Circulating adhesion molecules and subclinical interstitial lung disease: the Multi-Ethnic Study of Atherosclerosis.

Adhesion molecules may contribute to the development of interstitial lung disease (ILD) and have been proposed as prognostic biomarkers in idiopathic pulmonary fibrosis. Our objective was to determine whether the circulating adhesion molecules soluble intracellular adhesion molecule (sICAM)-1, soluble vascular cell adhesion molecule (sVCAM)-1 and P-selectin are associated with subclinical ILD in community-dwelling adults.The Multi-Ethnic Study of Atherosclerosis enrolled males and females aged 45-84 years from six communities in the United States in 2000-2002. High attenuation areas were defined as the percentage of imaged lung volume with attenuation -600--250 HU on cardiac computed tomography (CT). Interstitial lung abnormalities were visually assessed on full-lung CT. Spirometry was performed on a subset of individuals. ILD hospitalisations and deaths were adjudicated.In fully adjusted analyses, higher levels of sICAM-1, sVCAM-1 and P-selectin were associated with greater high attenuation areas (2.94%, 95% CI 1.80-4.07%; 1.24%, 95% CI 0.14-2.35%; and 1.58%, 95% CI 0.92-2.23%, respectively), and greater rate of ILD hospitalisations (HR 1.36, 95% CI 1.03-1.80; 1.40, 95% CI 1.07-1.85; and 2.03, 95% CI 1.16-3.5, respectively). sICAM-1 was associated with greater prevalence of interstitial lung abnormalities (OR 1.39, 95% CI 1.13-1.71). sICAM-1 and P-selectin were associated with lower forced vital capacity (44 mL, 95% CI 12-76 mL and 29 mL, 95% CI 8-49 mL, respectively). sVCAM-1 and P-selectin were associated with increased risk of ILD death (HR 2.15, 95% CI 1.26-3.64 and 3.61, 95% CI 1.54-8.46, respectively).Higher levels of circulating sICAM-1, sVCAM-1 and P-selectin are independently associated with CT and spirometric measures of subclinical ILD, and increased rate of adjudicated ILD events among community-dwelling adults.

Ambient air pollution and pulmonary vascular volume on computed tomography: the MESA Air Pollution and Lung cohort studies.

BACKGROUND: Air pollution alters small pulmonary vessels in animal models. We hypothesised that long-term ambient air pollution exposure would be associated with differences in pulmonary vascular volumes in a population-based study. METHODS: The Multi-Ethnic Study of Atherosclerosis recruited adults in six US cities. Personalised long-term exposures to ambient black carbon, nitrogen dioxide (NO2), oxides of nitrogen (NO x ), particulate matter with a 50% cut-off aerodynamic diameter of <2.5 µm (PM2.5) and ozone were estimated using spatiotemporal models. In 2010-2012, total pulmonary vascular volume was measured as the volume of detectable pulmonary arteries and veins, including vessel walls and luminal blood volume, on noncontrast chest computed tomography (TPVVCT). Peripheral TPVVCT was limited to the peripheral 2 cm to isolate smaller vessels. Linear regression adjusted for demographics, anthropometrics, smoking, second-hand smoke, renal function and scanner manufacturer. RESULTS: The mean±sd age of the 3023 participants was 69.3±9.3 years; 46% were never-smokers. Mean exposures were 0.80 µg·m-3 black carbon, 14.6 ppb NO2 and 11.0 µg·m-3 ambient PM2.5. Mean±sd peripheral TPVVCT was 79.2±18.2 cm3 and TPVVCT was 129.3±35.1 cm3. Greater black carbon exposure was associated with a larger peripheral TPVVCT, including after adjustment for city (mean difference 0.41 (95% CI 0.03-0.79) cm3 per interquartile range; p=0.036). Associations for peripheral TPVVCT with NO2 were similar but nonsignificant after city adjustment, while those for PM2.5 were of similar magnitude but nonsignificant after full adjustment. There were no associations for NO x or ozone, or between any pollutant and TPVVCT. CONCLUSIONS: Long-term black carbon exposure was associated with a larger peripheral TPVVCT, suggesting diesel exhaust may contribute to remodelling of small pulmonary vessels in the general population.

