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Association between air pollution and coronary artery calcification within six metropolitan areas in the USA (the Multi-Ethnic Study of Atherosclerosis and Air Pollution): a longitudinal cohort study
 
 
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"In conclusion, evidence from this study provides strong biological support for the observation that long-term exposures to outdoor particulate matter and traffic-related air pollution, specifically PM2⋅5 and NOX, are related to the development of atherosclerotic cardiovascular disease......
 
Our findings provide evidence that exposure to air pollution is associated with coronary artery calcium progression.......In this multi-ethnic prospectively studied population, ambient concentrations of PM2⋅5 and NOX were strongly associated with accelerated atherosclerosis, as shown by assessment of coronary artery calcium over a 10-year period. Air pollution was not associated with progression of intima-media thickness.
 
......Increased concentrations of PM2⋅5 and traffic-related air pollution within metropolitan areas, in ranges commonly encountered worldwide, are associated with progression in coronary calcification, consistent with acceleration of atherosclerosis. This study supports the case for global efforts of pollution reduction in prevention of cardiovascular diseases.
 
Calcified plaques in the coronary arteries have been consistently associated with cardiovascular disease in both clinical trials and observational research.15 Coronary artery calcium is a very strong risk marker of future ischaemic vascular events. Although most often studied as a one-time measure of atherosclerotic extent and plaque burden,16 change in coronary artery calcium also predicts subsequent ischaemic events.2 Risk factors that accelerate coronary artery calcium progression (including age, male sex, adiposity, systolic blood pressure, smoking, and diabetes) are also strong predictors of subsequent ischaemic events.17 Coronary artery calcium measurements might represent more mature atherosclerotic lesions than forming or vulnerable plaques.18"
 
Carotid wall thickness is a challenging outcome for observational studies because the change in intima-media thickness over time is small relative to the measurement error at each timepoint. The mechanism by which air pollution might accelerate atherosclerosis might also be unrelated to intima-media thickness, which is a marker of arterial injury rather than atherosclerosis per se.2. Unlike coronary artery calcium, change over time in intima-media thickness is not predictive of subsequent cardiovascular disease events in observational studies, although it is a commonly used outcome in pharmaceutical studies.28, 29 In MESA participants, coronary artery calcium has been a much stronger predictor of subsequent coronary heart disease events than intima-media thickness.30
 
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Association between air pollution and coronary artery calcification within six metropolitan areas in the USA (the Multi-Ethnic Study of Atherosclerosis and Air Pollution): a longitudinal cohort study
 
Lancet June 8 2016
 
Summary
 
Background

 
Long-term exposure to fine particulate matter less than 2⋅5 μm in diameter (PM2⋅5) and traffic-related air pollutant concentrations are associated with cardiovascular risk. The disease process underlying these associations remains uncertain. We aim to assess association between long-term exposure to ambient air pollution and progression of coronary artery calcium and common carotid artery intima-media thickness.
 
Methods

 
In this prospective 10-year cohort study, we repeatedly measured coronary artery calcium by CT in 6795 participants aged 45-84 years enrolled in the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) in six metropolitan areas in the USA. Repeated scans were done for nearly all participants between 2002 and 2005, for a subset of participants between 2005 and 2007, and for half of all participants between 2010 and 2012. Common carotid artery intima-media thickness was measured by ultrasound in all participants at baseline and in 2010-12 for 3459 participants. Residence-specific spatio-temporal pollution concentration models, incorporating community-specific measurements, agency monitoring data, and geographical predictors, estimated concentrations of PM2⋅5 and nitrogen oxides (NOX) between 1999 and 2012. The primary aim was to examine the association between both progression of coronary artery calcium and mean carotid artery intima-media thickness and long-term exposure to ambient air pollutant concentrations (PM2⋅5, NOX, and black carbon) between examinations and within the six metropolitan areas, adjusting for baseline age, sex, ethnicity, socioeconomic characteristics, cardiovascular risk factors, site, and CT scanner technology.
 
The designs of the MESA2 and MESA Air3 studies have been described previously. Briefly, MESA recruited a cohort of 6814 participants with no history of clinical cardiovascular disease from four ethnic groups (Hispanic, black, white, and Chinese), with sex balance and uniform age distribution (range 45-84 years at recruitment) in six areas of the USA: Baltimore, MD; Chicago, IL; Los Angeles County, CA; New York City, NY; St Paul, MN; and Winston-Salem, NC. Community-based strategies that varied by clinical centre were used to recruit participants.
 
