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Thứ Sáu, 26 tháng 4, 2013

Fine Particulate Air Pollution and the Progression of Carotid Intima-Medial Thickness




Background

Fine particulate matter (PM2.5) has been linked to cardiovascular disease, possibly via accelerated atherosclerosis. We examined associations between the progression of the intima-medial thickness (IMT) of the common carotid artery, as an indicator of atherosclerosis, and long-term PM2.5 concentrations in participants from the Multi-Ethnic Study of Atherosclerosis (MESA).

Methods and Results

MESA, a prospective cohort study, enrolled 6,814 participants at the baseline exam (2000–2002), with 5,660 (83%) of those participants completing two ultrasound examinations between 2000 and 2005 (mean follow-up: 2.5 years). PM2.5 was estimated over the year preceding baseline and between ultrasounds using a spatio-temporal model. Cross-sectional and longitudinal associations were examined using mixed models adjusted for confounders including age, sex, race/ethnicity, smoking, and socio-economic indicators. Among 5,362 participants (5% of participants had missing data) with a mean annual progression of 14 µm/y, 2.5 µg/m3 higher levels of residential PM2.5 during the follow-up period were associated with 5.0 µm/y (95% CI 2.6 to 7.4 µm/y) greater IMT progressions among persons in the same metropolitan area. Although significant associations were not found with IMT progression without adjustment for metropolitan area (0.4 µm/y [95% CI −0.4 to 1.2 µm/y] per 2.5 µg/m3), all of the six areas showed positive associations. Greater reductions in PM2.5 over follow-up for a fixed baseline PM2.5 were also associated with slowed IMT progression (−2.8 µm/y [95% CI −1.6 to −3.9 µm/y] per 1 µg/m3 reduction). Study limitations include the use of a surrogate measure of atherosclerosis, some loss to follow-up, and the lack of estimates for air pollution concentrations prior to 1999.


Conclusions

This early analysis from MESA suggests that higher long-term PM2.5 concentrations are associated with increased IMT progression and that greater reductions in PM2.5 are related to slower IMT progression. These findings, even over a relatively short follow-up period, add to the limited literature on air pollution and the progression of atherosclerotic processes in humans. If confirmed by future analyses of the full 10 years of follow-up in this cohort, these findings will help to explain associations between long-term PM2.5 concentrations and clinical cardiovascular events.