Association of thrombocytosis with COPD morbidity: the SPIROMICS and COPDGene cohorts.

BACKGROUND: Thrombocytosis has been associated with COPD prevalence and increased all-cause mortality in patients with acute exacerbation of COPD (AECOPD); but whether it is associated with morbidity in stable COPD is unknown. This study aims to determine the association of thrombocytosis with COPD morbidity including reported AECOPD, respiratory symptoms and exercise capacity. METHODS: Participants with COPD were included from two multi-center observational studies (SPIROMICS and COPDGene). Cross-sectional associations of thrombocytosis (platelet count ≥350 × 109/L) with AECOPD during prior year (none vs. any), exertional dyspnea (modified Medical Research Council (mMRC) score ≥ 2), COPD Assessment Test (CAT) score ≥ 10, six-minute-walk distance (6MWD), and St. George Respiratory questionnaire (SGRQ) were modeled using multivariable logistic or linear regression. A pooled effect estimate for thrombocytosis was produced using meta-analysis of data from both studies. RESULTS: Thrombocytosis was present in 124/1820 (6.8%) SPIROMICS participants and 111/2185 (5.1%) COPDGene participants. In meta-analysis thrombocytosis was associated with any AECOPD (adjusted odds ratio [aOR] 1.5; 95% confidence interval [95% CI]: 1.1-2.0), severe AECOPD (aOR 1.5; 95% CI: 1.1-2.2), dyspnea (mMRC ≥ 2 aOR 1.4; 95% CI: 1.0-1.9), respiratory symptoms (CAT ≥ 10 aOR 1.6; 95% CI: 1.1-2.4), and higher SGRQ score (ß 2.7; 95% CI: 0.5, 5). Thrombocytosis was also associated with classification into Global Initiative for Chronic Obstructive Lung Disease (GOLD) group D (aOR 1.7 95% CI: 1.2-2.4). CONCLUSIONS: Thrombocytosis was associated with higher likelihood of prior exacerbation and worse symptoms. Platelet count, a commonly measured clinical assay, may be a biomarker for moderate-severe COPD symptoms, guide disease classification and intensity of treatment. Future longitudinal studies investigating the role of platelets in COPD progression may be warranted. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01969344 (SPIROMICS) and NCT00608764 (COPDGene).

Physical activity and right ventricular structure and function. The MESA-Right Ventricle Study.

RATIONALE: Intense exercise in elite athletes is associated with increased left ventricular (LV) and right ventricular (RV) mass and volumes. However, the effect of physical activity on the RV in an older community-based population is unknown. OBJECTIVES: We studied the association between levels of physical activity in adults and RV mass and volumes. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac magnetic resonance imaging on community-based participants without clinical cardiovascular disease. RV volumes were determined from manually contoured endocardial margins. RV mass was determined from the difference between epicardial and endocardial volumes multiplied by the specific gravity of myocardium. Metabolic equivalent-minutes/day were calculated from the self-reported frequency, duration, and intensity of physical activity. MEASUREMENTS AND MAIN RESULTS: The study sample (n = 1,867) was aged 61.8 ± 10 years, 48% male, 44% white, 27% African American, 20% Hispanic, and 9% Chinese. Higher levels of moderate and vigorous physical activity were linearly associated with higher RV mass (P = 0.02) after adjusting for demographics, anthropometrics, smoking, cholesterol, diabetes mellitus, hypertension, and LV mass. Higher levels of intentional exercise (physical activity done for the sole purpose of conditioning or fitness) were nonlinearly associated with RV mass independent of LV mass (P = 0.03). There were similar associations between higher levels of physical activity and larger RV volumes. CONCLUSIONS: Higher levels of physical activity in adults were associated with greater RV mass independent of the associations with LV mass; similar results were found for RV volumes. Exercise-associated RV remodeling may have important clinical implications.

