GDF-15 plasma levels in chronic obstructive pulmonary disease are associated with subclinical coronary artery disease

Abstract

Background: 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).

Methods: 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.

Results: 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.

Conclusions: In ever-smokers with COPD free of clinical CVD, GDF-15 contributes independently to subclinical coronary atherosclerosis.

Trial registration: ClinicalTrials.gov, NCT00608764 . Registered 28 January 2008.

Keywords: Adult; Biomarkers; Coronary Artery Disease; Cross-Sectional Studies; Multivariate Analysis; Risk Factors.

Fig. 1

CAC scores & GDF-15 plasma levels by sex. CAC scores were determined by analysis of non-EKG-gated HRCT and GDF-15 plasma levels were measured by ELISA. a, CAC scores, as Agatston Units; b, GDF-15 concentrations, as pg/mL. Data are median (bar), 25th & 75th percentiles (box), 5th & 95th percentiles (whiskers) with outliers shown as individual points. p-values by Mann-Whitney test

Fig. 2

Correlation between Log₂ CAC & GDF-15 plasma concentrations. p-value by Spearman correlation (r _S), goodness of fit (R²) by linear regression (n = 694)

Fig. 3

Distribution of Log₂ CAC by GDF-15 tertiles. Lower tertile (<966 pg/mL) (n = 231), mid tertile (967-1438 pg/mL) (n = 232), higher tertile (>1439 pg/mL) (n = 231)