Centrilobular emphysema and coronary artery calcification: mediation analysis in the SPIROMICS cohort

For The Spiromics Investigators ,Surya P Bhatt,Wassim W Labaki,R Graham Barr,Rekha Ramachandran,Swati P Deshmane,Fernando J Martinez,Elizabeth C Oelsner,Meilan K Han,Sandeep Bodduluri,J Michael Wells,Hrudaya P Nath,Mark T Dransfield,Jubal R Watts,Prescott G Woodruff,Sushil Sonavane,Nina L J Terry,Young-Il Kim

doi:10.1186/s12931-018-0946-1

Abstract

BackgroundChronic obstructive pulmonary disease (COPD) is associated with a two-to-five fold increase in the risk of coronary artery disease independent of shared risk factors. This association is hypothesized to be mediated by systemic inflammation but this link has not been established.MethodsWe included 300 participants enrolled in the SPIROMICS cohort, 75 each of lifetime non-smokers, smokers without airflow obstruction, mild-moderate COPD, and severe-very severe COPD. We quantified emphysema and airway disease on computed tomography, characterized visual emphysema subtypes (centrilobular and paraseptal) and airway disease, and used the Weston visual score to quantify coronary artery calcification (CAC). We used the Sobel test to determine whether markers of systemic inflammation mediated a link between spirometric and radiographic features of COPD and CAC.ResultsFEV1/FVC but not quantitative emphysema or airway wall thickening was associated with CAC (p = 0.036), after adjustment for demographics, diabetes mellitus, hypertension, statin use, and CT scanner type. To explain this discordance, we examined visual subtypes of emphysema and airway disease, and found that centrilobular emphysema but not paraseptal emphysema or bronchial thickening was independently associated with CAC (p = 0.019). MMP3, VCAM1, CXCL5 and CXCL9 mediated 8, 8, 7 and 16% of the association between FEV1/FVC and CAC, respectively. Similar biomarkers partially mediated the association between centrilobular emphysema and CAC.ConclusionsThe association between airflow obstruction and coronary calcification is driven primarily by the centrilobular subtype of emphysema, and is linked through bioactive molecules implicated in the pathogenesis of atherosclerosis.Trial RegistrationClinicalTrials.gov: Identifier: NCT01969344.

Highlights

Chronic obstructive pulmonary disease (COPD) is associated with a two-to-five fold increase in the risk of coronary artery disease [1, 2] and epidemiologic studies indicate that this relationship is independent of shared risk factors such as age and cigarette smoking [1, 2]
The systemic inflammation observed in other chronic diseases is associated with atherosclerosis, [13] and it is plausible that it is the prime driver of coronary artery disease in COPD
We found a partial mediation effect for MMP3, VCAM1, CXCL5 and CXCL9 for the association between Forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) and log CAC, and these biomarkers partially mediated approximately 8, 8, 7 and 16% of the effect, respectively

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is associated with a two-to-five fold increase in the risk of coronary artery disease [1, 2] and epidemiologic studies indicate that this relationship is independent of shared risk factors such as age and cigarette smoking [1, 2]. Chronic obstructive pulmonary disease (COPD) is associated with a two-to-five fold increase in the risk of coronary artery disease independent of shared risk factors. This association is hypothesized to be mediated by systemic inflammation but this link has not been established

Methods

Results

Discussion

Conclusion