The Association of Ambient Air Pollution with Sleep Apnea: The Multi-Ethnic Study of Atherosclerosis.

RATIONALE: Air pollution may influence sleep through airway inflammation or autonomic nervous system pathway alterations. Epidemiological studies may provide evidence of relationships between chronic air pollution exposure and sleep apnea. OBJECTIVES: To determine whether ambient-derived pollution exposure is associated with obstructive sleep apnea and objective sleep disruption. METHODS: We analyzed data from a sample of participants in MESA (Multi-Ethnic Study of Atherosclerosis) who participated in both the Sleep and Air studies. Mean annual and 5-year exposure levels to nitrogen dioxide (NO2) and particulate matter ≤ 2.5 µm in aerodynamic diameter (PM2.5) were estimated at participants' homes using spatiotemporal models based on cohort-specific monitoring. Participants completed in-home full polysomnography and 7 days of wrist actigraphy. We used multivariate models, adjusted for demographics, comorbidities, socioeconomic factors, and site, to assess whether air pollution was associated with sleep apnea (apnea-hypopnea index ≥ 15) and actigraphy-measured sleep efficiency. RESULTS: The participants (n = 1,974) were an average age of 68 (±9) years, 46% male, 36% white, 24% Hispanic, 28% black, and 12% Asian; 48% had sleep apnea and 25% had a sleep efficiency of ≤88%. A 10 ppb annual increase in NO2 exposure was associated with 39% greater adjusted odds of sleep apnea (95% confidence interval [CI], 1.03-1.87). A 5 µg/m3 greater annual PM2.5 exposure was also associated with 60% greater odds of sleep apnea (95% CI, 0.98-2.62). Sleep efficiency was not associated with air pollution levels in fully adjusted models. CONCLUSIONS: Individuals with higher annual NO2 and PM2.5 exposure levels had a greater odds of sleep apnea. These data suggest that in addition to individual risk factors, environmental factors also contribute to the variation of sleep disorders across groups, possibly contributing to health disparities.

Aspirin Use and Respiratory Morbidity in COPD: A Propensity Score-Matched Analysis in Subpopulations and Intermediate Outcome Measures in COPD Study.

BACKGROUND: Aspirin use in COPD has been associated with reduced all-cause mortality in meta-regression analysis with few equivocal studies. However, the effect of aspirin on COPD morbidity is unknown. METHODS: Self-reported daily aspirin use was obtained at baseline from SPIROMICS participants with COPD (FEV1/FVC < 70%). Acute exacerbations of COPD (AECOPD) were prospectively ascertained through quarterly structured telephone questionnaires up to 3 years and categorized as moderate (symptoms treated with antibiotics or oral corticosteroids) or severe (requiring ED visit or hospitalization). Aspirin users were matched one-to-one with nonusers, based on propensity score. The association of aspirin use with total, moderate, and severe AECOPD was investigated using zero-inflated negative binomial models. Linear or logistic regression was used to investigate the association with baseline respiratory symptoms, quality of life, and exercise tolerance. RESULTS: Among 1,698 participants, 45% reported daily aspirin use at baseline. Propensity score matching resulted in 503 participant pairs. Aspirin users had a lower incidence rate of total AECOPD (adjusted incidence rate ratio [IRR], 0.78; 95% CI, 0.65-0.94), with similar effect for moderate but not severe AECOPD (IRR, 0.86; 95% CI, 0.63-1.18). Aspirin use was associated with lower total St. George's Respiratory Questionnaire score (ß, -2.2; 95% CI, -4.1 to -0.4), reduced odds of moderate-severe dyspnea (modified Medical Research Council questionnaire score ≥ 2; adjusted odds ratio, 0.69; 95% CI, 0.51-0.93), and COPD Assessment Test score (ß, -1.1; 95% CI, -1.9 to -0.2) but not 6-min walk distance (ß, 0.7 m; 95% CI, -14.3 to 15.6). CONCLUSIONS: Daily aspirin use is associated with reduced rate of COPD exacerbations, less dyspnea, and better quality of life. Randomized clinical trials of aspirin use in COPD are warranted to account for unmeasured and residual confounding. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01969344; URL: www.clinicaltrials.gov.

