Proteomics, Human Environmental Exposure, and Cardiometabolic Risk.

BACKGROUND: The biological mechanisms linking environmental exposures with cardiovascular disease pathobiology are incompletely understood. We sought to identify circulating proteomic signatures of environmental exposures and examine their associations with cardiometabolic and respiratory disease in observational cohort studies. METHODS: We tested the relations of >6500 circulating proteins with 29 environmental exposures across the built environment, green space, air pollution, temperature, and social vulnerability indicators in ≈3000 participants of the CARDIA study (Coronary Artery Risk Development in Young Adults) across 4 centers using penalized and ordinary linear regression. In >3500 participants from FHS (Framingham Heart Study) and JHS (Jackson Heart Study), we evaluated the prospective relations of proteomic signatures of the envirome with cardiovascular disease and mortality using Cox models. RESULTS: Proteomic signatures of the envirome identified novel/established cardiovascular disease-relevant pathways including DNA damage, fibrosis, inflammation, and mitochondrial function. The proteomic signatures of the envirome were broadly related to cardiometabolic disease and respiratory phenotypes (eg, body mass index, lipids, and left ventricular mass) in CARDIA, with replication in FHS/JHS. A proteomic signature of social vulnerability was associated with a composite of cardiovascular disease/mortality (1428 events; FHS: hazard ratio, 1.16 [95% CI, 1.08-1.24]; P=1.77×10-5; JHS: hazard ratio, 1.25 [95% CI, 1.14-1.38]; P=6.38×10-6; hazard ratio expressed as per 1 SD increase in proteomic signature), robust to adjustment for known clinical risk factors. CONCLUSIONS: Environmental exposures are related to an inflammatory-metabolic proteome, which identifies individuals with cardiometabolic disease and respiratory phenotypes and outcomes. Future work examining the dynamic impact of the environment on human cardiometabolic health is warranted.

Out-of-Pocket Prescription Drug Savings for Medicare Beneficiaries with Asthma and COPD Under the Inflation Reduction Act.

BACKGROUND: High and rising prescription drug costs for asthma and chronic obstructive pulmonary disease (COPD) contribute to medication nonadherence and poor clinical outcomes. The recently enacted Inflation Reduction Act includes provisions that will cap out-of-pocket prescription drug spending at $2,000 per year and expand low-income subsidies. However, little is known about how these provisions will impact out-of-pocket drug spending for Medicare beneficiaries with asthma and COPD. OBJECTIVE: To estimate the impact of the Inflation Reduction Act's out-of-pocket spending cap and expansion of low-income subsidies on Medicare beneficiaries with obstructive lung disease. DESIGN: We calculated the number of Medicare beneficiaries ≥ 65 years with asthma and/or COPD and out-of-pocket prescription drug spending > $2,000/year, and then estimated their median annual out-of-pocket savings under the Inflation Reduction Act's spending cap. We then estimated the number of beneficiaries with incomes > 135% and ≤ 150% of the federal poverty level who would become newly eligible for low-income subsidies under this policy. PARTICIPANTS: Respondents to the 2016-2019 Medical Expenditure Panel Survey (MEPS). MAIN MEASURES: Annual out-of-pocket prescription drug spending. KEY RESULTS: An annual estimated 5.2 million Medicare beneficiaries had asthma and/or COPD. Among them, 360,160 (SE ± 38,021) experienced out-of-pocket drug spending > $2,000/year, with median out-of-pocket costs of $3,003/year (IQR $2,360-$3,941). Therefore, median savings under the Inflation Reduction Act's spending cap would be $1,003/year (IQR $360-$1,941), including $738/year and $1,137/year for beneficiaries with asthma and COPD, respectively. Total annual estimated savings would be $504 million (SE ± $42 M). In addition, 232,155 (SE ± 4,624) beneficiaries would newly qualify for low-income subsidies, which will further reduce prescription drug costs. CONCLUSIONS: The Inflation Reduction Act will have major implications on out-of-pocket prescription drug spending for Medicare beneficiaries with obstructive lung disease resulting in half-a-billion dollars in total out-of-pocket savings per year, which could ultimately have implications on medication adherence and clinical outcomes.

Associations of Personal Hourly Exposures to Air Temperature and Pollution with Resting Heart Rate in Chronic Obstructive Pulmonary Disease.

