title: GDF-15 plasma levels in chronic obstructive pulmonary disease are associated with subclinical coronary artery disease.
abstract: Growth differentiation factor-15 (GDF-15), a cytokine associated with cardiovascular mortality, increases during chronic obstructive pulmonary disease (COPD) exacerbations, but any role in stable COPD is unknown. We tested associations between GDF-15 and subclinical coronary atherosclerosis, assessed by coronary artery calcium (CAC) score, in COPD subjects free of clinical cardiovascular disease (CVD).
  
  
  
  Cross-sectional analysis of COPD participants (GOLD stages 2-4) in the COPDGene cohort without CVD at enrollment, using baseline CAC (from non-EKG-gated chest computed tomography) and plasma GDF-15 (by custom ELISA). We used multinomial logistic modeling of GDF-15 associations with CAC, adjusting for demographics, baseline risk (calculated using the HEART: Personal Heart Early Assessment Risk Tool (Budoff et al. 114:1761-1791, 2006) score), smoking history, measures of airflow obstruction, emphysema and airway disease severity.
  
  
  
  Among 694 participants with COPD (47% women, mean age 63.6 years) mean GDF-15 was 1,304 pg/mL, and mean CAC score was 198. Relative to the lower GDF-15 tertile, higher tertiles showed bivariate association with increasing CAC score (mid tertile odds ratio [OR] 1.80, 95% confidence interval [CI] 1.29, 2.51; higher tertile OR 2.86, CI 2.04, 4.02). This association was maintained after additionally adjusting for baseline CVD risk, for co-morbidities and descriptors of COPD severity and impact, markers of cardiac stress (N-terminal pro-B-type natriuretic peptide, troponin T) and of inflammation (Interleukin-6), and in subgroup analysis excluding men, diabetics, current smokers or those with limited ambulation.
  
  
  
  In ever-smokers with COPD free of clinical CVD, GDF-15 contributes independently to subclinical coronary atherosclerosis.
  
  
  
  ClinicalTrials.gov, NCT00608764 . Registered 28 January 2008.
authors.affiliation: Division of Pulmonary & Critical Care Medicine, University of Michigan Health System, 2215 Fuller Road, Ann Arbor, MI, 48105-2303, USA.
authors.forename: Carlos H
authors.initials: CH
authors.lastname: Martinez
authors.affiliation: Division of Pulmonary & Critical Care Medicine, University of Michigan Health System, 2215 Fuller Road, Ann Arbor, MI, 48105-2303, USA.|Research Service, VA Ann Arbor Healthcare System, Ann Arbor, MI, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Freeman
authors.affiliation: Division of Pulmonary & Critical Care Medicine, University of Michigan Health System, 2215 Fuller Road, Ann Arbor, MI, 48105-2303, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Nelson
authors.affiliation: Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Murray
authors.affiliation: Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Budoff
authors.affiliation: The Lung Health Center, Division of Pulmonary, Allergy & Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.|Medical Service, Birmingham Veteran Affairs Medical Center, Birmingham, AL, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Dransfield
authors.affiliation: School of Public Health, University of Colorado, Aurora, CO, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Hokanson
authors.affiliation: Radiology Department, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Ella A
authors.initials: EA
authors.lastname: Kazerooni
authors.affiliation: School of Public Health, University of Colorado, Aurora, CO, USA.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Kinney
authors.affiliation: National Jewish Health & Research Center, Denver, CO, USA.|Pulmonary & Critical Care Medicine Division, Department of Medicine, University of Colorado, Denver, CO, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Regan
authors.affiliation: The Lung Health Center, Division of Pulmonary, Allergy & Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.|Medical Service, Birmingham Veteran Affairs Medical Center, Birmingham, AL, USA.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Wells
authors.affiliation: Pulmonary & Critical Care Medicine Division, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Martinez
authors.affiliation: Division of Pulmonary & Critical Care Medicine, University of Michigan Health System, 2215 Fuller Road, Ann Arbor, MI, 48105-2303, USA.
authors.forename: MeiLan K
authors.initials: MK
authors.lastname: Han
authors.affiliation: Division of Pulmonary & Critical Care Medicine, University of Michigan Health System, 2215 Fuller Road, Ann Arbor, MI, 48105-2303, USA. jlcurtis@umich.edu.|Graduate Program in Immunology, University of Michigan, 2215 Fuller Road, Ann Arbor, MI, 48105-2303, USA. jlcurtis@umich.edu.|Medical Service, VA Ann Arbor Healthcare System, 2215 Fuller Road, Ann Arbor, MI, 48105-2303, USA. jlcurtis@umich.edu.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Curtis
mesh_terms: D000368:Aged; D058070:Asymptomatic Diseases; D015415:Biomarkers / Q000097:blood; D015984:Causality; D015897:Comorbidity; D003324:Coronary Artery Disease / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology*; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000097:blood*; D006801:Humans; D015994:Incidence; D008297:Male; D008824:Michigan / Q000453:epidemiology; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology*; D015203:Reproducibility of Results; D012307:Risk Factors; D012680:Sensitivity and Specificity
chemical_list: D015415:Biomarkers; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15
keywords: Adult; Biomarkers; Coronary Artery Disease; Cross-Sectional Studies; Multivariate Analysis; Risk Factors