A Longitudinal Cohort Study of Aspirin Use and Progression of Emphysema-like Lung Characteristics on CT Imaging: The MESA Lung Study.

BACKGROUND: Platelet activation reduces pulmonary microvascular blood flow and contributes to inflammation; these factors have been implicated in the pathogenesis of COPD and emphysema. We hypothesized that regular use of aspirin, a platelet inhibitor, would be associated with a slower progression of emphysema-like lung characteristics on CT imaging and a slower decline in lung function. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) enrolled participants 45 to 84 years of age without clinical cardiovascular disease from 2000 to 2002. The MESA Lung Study assessed the percentage of emphysema-like lung below -950 Hounsfield units ("percent emphysema") on cardiac (2000-2007) and full-lung CT scans (2010-2012). Regular aspirin use was defined as 3 or more days per week. Mixed-effect models adjusted for demographics, anthropometric features, smoking, hypertension, angiotensin-converting enzyme inhibitor or angiotensin II-receptor blocker use, C-reactive protein levels, sphingomyelin levels, and scanner factors. RESULTS: At baseline, the 4,257 participants' mean (± SD) age was 61 ± 10 years, 54% were ever smokers, and 22% used aspirin regularly. On average, percent emphysema increased 0.60 percentage points over 10 years (95% CI, 0.35-0.94). Progression of percent emphysema was slower among regular aspirin users compared with patients who did not use aspirin (fully adjusted model: -0.34% /10 years, 95% CI, -0.60 to -0.08; P = .01). Results were similar in ever smokers and with doses of 81 and 300 to 325 mg and were of greater magnitude among those with airflow limitation. No association was found between aspirin use and change in lung function. CONCLUSIONS: Regular aspirin use was associated with a more than 50% reduction in the rate of emphysema progression over 10 years. Further study of aspirin and platelets in emphysema may be warranted.

Angiotensin-Converting Inhibitors and Angiotensin II Receptor Blockers and Longitudinal Change in Percent Emphysema on Computed Tomography. The Multi-Ethnic Study of Atherosclerosis Lung Study.

RATIONALE: Although emphysema on computed tomography (CT) is associated with increased morbidity and mortality in patients with and without spirometrically defined chronic obstructive pulmonary disease, no available medications target emphysema outside of alpha-1 antitrypsin deficiency. Transforming growth factor-ß and endothelial dysfunction are implicated in emphysema pathogenesis, and angiotensin II receptor blockers (ARBs) inhibit transforming growth factor-ß, improve endothelial function, and restore airspace architecture in murine models. Evidence in humans is, however, lacking. OBJECTIVES: To determine whether angiotensin-converting enzyme (ACE) inhibitor and ARB dose is associated with slowed progression of percent emphysema by CT. METHODS: The Multi-Ethnic Study of Atherosclerosis researchers recruited participants ages 45-84 years from the general population from 2000 to 2002. Medication use was assessed by medication inventory. Percent emphysema was defined as the percentage of lung regions less than -950 Hounsfield units on CTs. Mixed-effects regression models were used to adjust for confounders. RESULTS: Among 4,472 participants, 12% used an ACE inhibitor and 6% used an ARB at baseline. The median percent emphysema was 3.0% at baseline, and the rate of progression was 0.64 percentage points over a median of 9.3 years. Higher doses of ACE or ARB were independently associated with a slower change in percent emphysema (P = 0.03). Over 10 years, in contrast to a predicted mean increase in percent emphysema of 0.66 percentage points in those who did not take ARBs or ACE inhibitors, the predicted mean increase in participants who used maximum doses of ARBs or ACE inhibitors was 0.06 percentage points (P = 0.01). The findings were of greatest magnitude among former smokers (P < 0.001). Indications for ACE inhibitor or ARB drugs (hypertension and diabetes) and other medications for hypertension and diabetes were not associated independently with change in percent emphysema. There was no evidence that ACE inhibitor or ARB dose was associated with decline in lung function. CONCLUSIONS: In a large population-based study, ACE inhibitors and ARBs were associated with slowed progression of percent emphysema by chest CT, particularly among former smokers. Randomized clinical trials of ACE and ARB agents are warranted for the prevention and treatment of emphysema.