Editors' Summary
Background
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a major cause of illness and death worldwide. In the US, for example, the leading cause of death among adults is coronary artery disease, a CVD in which narrowing of the heart's arteries by atherosclerotic plaques (fatty deposits that build up with age inside arteries) slows the blood supply to the heart and may eventually cause a heart attack (myocardial infarction). The fourth leading cause of death in the US is stroke, a CVD in which atherosclerotic plaques interrupt the brain's blood supply. Smoking, high blood pressure, high blood cholesterol levels, diabetes, being overweight, and being physically inactive all increase an individual's risk of developing CVD. Treatments for CVD include lifestyle changes and taking drugs that lower blood pressure or blood cholesterol levels.
Why Was This Study Done?
Another risk factor for CVD is long-term exposure to fine particulate air pollution. Fine particulate matter (PM2.5)—particles with a diameter of less than 2.5 µm or 1/30th the width of a human hair—is mainly produced by motor vehicles, power plants, and other combustion sources. Why PM2.5 increases CVD risk is unclear, but one hypothesis is that it initiates or accelerates atherosclerosis. In this prospective cohort study, which is part of the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air), the researchers investigate whether there is an association between long-term PM2.5 exposure and the progression of intima-medial thickness (IMT; the tunica intima and media are the innermost layers of the arterial wall) in the right common carotid artery (one of the arteries that supplies the head and neck with blood). A prospective cohort study enrolls a group of individuals and follows them to see whether exposure to certain risk factors affects their risk of developing a specific disease; progression of IMT—thickening of the arterial wall with time—in the common carotid artery is a surrogate measure of atherosclerosis.
Methods
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Common Carotid IMT
Trained technicians captured images of the right common carotid artery from supine participants using high resolution B-mode ultrasound (Logiq 700, 13MHz; GE Medical Systems). Images collected over a distance 10 mm proximal to the common carotid bulb were transferred from each study center to the Tufts Medical Center for quantification [16]. This analysis examined the mean far wall thickness of the right common carotid, retrospectively gated to end-diastole. Blinded replicate readings gave inter-reader intra-class correlation coefficients of 0.84 and 0.86 for two separate sets of readers [17]. IMT was collected from all participants at baseline with follow-up measures collected on a subset in exam 2 and a different subset in exam 3.
Discussion
In a large prospective cohort study of adults without pre-existing cardiovascular disease, we found evidence that individuals with higher long-term residential concentrations of PM2.5 experience a faster rate of IMT progression as compared to other people within the same metropolitan area. Improvements in air quality over the duration of the study were similarly associated with changes in IMT progression, with greater reductions in PM2.5 showing slower IMT progression. These findings suggest that higher long-term PM2.5 exposures may be associated with an acceleration of vascular pathologies over time. As such, they may help explain why epidemiological studies have repeatedly found much larger associations between mortality and chronic air pollution exposures than can be explained by short-term triggering of cardiovascular events alone. Our findings furthermore bolster recent reports that falling pollution levels in the United States after the adoption of the Clean Air Act are associated with reduced mortality [25] and increased life expectancy [26],[27].
Our results indicate that persons living in residences with a 2.5 µg/m3 greater PM2.5 concentration could experience a 5.0 µm/y (95% CI 2.6–7.4 µm/y) faster rate of IMT progression than other persons in the same city. Similarly, a person who experienced a 1 µg/m3 larger reduction in PM2.5 over the follow-up period would have a 2.8 µm/y (95% CI 1.6–3.9 µm/y) slower IMT progression than another in the same city with the same baseline PM2.5. Although a recent meta-analysis [28] raises some questions as to the exact clinical implications of a larger IMT progression, results from the MESA cohort [17] suggest that participants living in parts of town with 2.5 µg/m3 higher concentrations of PM2.5 would have a 2% relative increase risk in stroke as compared to persons in a less polluted part of the metropolitan area. These findings have practical relevance since associations with IMT progression were found at concentrations commonly occurring in developed nations and well below those in developing countries. Although our mean long-term concentrations (range 10–23 µg/m3) were slightly above the new annual average US National Ambient Air Quality Standard of 12 µg/m3 and the World Health Organization guideline of 10 µg/m3, our findings are expected to hold even at lower concentrations as past evidence suggests that there is likely no safe threshold for air pollution [29].
The acceleration of atherosclerosis has been proposed as a possible mechanism linking chronic exposures to air pollution to clinical cardiovascular disease [30]32; yet this is only the second publication to investigate the longitudinal relationships between air pollution and a surrogate of atherosclerosis in humans. Our findings support the hypothesis proposed by Künzli and colleagues [33] that persons living in areas with higher long-term concentrations of PM2.5 may experience a more rapid development of vascular pathologies, which leads to the development of clinically relevant atherosclerosis at an earlier age, and increases the population at risk of cardiovascular events. Our findings that concentrations preceding baseline had slightly weaker associations with IMT progression per unit change than those during the follow-up period may indicate the importance of recent exposures or reduced exposure measurement error during the study period.