Previous studies linked higher daily ambient air temperature and pollution with increased cardiorespiratory morbidity, but immediate effects of personal, hourly exposures on resting heart rate remained unclear. We followed 30 older former smokers with chronic obstructive pulmonary disease (COPD) in Massachusetts for four nonconsecutive 30-day periods over 12 months, collecting 54,487 hourly observations of personal air temperature, fine particulate matter (PM2.5), nitrogen dioxide (NO2), ozone (O3), and resting heart rate. We explored the single lag effects (0-71 h) and cumulative effects (0-5 h, the significant lag windows) of air temperature and pollution on resting heart rate using generalized additive mixed models with distributed lag nonlinear models. Single lag effects of higher air temperature and pollutants on higher resting heart rate were most pronounced at lag 0 to 5 h. Cumulative effects of higher air temperature, PM2.5, O3, and NO2 (each interquartile range increment) on higher resting heart rate at lag 0-5 h, show differences of (beats per minute [bpm], 95% CI) 1.46 (1.31-1.62), 0.35 (0.32-0.39), 2.32 (2.19-2.45), and 1.79 (1.66-1.92), respectively. In conclusion, higher personal hourly air temperature, PM2.5, O3, and NO2 exposures at lag 0-5 h are associated with higher resting heart rate in COPD patients.

Air pollution and lung function in children.

In this narrative review, we summarize the literature and provide updates on recent studies of air pollution exposures and child lung function and lung function growth. We include exposures to outdoor air pollutants that are monitored and regulated through air quality standards, and air pollutants that are not routinely monitored or directly regulated, including wildfires, indoor biomass and coal burning, gas and wood stove use, and volatile organic compounds. Included is a more systematic review of the recent literature on long-term air pollution and child lung function because this is an indicator of future adult respiratory health and exposure assessment tools have improved dramatically in recent years. We present "summary observations" and "knowledge gaps." We end by discussing what is known about what can be done at the individual/household, local/regional, and national levels to overcome structural impediments, reduce air pollution exposures, and improve child lung function. We found a large literature on adverse air pollution effects on children's lung function level and growth; however, many questions remain. Important areas needing further research include whether early-life effects are fixed or reversible; and what are windows of increased susceptibility, long-term effects of repeated wildfire events, and effects of air quality interventions.

Should You Recommend Inhaled Corticosteroids for This Patient With Chronic Obstructive Pulmonary Disease?: Grand Rounds Discussion From Beth Israel Deaconess Medical Center.

Approximately 12 million adults in the United States receive a diagnosis of chronic obstructive pulmonary disease (COPD) each year, and it is the fourth leading cause of death. Chronic obstructive pulmonary disease refers to a group of diseases that cause airflow obstruction and a constellation of symptoms, including cough, sputum production, and shortness of breath. The main risk factor for COPD is tobacco smoke, but other environmental exposures also may contribute. The GOLD (Global Initiative for Chronic Obstructive Lung Disease) 2020 Report aims to provide a nonbiased review of the current evidence for the assessment, diagnosis, and treatment of patients with COPD. To date, no conclusive evidence exists that any existing medications for COPD modify mortality. The mainstay of treatment for COPD is inhaled bronchodilators, whereas the role of inhaled corticosteroids is less clear. Inhaled corticosteroids have substantial risks, including an increased risk for pneumonia. Here, 2 experts, both pulmonologists, reflect on the care of a woman with severe COPD, a 50-pack-year smoking history, frequent COPD exacerbations, and recurrent pneumonia. They consider the indications for inhaled corticosteroids in COPD, when inhaled corticosteroids should be withdrawn, and what other treatments are available.

Ambient air pollution exposure and risk and progression of interstitial lung abnormalities: the Framingham Heart Study.

BACKGROUND: Ambient air pollution accelerates lung function decline among adults, however, there are limited data about its role in the development and progression of early stages of interstitial lung disease. AIMS: To evaluate associations of long-term exposure to traffic and ambient pollutants with odds of interstitial lung abnormalities (ILA) and progression of ILA on repeated imaging. METHODS: We ascertained ILA on chest CT obtained from 2618 Framingham participants from 2008 to 2011. Among 1846 participants who also completed a cardiac CT from 2002 to 2005, we determined interval ILA progression. We assigned distance from home address to major roadway, and the 5-year average of fine particulate matter (PM2.5), elemental carbon (EC, a traffic-related PM2.5 constituent) and ozone using spatio-temporal prediction models. Logistic regression models were adjusted for age, sex, body mass index, smoking status, packyears of smoking, household tobacco exposure, neighbourhood household value, primary occupation, cohort and date. RESULTS: Among 2618 participants with a chest CT, 176 (6.7%) had ILA, 1361 (52.0%) had no ILA, and the remainder were indeterminate. Among 1846 with a preceding cardiac CT, 118 (6.4%) had ILA with interval progression. In adjusted logistic regression models, an IQR difference in 5-year EC exposure of 0.14 µg/m3 was associated with a 1.27 (95% CI 1.04 to 1.55) times greater odds of ILA, and a 1.33 (95% CI 1.00 to 1.76) times greater odds of ILA progression. PM2.5 and O3 were not associated with ILA or ILA progression. CONCLUSIONS: Exposure to EC may increase risk of progressive ILA, however, associations with other measures of ambient pollution were inconclusive.