Percent Emphysema and Daily Motor Activity Levels in the General Population: Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: COPD is associated with reduced physical capacity. However, it is unclear whether pulmonary emphysema, which can occur without COPD, is associated with reduced physical activity in daily life, particularly among people without COPD and never smokers. We hypothesized that greater percentage of emphysema-like lung on CT scan is associated with reduced physical activity assessed by actigraphy and self-report. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) enrolled participants free of clinical cardiovascular disease from the general population. Percent emphysema was defined as percentage of voxels < -950 Hounsfield units on full-lung CT scans. Physical activity was measured by wrist actigraphy over 7 days and a questionnaire. Multivariable linear regression was used to adjust for age, sex, race/ethnicity, height, weight, education, smoking, pack-years, and lung function. RESULTS: Among 1,435 participants with actigraphy and lung measures, 47% had never smoked, and 8% had COPD. Percent emphysema was associated with lower activity levels on actigraphy (P = .001), corresponding to 1.5 hour less per week of moderately paced walking for the average participant in quintile 2 vs 4 of percent emphysema. This association was significant among participants without COPD (P = .004) and among ever (P = .01) and never smokers (P = .03). It was also independent of coronary artery calcium and left ventricular ejection fraction. There was no evidence that percent emphysema was associated with self-reported activity levels. CONCLUSIONS: Percent emphysema was associated with decreased physical activity in daily life objectively assessed by actigraphy in the general population, among participants without COPD, and nonsmokers.

Pulmonary vascular volume, impaired left ventricular filling and dyspnea: The MESA Lung Study.

BACKGROUND: Evaluation of impaired left ventricular (LV) filling has focused on intrinsic causes of LV dysfunction; however, pulmonary vascular changes may contribute to reduced LV filling and dyspnea. We hypothesized that lower total pulmonary vascular volume (TPVV) on computed tomography (CT) would be associated with dyspnea and decrements in LV end-diastolic volume, particularly among ever-smokers. METHODS: The Multi-Ethnic Study of Atherosclerosis recruited adults without clinical cardiovascular disease in 2000-02. In 2010-12, TPVV was ascertained as the volume of arteries and veins in the lungs detectable on non-contrast chest CT (vessels ≥1 mm diameter). Cardiac measures were assessed by magnetic resonance imaging (MRI). Dyspnea was self-reported. RESULTS: Of 2303 participants, 53% had ever smoked cigarettes. Among ever-smokers, a lower TPVV was associated with a lower LV end-diastolic volume (6.9 mL per SD TPVV), stroke volume, and cardiac output and with dyspnea (all P-values <0.001). Findings were similar among those without lung disease and those with 0-10 pack-years but were mostly non-significant among never-smokers. TPVV was associated smaller left atrial volume but not with LV ejection fraction or MRI measures of impaired LV relaxation. In a second sample of ever-smokers, a lower pulmonary microvascular blood volume on contrast-enhanced MRI was also associated with a lower LV end-diastolic volume (P-value = 0.008). CONCLUSION: Reductions in pulmonary vascular volume were associated with lower LV filling and dyspnea among ever-smokers, including those without lung disease, suggesting that smoking-related pulmonary vascular changes may contribute to symptoms and impair cardiac filling and function without evidence of impaired LV relaxation.