Findings
 
In this population, coronary calcium increased on average by 24 Agatston units per year (SD 58), and intima-media thickness by 12 μm per year (10), before adjusting for risk factors or air pollutant exposures. Participant-specific pollutant concentrations averaged over the years 2000-10 ranged from 9⋅2-22⋅6 μg PM2⋅5/m3 and 7⋅2-139⋅2 parts per billion (ppb) NOX. For each 5 μg PM2⋅5/m3 increase, coronary calcium progressed by 4⋅1 Agatston units per year (95% CI 1⋅4-6⋅8) and for each 40 ppb NOX coronary calcium progressed by 4⋅8 Agatston units per year (0⋅9-8⋅7). Pollutant exposures were not associated with intima-media thickness change. The estimate for the effect of a 5 μg/m3 higher long-term exposure to PM2⋅5 in intima-media thickness was -0⋅9 μm per year (95% CI -3⋅0 to 1⋅3). For 40 ppb higher NOX, the estimate was 0⋅2 μm per year (-1⋅9 to 2⋅4).
 
Interpretation
 
Increased concentrations of PM2⋅5 and traffic-related air pollution within metropolitan areas, in ranges commonly encountered worldwide, are associated with progression in coronary calcification, consistent with acceleration of atherosclerosis. This study supports the case for global efforts of pollution reduction in prevention of cardiovascular diseases.
 
Funding
 
US Environmental Protection Agency and US National Institutes of Health.
 
Discussion
 
In this multi-ethnic prospectively studied population, ambient concentrations of PM2⋅5 and NOX were strongly associated with accelerated atherosclerosis, as shown by assessment of coronary artery calcium over a 10-year period. Air pollution was not associated with progression of intima-media thickness. This study benefited from state-of-the-art exposure estimation at the time and location of each residence during follow-up and incorporated high-quality information about potential confounding factors, including time-varying covariates such as statin use. The cohort-focused air quality monitoring effort and spatio-temporal modelling methods enabled us to generate individually resolved exposures and examine relationships between atherosclerosis progression and air pollution over time, using within-city contrasts with an unprecedented level of accuracy. These results provide important evidence that long-term exposure to these ambient air pollutants is associated with atherosclerosis progression in the coronary arteries and can explain previous findings that pollutants are associated with cardiovascular events and mortality.
 
Exposures during follow-up of this cohort were low by historical and international standards. The present US National Ambient Air Quality Standards12 permit annual average PM2⋅5 concentrations of 12 μg/m3 and the European Union Air Quality Standards13 permit 25 μg/m3, whereas the mean ambient PM2⋅5 concentration that participants in our study were exposed to over 2000-10 was 14⋅2 μg/m3 (range 9⋅2-22⋅6). The concentrations in rapidly industrialising countries are substantially higher.14
 
Calcified plaques in the coronary arteries have been consistently associated with cardiovascular disease in both clinical trials and observational research.15 Coronary artery calcium is a very strong risk marker of future ischaemic vascular events. Although most often studied as a one-time measure of atherosclerotic extent and plaque burden,16 change in coronary artery calcium also predicts subsequent ischaemic events.2 Risk factors that accelerate coronary artery calcium progression (including age, male sex, adiposity, systolic blood pressure, smoking, and diabetes) are also strong predictors of subsequent ischaemic events.17 Coronary artery calciumd measurements might represent more mature atherosclerotic lesions than forming or vulnerable plaques.18
 
The association between coronary artery calcium progression and air pollution has not been reported, although the plausibility of a causal relationship between air pollution and atherosclerosis is suggested through several mechanisms.19 In a cross-sectional analysis in the the Heinz-Nixdorf Recall study,20 coronary artery calcium was higher in individuals living near roads than in those who did not live near major roads. Our findings provide evidence that exposure to air pollution is associated with coronary artery calcium progression.
 
