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

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Abstract

Background

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

We 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.

Results

FEV ₁/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 FEV ₁/FVC and CAC, respectively. Similar biomarkers partially mediated the association between centrilobular emphysema and CAC.

Conclusions

The 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 Registration

ClinicalTrials.gov: Identifier: NCT01969344.

Electronic supplementary material

The online version of this article (10.1186/s12931-018-0946-1) contains supplementary material, which is available to authorized users.

Related collections

Most cited references 41

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M Cybulsky, K Iiyama, H. Li … (2001)

VCAM-1 and ICAM-1 are endothelial adhesion molecules of the Ig gene superfamily that may participate in atherogenesis by promoting monocyte accumulation in the arterial intima. Both are expressed in regions predisposed to atherosclerosis and at the periphery of established lesions, while ICAM-1 is also expressed more broadly. To evaluate functions of VCAM-1 in chronic disease, we disrupted its fourth Ig domain, producing the murine Vcam1(D4D) allele. VCAM-1(D4D) mRNA and protein were reduced to 2-8% of wild-type allele (Vcam1(+)) levels but were sufficient to partially rescue the lethal phenotype of VCAM-1-null embryos. After crossing into the LDL receptor-null background, Vcam1(+/+) and Vcam1(D4D/D4D) paired littermates were generated from heterozygous intercrosses and fed a cholesterol-enriched diet for 8 weeks. The area of early atherosclerotic lesions in the aorta, quantified by en face oil red O staining, was reduced significantly in Vcam1(D4D/D4D) mice, although cholesterol levels, lipoprotein profiles, and numbers of circulating leukocytes were comparable to wild-type. In contrast, deficiency of ICAM-1 either alone or in combination with VCAM-1 deficiency did not alter nascent lesion formation. Therefore, although expression of both VCAM-1 and ICAM-1 is upregulated in atherosclerotic lesions, our data indicate that VCAM-1 plays a dominant role in the initiation of atherosclerosis.

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CT-Definable Subtypes of Chronic Obstructive Pulmonary Disease: A Statement of the Fleischner Society.

David A Lynch, John Austin, James C Hogg … (2015)

The purpose of this statement is to describe and define the phenotypic abnormalities that can be identified on visual and quantitative evaluation of computed tomographic (CT) images in subjects with chronic obstructive pulmonary disease (COPD), with the goal of contributing to a personalized approach to the treatment of patients with COPD. Quantitative CT is useful for identifying and sequentially evaluating the extent of emphysematous lung destruction, changes in airway walls, and expiratory air trapping. However, visual assessment of CT scans remains important to describe patterns of altered lung structure in COPD. The classification system proposed and illustrated in this article provides a structured approach to visual and quantitative assessment of COPD. Emphysema is classified as centrilobular (subclassified as trace, mild, moderate, confluent, and advanced destructive emphysema), panlobular, and paraseptal (subclassified as mild or substantial). Additional important visual features include airway wall thickening, inflammatory small airways disease, tracheal abnormalities, interstitial lung abnormalities, pulmonary arterial enlargement, and bronchiectasis.

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Computed tomographic measurements of airway dimensions and emphysema in smokers. Correlation with lung function.

Y Nakano, S Muro, H Sakai … (2000)

Chronic obstructive pulmonary disease (COPD) is characterized by the presence of airflow obstruction caused by emphysema or airway narrowing, or both. Low attenuation areas (LAA) on computed tomography (CT) have been shown to represent macroscopic or microscopic emphysema, or both. However CT has not been used to quantify the airway abnormalities in smokers with or without airflow obstruction. In this study, we used CT to evaluate both emphysema and airway wall thickening in 114 smokers. The CT measurements revealed that a decreased FEV(1) (%predicted) is associated with an increase of airway wall area and an increase of emphysema. Although both airway wall thickening and emphysema (LAA) correlated with measurements of lung function, stepwise multiple regression analysis showed that the combination of airway and emphysema measurements improved the estimate of pulmonary function test abnormalities. We conclude that both CT measurements of airway dimensions and emphysema are useful and complementary in the evaluation of the lung of smokers.