Association of outdoor temperature with lung function in a temperate climate.

Acute exposure to cold dry air is a trigger of bronchoconstriction, but little is known about how daily outdoor temperature influences lung function.We investigated associations of temperature from a model using satellite remote sensing data with repeated measures of lung function among 5896 participants of the Framingham Heart Study Offspring and Third Generation cohorts residing in the Northeastern US. We further tested if temperature modified previously reported associations between pollution and lung function. We constructed linear mixed-effects models, and assessed departures from linearity using penalised splines.In fully adjusted linear models, 1-, 2- and 7-day average temperatures were all associated with lower lung function: each 5°C higher previous-week temperature was associated with a 20 mL lower (95% CI -34---6) forced expiratory volume in 1 s. There was significant effect modification by season: negative associations of temperature and lung function were present in winter and spring only. Negative associations between previous-day fine particulate matter and lung function were present during unseasonably warm but not unseasonably cool days, with a similar pattern for other pollutants.We speculate that temperature-related differences in lung function may be explained by behavioural changes on relatively warm days, which may increase outdoor exposures.

Radiographic pulmonary vessel volume, lung function and airways disease in the Framingham Heart Study.

Radiographic abnormalities of the pulmonary vessels, such as vascular pruning, are common in advanced airways disease, but it is unknown if pulmonary vascular volumes are related to measures of lung health and airways disease in healthier populations.In 2388 participants of the Framingham Heart Study computed tomography (CT) sub-study, we calculated total vessel volumes and the small vessel fraction using automated CT image analysis. We evaluated associations with measures of lung function, airflow obstruction on spirometry and emphysema on CT. We further tested if associations of vascular volumes with lung function were present among those with normal forced expiratory volume in 1 s and forced vital capacity.In fully adjusted linear and logistic models, we found that lower total and small vessel volumes were consistently associated with worse measures of lung health, including lower spirometric volumes, lower diffusing capacity and/or higher odds of airflow obstruction. For example, each standard deviation lower small vessel fraction (indicating more severe pruning) was associated with a 37% greater odds of obstruction (OR 1.37, 95% CI 1.11-1.71, p=0.004). A similar pattern was observed in the subset of participants with normal spirometry.Lower total and small vessel pulmonary vascular volumes were associated with poorer measures of lung health and/or greater odds of airflow obstruction in this cohort of generally healthy adults without high burdens of smoking or airways disease. Our findings suggest that quantitative CT assessment may detect subtle pulmonary vasculopathy that occurs in the setting of subclinical and early pulmonary and airways pathology.

Short-term exposure to ambient air pollution and circulating biomarkers of endothelial cell activation: The Framingham Heart Study.

BACKGROUND: Short-term exposure to air pollution has been associated with cardiovascular events, potentially by promoting endothelial cell activation and inflammation. A few large-scale studies have examined the associations and have had mixed results. METHODS: We included 3820 non-current smoking participants (mean age 56 years, 54% women) from the Framingham Offspring cohort examinations 7 (1998-2001) and 8 (2005-2008), and Third Generation cohort examination 1 (2002-2005), who lived within 50 km of a central monitoring station. We calculated the 1- to 7-day moving averages of fine particulate matter (PM2.5), black carbon (BC), sulfate (SO42-), nitrogen oxides (NOx), and ozone before examination visits. We used linear mixed effect models for P-selectin, monocyte chemoattractant protein 1 (MCP-1), intercellular adhesion molecule 1, lipoprotein-associated phospholipase A2 activity and mass, and osteoprotegerin that were measured up to twice, and linear regression models for CD40 ligand and interleukin-18 that were measured once, adjusting for demographics, life style and clinical factors, socioeconomic position, time, and meteorology. RESULTS: We found negative associations of PM2.5 and BC with P-selectin, of ozone with MCP-1, and of SO42- and NOx with osteoprotegerin. At the 5-day moving average, a 5 µg/m3 higher PM2.5 was associated with 1.6% (95% CI: - 2.8, - 0.3) lower levels of P-selectin; a 10 ppb higher ozone was associated with 1.7% (95% CI: - 3.2, - 0.1) lower levels of MCP-1; and a 20 ppb higher NOx was associated with 2.0% (95% CI: - 3.6, - 0.4) lower levels of osteoprotegerin. CONCLUSIONS: We did not find evidence of positive associations between short-term air pollution exposure and endothelial cell activation. On the contrary, short-term exposure to higher levels of ambient pollutants were associated with lower levels of P-selectin, MCP-1, and osteoprotegerin in the Framingham Heart Study.