Particulate Matter Exposure and Cardiopulmonary Differences in the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Particulate matter (PM) exposure may directly affect the pulmonary vasculature. Although the pulmonary vasculature is not easily measurable, differential associations for right ventricular (RV) and left ventricular (LV) mass may provide an indirect assessment of pulmonary vascular damage. OBJECTIVES: We tested whether long-term exposure to PM < 2.5 µm (PM2.5) is associated with greater RV mass and RV mass/end-diastolic volume ratio relative to the LV. METHODS: The Multi-Ethnic Study of Atherosclerosis performed cardiac magnetic resonance (CMR) imaging among participants 45-84 years old without clinical cardiovascular disease in 2000-2002 in six U.S. cities. A fine-scale spatiotemporal model estimated ambient PM2.5 exposure in the year before CMR; individually weighted estimates accounted for indoor exposure to ambient PM2.5. Linear regression models were adjusted for demographics, anthropometrics, smoking status, cardiac risk factors, and LV parameters, with additional adjustment for city. RESULTS: The 4,041 included participants had a mean age of 61.5 years, and 47% were never smokers. The mean ambient PM2.5 was 16.4 µg/m3 and individually weighted PM2.5 was 11.0 µg/m3. PM2.5 exposure was associated with greater RV mass [ambient: 0.11 g per 5 µg/m3 (95% CI: -0.05, 0.27); individually weighted: 0.20 g per 5 µg/m3 (95% CI: 0.04, 0.36)] and a greater RV mass/end-diastolic volume ratio conditional on LV parameters. City-adjusted results for RV mass were of greater magnitude and were statistically significant for both measures of PM2.5, whereas those for RV mass/end-diastolic volume ratio were attenuated. CONCLUSIONS: Long-term PM2.5 exposures were associated with greater RV mass and RV mass/end-diastolic volume ratio conditional on the LV; however, additional adjustment for city attenuated the RV mass/end-diastolic volume findings. These findings suggest that PM2.5 exposure may be associated with subclinical cardiopulmonary differences in this general population sample. CITATION: Aaron CP, Chervona Y, Kawut SM, Diez Roux AV, Shen M, Bluemke DA, Van Hee VC, Kaufman JD, Barr RG. 2016. Particulate matter exposure and cardiopulmonary differences in the Multi-Ethnic Study of Atherosclerosis. Environ Health Perspect 124:1166-1173; http://dx.doi.org/10.1289/ehp.1409451.

Intercellular adhesion molecule 1 and progression of percent emphysema: the MESA Lung Study.

BACKGROUND: Endothelial intercellular adhesion molecule (ICAM) 1 binds neutrophils and facilitates their transmigration into the lung; E-selectin facilitates leukocyte rolling. As neutrophils contribute to tissue destruction in emphysema and chronic obstructive pulmonary disease, we hypothesized that soluble ICAM-1 (sICAM-1) and E-selectin (sE-selectin) would be associated with longitudinal progression of emphysema and lung function decline. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) enrolled participants 45-84 years old without clinical cardiovascular disease in 2000-02. The MESA Lung Study assessed percent emphysema (<-950 Hounsfield units) on cardiac (2000-07) and full-lung CT scans (2010-12), and spirometry was assessed twice over five years. sICAM-1 and sE-selectin were measured at baseline. Mixed-effect models adjusted for demographics, anthropometry, smoking, C-reactive protein, sphingomyelin and scanner factors. RESULTS: Among 1865 MESA Lung participants with measurement of sICAM-1 and percent emphysema the mean log-sICAM-1 was 5.5 ± 0.3 ng/mL and percent emphysema increased 0.73 percentage points (95% CI: 0.34, 1.12; P < 0.001) over ten years. A one SD increase in sICAM-1 was associated with an accelerated increase in percent emphysema of 0.23 percentage points over ten years (95% CI: 0.06, 0.39; P = 0.007). No significant association was found for sE-selectin, or between any adhesion molecule and lung function. CONCLUSIONS: Higher levels of sICAM-1 were independently associated with progression of percent emphysema in a general population sample.