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Author and article information

Contributors

Surya P. Bhatt:

ORCID: http://orcid.org/0000-0002-8418-4497

205-934-6148 , sbhatt@uabmc.edu

Journal

Journal ID (nlm-ta): Respir Res

Journal ID (iso-abbrev): Respir. Res

Title: Respiratory Research

Publisher: BioMed Central (London )

ISSN (Print): 1465-9921

ISSN (Electronic): 1465-993X

Publication date (Electronic): 18 December 2018

Publication date PMC-release: 18 December 2018

Publication date (Print): 2018

Volume: 19

Electronic Location Identifier: 257

Affiliations

[1 ]ISNI 0000000106344187, GRID grid.265892.2, Division of Pulmonary, Allergy and Critical Care Medicine and Lung Health Center, , University of Alabama at Birmingham, ; THT 422, 1720, 2nd Avenue South, Birmingham, AL 35294 USA

[2 ]ISNI 0000000106344187, GRID grid.265892.2, UAB Lung Imaging Core, , University of Alabama at Birmingham, ; Birmingham, AL 35294 USA

[3 ]ISNI 0000000106344187, GRID grid.265892.2, Department of Radiology, , University of Alabama at Birmingham, ; Birmingham, AL 35294 USA

[4 ]ISNI 0000000106344187, GRID grid.265892.2, Department of Preventive Medicine, , University of Alabama at Birmingham, ; Birmingham, AL 35294 USA

[5 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, , University California San Francisco, ; San Francisco, CA 94143 USA

[6 ]Birmingham Veterans Affairs Hospital, Birmingham, AL 35294 USA

[7 ]ISNI 0000 0001 2285 2675, GRID grid.239585.0, Division of Pulmonary, Allergy and Critical Care Medicine, , Columbia University Medical Center, ; New York, NY 10032 USA

[8 ]ISNI 0000000086837370, GRID grid.214458.e, Division of Pulmonary and Critical Care Medicine, , University of Michigan, ; Ann Arbor, MI 48109 USA

[9 ]ISNI 0000 0004 1936 8753, GRID grid.137628.9, Division of Pulmonary and Critical Care Medicine, , Weill Cornell School of Medicine, ; New York, NY 10065 USA

Author information

Surya P. Bhatt http://orcid.org/0000-0002-8418-4497

Article

Publisher ID: 946

DOI: 10.1186/s12931-018-0946-1

PMC ID: 6299495

PubMed ID: 30563576

SO-VID: 56c5da62-f4ae-4d39-8059-e1e3544c3daf

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 5 July 2018

Date accepted : 20 November 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;

Award ID: K23HL133438

Award ID: HHSN268200900013C

Award ID: HHSN268200900014C

Award ID: HHSN268200900015C

Award ID: HHSN268200900016C

Award ID: HHSN268200900017C

Award ID: HHSN268200900018C

Award ID: HHSN268200900019C

Award ID: HHSN268200900020C

Award Recipient : Surya P. Bhatt

Custom metadata

ScienceOpen disciplines: Respiratory medicine

Keywords: emphysema,copd,coronary artery calcification,cardiovascular disease,mediators

Data availability:

ScienceOpen disciplines: Respiratory medicine

Keywords: emphysema, copd, coronary artery calcification, cardiovascular disease, mediators

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

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Abstract

Background

Methods

Results

Conclusions

Trial Registration

Electronic supplementary material

Related collections

Core Readings in Statistical Mediation Analysis

Most cited references 41

A major role for VCAM-1, but not ICAM-1, in early atherosclerosis.

CT-Definable Subtypes of Chronic Obstructive Pulmonary Disease: A Statement of the Fleischner Society.

Computed tomographic measurements of airway dimensions and emphysema in smokers. Correlation with lung function.

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