Although coronary artery calcium progression was associated with PM2⋅5 and NOX, it was not associated with black carbon. Unlike the other pollutants, for which exposures were estimated between 1999 and 2012, black carbon exposures were limited to only spatial contrasts in 2006-08; hence, analyses could not capture the decreasing trends in pollutant concentrations recorded during follow-up.21 Additionally, coronary artery calcium progression was not as strongly associated with NO2 as it was with total NOX. The total NOX is highest in the most near-road environments (measured in previous research as proximity to a major roadway or time in traffic),22 and might better represent the group of primarily emitted traffic-related air pollutants present in these locations. Therefore, characterisation of NOX exposure might be a better way to capture the effects of the near-road environment on health.
 
We noted a somewhat stronger association between PM2⋅5 and coronary artery calcium progression in hypertensive, in non-obese, and in individuals older than 65 years. The findings with age and hypertension suggest a synergistic association between air pollutants and these two strong risk factors for progression of atherosclerosis, though this association was not found for other strong risk factors such as diabetes or elevated cholesterol levels. The finding that pollutant associations with coronary artery calcium progression appeared stronger in non-obese participants is not what would be expected because inflammatory and metabolic consequences of obesity are thought to share mechanistic pathways with those of air pollutants.19 Although this study's sample size and precision provided adequate statistical power for the primary comparisons, analyses of effect modification were less well powered.
 
Our findings for the effect of pollutants on coronary artery calcium progression were robust to a variety of sensitivity analyses and did not differ depending on stages of control of potential confounding variables. This result strengthens our confidence in these associations. In addition, air pollutant relationships were recorded whether the outcome was measured as an absolute or relative change in calcification. Although absolute change in the extent of calcifications was our a-priori outcome choice, assessment of the outcome as a relative change did suggest additional associations with NO2 and ambient-derived PM2⋅5 that were not observed with the absolute change outcome. An association between air pollution and progression of carotid wall thickness has been noted in some, but not all, previous studies.23, 24 An interim analysis25 in MESA showed that exposure to a 2⋅5 μg/m3 higher PM2⋅5 concentration was associated with a 5 μm per year increase in intima-media thickness progression; the interim study used a different approach to image analysis, a less-developed approach to exposure estimation, and a much shorter period of follow-up. An observational study26 within clinical trial data showed associations between PM2⋅5 and intima-media thickness progression in some subgroups. Carotid wall thickness is a challenging outcome for observational studies because the change in intima-media thickness over time is small relative to the measurement error at each timepoint. The mechanism by which air pollution might accelerate atherosclerosis might also be unrelated to intima-media thickness, which is a marker of arterial injury rather than atherosclerosis per se.27 Unlike coronary artery calcium, change over time in intima-media thickness is not predictive of subsequent cardiovascular disease events in observational studies, although it is a commonly used outcome in pharmaceutical studies.28, 29 In MESA participants, coronary artery calcium has been a much stronger predictor of subsequent coronary heart disease events than intima-media thickness.30
 
The MESA cohort provides an extraordinarily well characterised population in terms of potential confounders of the relationship between air pollution and cardiovascular disease. Nevertheless, residual confounding by unmeasured factors remains a possibility. Additionally, though we chose a-priori exposures and outcomes of interest, the presence of more than one exposure and outcome in our analyses could be criticised for including multiple comparisons.
 
This study focused on the health effects of ambient-derived air pollutants on cardiovascular health. Our primary exposure metrics focused on concentrations of pollutants outside homes, although individuals spend time in specific micro-environments, including indoors. We developed the ambient-derived PM2⋅5 measure specifically to address this issue, to better characterise actual exposure to ambient PM2⋅5 by adjusting outdoor concentrations by time spent indoors and infiltration of particles into the home. Because these predictions represent the product of two different modifiers of outdoor concentration (each imperfectly assessed and not available for all study participants) we believe that the additional error in exposure estimation was the primary driver for the weak associations reported for ambient-derived PM2⋅5. Full characterisation of time-location patterns and indoor exposures is notoriously difficult. Ascertainment of highly resolved, individualised micro-environmental exposure estimates over several years of follow-up is elusive, hence our primary exposure estimation approach relies on outdoor concentrations.
 
In conclusion, evidence from this study provides strong biological support for the observation that long-term exposures to outdoor particulate matter and traffic-related air pollution, specifically PM2⋅5 and NOX, are related to the development of atherosclerotic cardiovascular disease.
 
 
 
 
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