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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.

SUBMITTER: Martinez CH

PROVIDER: S-EPMC5331711 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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

Martinez Carlos H CH Freeman Christine M CM Nelson Joshua D JD Murray Susan S Wang Xin X Budoff Matthew J MJ Dransfield Mark T MT Hokanson John E JE Kazerooni Ella A EA Kinney Gregory L GL Regan Elizabeth A EA Wells J Michael JM Martinez Fernando J FJ Han MeiLan K MK Curtis Jeffrey L JL

Respiratory research 20170228 1

<h4>Background</h4>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).<h4>Methods</h4>Cross-sectional analysis of COPD participants (GOLD stages 2 ...[more]

PMID: 28245821

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Project description:The metalloproteinase family of a disintegrin and metalloproteinase with thrombospondin motifs-7 (ADAMTS-7) was reported to be a novel locus associated with human coronary artery disease. This study aimed to investigate plasma ADAMTS-7 levels in stable obstructive CAD patients and elucidate the relationship between plasma ADAMTS-7 levels and the severity of CAD assessed by the Syntax score.This was a single center cross-sectional study performed in 182 CAD patients. ELISA was used to measure plasma ADAMTS-7 levels. All patients were divided into subgroup according to the ADAMTS-7 median in this cohort: high group with ADAMTS-7 ≥0.99 ng/mL and low group with ADAMTS-7 <0.99 ng/mL. Furthermore, all patients were divided into tertiles according to their Syntax scores (low group: Syntax score ≤10.0; moderate group: 10.0 <Syntax score ≤18.0; high group: Syntax score >18.0). We followed up the participants continuously until the first major adverse cardiovascular event (MACE) for a mean time of 22.0 months.Plasma ADAMTS-7 levels in the high Syntax score group were significantly higher compared with the low Syntax score group (3.29 [0.08-26.3] ng/mL vs 1.24 [0.15-8.78] ng/mL, P = 0.010). Plasma ADAMTS-7 levels were significantly positively correlated with the Syntax score tertiles (r = 0.157, P = 0.035). Logistic regression analysis indicated that the plasma ADAMTS-7 level was one of the independent predictors for the Syntax score tertiles (B = 1.118, 95% CI: 1.194-7.830, P = 0.020), together with HbA1c (B = 0.946, 95% CI: 1.248-5.312, P = 0.010), uric acid (B = -0.019, 95% CI: 0.974-0.988, P<0.001), and coronary artery calcium score (B = -0.001, 95% CI: 0.998-0.999, P < 0.001). Compared with the low ADAMTS-7 group, the high ADAMTS-7 group had significantly higher Syntax score (17.10±8.42 vs 14.96 ± 8.11, P = 0.047). Kaplan-Meier analysis showed patients in the high plasma ADAMTS-7 group tend to have a lower event-free survival rate than patients in the low plasma ADAMTS-7 group, unfortunately, no difference was detected (86.8% vs 88.0%, log rank = 0.314, P = 0.575).The plasma ADAMTS-7 level was positively correlated with the Syntax score significantly. The elevated plasma ADAMTS-7 level may be involved in the severity of disease in patients with stable coronary artery disease.

Project description:BackgroundAlthough T cells, especially CD8+, have been implicated in chronic obstructive pulmonary disease (COPD) pathogenesis, their role during acute exacerbations (AE-COPD) is uncertain.MethodsWe recruited subjects with COPD and a history of previous AE-COPD and studied them quarterly to collect blood and spontaneously expectorated sputum while stable. During exacerbations (defined by a change in symptoms plus physician diagnosis and altered medications), we collected blood and sputum before administering antibiotics or steroids. We used flow cytometry to identify leukocytes in peripheral blood, plus Luminex® analysis or ELISA to determine levels of inflammatory biomarkers in serum and sputum supernatants.ResultsOf 33 enrolled subjects, 13 participated in multiple stable visits and had ≥1 AE-COPD visit, yielding 18 events with paired data. Flow cytometric analyses of peripheral blood demonstrated decreased CD4+ and CD8+ T cells during AE-COPD (both absolute and as a percentage of all leukocytes) and significantly increased granulocytes, all of which correlated significantly with serum C-reactive protein (CRP) concentrations. No change was observed in other leukocyte populations during AE-COPD, although the percentage of BDCA-1+ dendritic cells expressing the activation markers CD40 and CD86 increased. During AE-COPD, sICAM-1, sVCAM-1, IL-10, IL-15 and GDF-15 increased in serum, while in sputum supernatants, CRP and TIMP-2 increased and TIMP-1 decreased.ConclusionsThe decrease in CD4+ and CD8+ T cells (but not other lymphocyte subsets) in peripheral blood during AE-COPD may indicate T cell extravasation into inflammatory sites or organized lymphoid tissues. GDF-15, a sensitive marker of cardiopulmonary stress that in other settings independently predicts reduced long-term survival, is acutely increased in AE-COPD. These results extend the concept that AE-COPD are systemic inflammatory events to which adaptive immune mechanisms contribute.Trial registrationNCT00281216 , ClinicalTrials.gov.

Dataset Information

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

Publications

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

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