Exposure to Traffic Emissions and Fine Particulate Matter and Computed Tomography Measures of the Lung and Airways.

BACKGROUND: Exposure to ambient air pollution has been associated with lower lung function in adults, but few studies have investigated associations with radiographic lung and airway measures. METHODS: We ascertained lung volume, mass, density, visual emphysema, airway size, and airway wall area by computed tomography (CT) among 2,545 nonsmoking Framingham CT substudy participants. We examined associations of home distance to major road and PM2.5 (2008 average from a spatiotemporal model using satellite data) with these outcomes using linear and logistic regression models adjusted for age, sex, height, weight, census tract median household value and population density, education, pack-years of smoking, household tobacco exposure, cohort, and date. We tested for differential susceptibility by sex, smoking status (former vs. never), and cohort. RESULTS: The mean participant age was 60.1 years (standard deviation 11.9 years). Median PM2.5 level was 9.7 µg/m (interquartile range, 1.6). Living <100 m from a major road was associated with a 108 ml (95% CI = 8, 207) higher lung volume compared with ≥400 m away. There was also a log-linear association between proximity to road and higher lung volume. There were no convincing associations of proximity to major road or PM2.5 with the other pulmonary CT measures. In subgroup analyses, road proximity was associated with lower lung density among men and higher odds of emphysema among former smokers. CONCLUSIONS: Living near a major road was associated with higher average lung volume, but otherwise, we found no association between ambient pollution and radiographic measures of emphysema or airway disease.

Short-Term Exposure to Ambient Air Pollution and Biomarkers of Systemic Inflammation: The Framingham Heart Study.

OBJECTIVE: The objective of this study is to examine associations between short-term exposure to ambient air pollution and circulating biomarkers of systemic inflammation in participants from the Framingham Offspring and Third Generation cohorts in the greater Boston area. APPROACH AND RESULTS: We included 3996 noncurrent smoking participants (mean age, 53.6 years; 54% women) who lived within 50 km from a central air pollution monitoring site in Boston, MA, and calculated the 1- to 7-day moving averages of fine particulate matter (diameter<2.5 µm), black carbon, sulfate, nitrogen oxides, and ozone before the examination visits. We used linear mixed effects models for C-reactive protein and tumor necrosis factor receptor 2, which were measured up to twice for each participant; we used linear regression models for interleukin-6, fibrinogen, and tumor necrosis factor α, which were measured once. We adjusted for demographics, socioeconomic position, lifestyle, time, and weather. The 3- to 7-day moving averages of fine particulate matter (diameter<2.5 µm) and sulfate were positively associated with C-reactive protein concentrations. A 5 µg/m3 higher 5-day moving average fine particulate matter (diameter<2.5 µm) was associated with 4.2% (95% confidence interval: 0.8, 7.6) higher circulating C-reactive protein. Positive associations were also observed for nitrogen oxides with interleukin-6 and for black carbon, sulfate, and ozone with tumor necrosis factor receptor 2. However, black carbon, sulfate, and nitrogen oxides were negatively associated with fibrinogen, and sulfate was negatively associated with tumor necrosis factor α. CONCLUSIONS: Higher short-term exposure to relatively low levels of ambient air pollution was associated with higher levels of C-reactive protein, interleukin-6, and tumor necrosis factor receptor 2 but not fibrinogen or tumor necrosis factor α in individuals residing in the greater Boston area.

Residential Proximity to Major Roadways, Fine Particulate Matter, and Hepatic Steatosis: The Framingham Heart Study.

