Cardiovascular Research Unit, Department of Clinical Sciences, Malmö, Skåne University Hospital, Lund University, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Nilsson
authors.affiliation: Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Gert J
authors.initials: GJ
authors.lastname: de Borst
authors.affiliation: Department of Vascular Surgery, St. Antonius Hospital Nieuwegein, Nieuwegein, the Netherlands.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: de Vries
authors.affiliation: Laboratory for Experimental Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands; Laboratory for clinical chemistry and haematology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.affiliation: Laboratory for Experimental Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Hester M
authors.initials: HM
authors.lastname: den Ruijter
authors.affiliation: Experimental Cardiovascular Research Unit, Department of Clinical Sciences, Malmö, Skåne University Hospital, Lund University, Sweden.
authors.forename: Harry
authors.initials: H
authors.lastname: Björkbacka
authors.affiliation: Laboratory for Experimental Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands; Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: S.C.A.deJager@umcutrecht.nl.
authors.forename: Saskia C A
authors.initials: SCA
authors.lastname: de Jager
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood* / Q000175:diagnosis; D002340:Carotid Artery Diseases / Q000097:blood* / Q000175:diagnosis; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D055436:Growth Differentiation Factor 15 / Q000097:blood*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012727:Sex Characteristics
chemical_list: D015415:Biomarkers; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15
keywords: Atherosclerosis; Biomarker; GDF-15; Prognosis; Secondary outcome; Women