We examined associations between ambient air pollution and hepatic steatosis among 2,513 participants from the Framingham (Massachusetts) Offspring Study and Third Generation Cohort who underwent a computed tomography scan (2002-2005), after excluding men who reported >21 drinks/week and women who reported >14 drinks/week. We calculated each participant's residential-based distance to a major roadway and used a spatiotemporal model to estimate the annual mean concentrations of fine particulate matter. Liver attenuation was measured by computed tomography, and liver-to-phantom ratio (LPR) was calculated. Lower values of LPR represent more liver fat. We estimated differences in continuous LPR using linear regression models and prevalence ratios for presence of hepatic steatosis (LPR ≤ 0.33) using generalized linear models, adjusting for demographics, individual and area-level measures of socioeconomic position, and clinical and lifestyle factors. Participants who lived 58 m (25th percentile) from major roadways had lower LPR (ß = -0.003, 95% confidence interval: -0.006, -0.001) and higher prevalence of hepatic steatosis (prevalence ratio = 1.16, 95% confidence interval: 1.05, 1.28) than those who lived 416 m (75th percentile) away. The 2003 annual average fine particulate matter concentration was not associated with liver-fat measurements. Our findings suggest that living closer to major roadways was associated with more liver fat.

Residential Proximity to Major Roads, Exposure to Fine Particulate Matter, and Coronary Artery Calcium: The Framingham Heart Study.

OBJECTIVE: Long-term exposure to traffic and particulate matter air pollution is associated with a higher risk of cardiovascular disease, potentially via atherosclerosis promotion. Prior research on associations of traffic and particulate matter with coronary artery calcium Agatston score (CAC), an atherosclerosis correlate, has yielded inconsistent findings. Given this background, we assessed whether residential proximity to major roadway or fine particulate matter were associated with CAC in a Northeastern US study. APPROACH AND RESULTS: We measured CAC ≤2 times from 2002 to 2005 and 2008 to 2011 among Framingham Offspring or Third-Generation Cohort participants. We assessed associations of residential distance to major roadway and residential fine particulate matter (2003 average; spatiotemporal model) with detectable CAC, using generalized estimating equation regression. We used linear mixed effects models to assess associations with loge(CAC). We also assessed associations with CAC progression. Models were adjusted for demographic variables, socioeconomic position markers, and time. Among 3399 participants, 51% had CAC measured twice. CAC was detectable in 47% of observations. At first scan, mean age was 52.2 years (standard deviation 11.7); 51% male. There were no consistent associations with detectable CAC, continuous CAC, or CAC progression. We observed heterogeneous associations of distance to major roadway with odds of detectable CAC by hypertensive status; interpretation of these findings is questionable. CONCLUSIONS: Our findings add to prior work and support evidence against strong associations of traffic or fine particulate matter with the presence, extent, or progression of CAC in a region with relatively low levels of and little variation in fine particulate matter.

Lifetime Exposure to Ambient Pollution and Lung Function in Children.

RATIONALE: Few studies have examined associations between exposure to air pollution and childhood lung function after implementation of strict air quality regulations in the 1990s. OBJECTIVES: To assess traffic-related pollution exposure and childhood lung function. METHODS: We geocoded addresses for 614 mother-child pairs enrolled during pregnancy in the Boston area 1999-2002 and followed them until a mid-childhood visit (median age, 7.7). We calculated the proximity of the home to the nearest major roadway. We estimated first year of life, lifetime, and prior-year exposure to particulate matter with a diameter smaller than 2.5 µm (PM2.5) by a hybrid model using satellite-derived aerosol optical depth, and to black carbon (BC) by a land-use regression model. MEASUREMENTS AND MAIN RESULTS: Residential proximity to roadway and prior-year and lifetime PM2.5 and BC exposure were all associated with lower FVC. Associations with FEV1 were also negative and proportionally similar. Pollution exposures were not associated with the FEV1/FVC ratio or bronchodilator response. Compared with distances greater than or equal to 400 m, living less than 100 m from a major roadway was associated with lower FVC (-98.6 ml; -176.3 to -21.0). Each 2 µg/m(3) increment in prior-year PM2.5 was associated with lower FVC (-21.8 ml; -43.9 to 0.2) and higher odds of FEV1 less than 80% predicted (1.41; 1.03-1.93). Each 0.2 µg/m(3) increment in prior-year BC was associated with a 38.9 ml (-70.4 to -7.3) lower FVC. CONCLUSIONS: Estimates of long-term exposure to ambient pollution, including proximity to major roadway, PM2.5, and BC (a traffic-related PM2.5 constituent), were associated with lower lung function in this Boston-area cohort of children with relatively low pollution exposures.