The magnitude of our findings are consistent with Künzli et al., which reported a 0.6 µm/y (95% CI −0.1 to 1.4 µm/y) larger IMT progression per 2.5 µg/m3 of PM2.5 and a 5.5 µm/y (95% CI 0.1–10.8 µm/y) larger progression for living within close proximity to a major roadway [14]. While we observed larger PM2.5 associations, the 1,483 adult participants of that collection of studies were slightly younger, more white and Hispanic, better educated, and with lower overall rates of progression than our cohort. In addition, that study used a different exposure prediction modeling approach and relied on far fewer air pollution monitors than were available to us, resulting in nearly 5 times less variable PM2.5 estimates for Los Angeles than in this investigation. Nevertheless, their PM2.5 association was well within our confidence intervals for MESA participants in Los Angeles (3.4 µm/y; 95% CI −0.002 to 6.8 µm/y per 2.5 µg/m3). Toxicological data also support our findings, with several studies documenting the growth of atherosclerotic lesions in the coronary arteries and aortas of rabbits and mice following controlled exposures to particulate matter. [2][4],[34].
We also demonstrated positive cross-sectional associations between baseline IMT and long-term exposure but these were blunted and could not be distinguished from no association after control for metropolitan area. Associations similar to our between-city results have been previously reported for long-term exposure to PM2.5 among the older adults enrolled in the Los Angeles clinical trials [8], an earlier investigation of the MESA cohort at baseline [7], and a large population-based cohort of German older adults [9]. In fact, our result of a 3–10 µm difference in IMT at baseline is very consistent with the range of 5 to 17 µm predicted by these other studies for the same unit change in PM2.5 and slightly higher than a recent investigation of young adults that reported a 2 µm larger IMT predicted per 2.5 µg/m3 [10]. Associations between air pollution and other indicators of atherosclerosis extent have been somewhat suggestive but inconsistent [7],[11][13]. Since our cross-sectional results were driven by differences in baseline IMT between the two areas with the highest (Los Angeles) and lowest (St Paul) concentrations of PM2.5, however, and were not robust to control for metropolitan area, there is the possibility of residual confounding by regional factors.
In contrast to our cross-sectional results for baseline IMT, associations with IMT progression were strongest after control for metropolitan area. The reasons for the opposite effect of site adjustment on associations with baseline IMT and IMT progression remain to be determined. Because cross-sectional associations with baseline IMT are based on between-person contrasts, these relations may be more affected by confounding by personal factors than those in our progression models, which leverage information from the same individual. Within-area associations for IMT progression showed little change with control for neighborhood socio-economic characteristics, personal education, and perceived noise and demonstrated positive associations across all six metropolitan areas in stratified analyses. Changes in concentrations over the follow-up period were also associated with IMT progression in models with and without control for metropolitan area. Thus, while some questions are raised as to the robustness of cross-sectional associations with baseline IMT, sensitivity analyses raise our confidence in the associations with IMT progression as potentially reflecting a causal association.
These data come from a well-defined prospective cohort study with an uncommonly rich set of air pollution measurements in participants' communities and homes, including individual-level perceived noise exposures. The inclusion of noise data is a unique feature of this analysis as noise has generally not been accounted for in American epidemiological studies of air pollution to date. Although noise has been independently associated with cardiovascular disease and perceived noise was related to air pollution concentrations in MESA [35],[36], interestingly, we found no evidence of confounding of the relationship between air pollution and IMT progression by perceived noise in this analysis.
Despite the many strengths of this study, this work is not without its weaknesses. First, IMT likely does not capture all of the relevant pathophysiology related to air pollution exposures [37]. Second, our exposure assignment is currently limited to predictions of pollution from ambient origin after 1999 but restriction of the analysis to non-movers (≥10 y at baseline address) did not alter our findings. Third, we did not achieve complete follow-up of all participants and data. The probability of being lost to follow-up over these first three exams was unrelated to baseline IMT levels, however, and the likelihood of missing covariate or exposure data was also unrelated to baseline IMT or IMT progression. Missing covariate information was similarly unrelated to baseline exposure concentrations. This finding suggests that bias in our primary associations due to selection is unlikely although it is always a possibility in any longitudinal study. Furthermore, we are currently not accounting for changes in neighborhood characteristics that also may have occurred during the study period. Control for time-varying vascular risk factors in our extended adjustment model, which may capture some time-varying socio-economic trends, did not substantially alter our findings so we might hypothesize that this is not a major source of confounding. The lack of an association between reductions in air pollution and changes in healthy food stores is further supportive of this hypothesis. Nevertheless, future work through MESA will address this question more thoroughly as they explore the impacts of changing neighborhoods on health. Similarly, our exposure assessment does not currently account for the penetration of outdoor particles into indoor air but correlations of outdoor and indoor PM2.5 of outdoor origin have been shown to be high [38]. Future analyses of MESA Air will confirm the findings of this early dataset using IMT data collected during MESA clinical visits 4 and 5. These analyses will furthermore incorporate estimates of air pollution infiltration into participant homes and participant time-activity information, as well as investigate other correlated pollutants that may explain some of this PM2.5 association and explore relationships with clinical events.
Overall, these results for IMT in the first three exams of a large, multi-center, population-based cohort study support the hypothesis that PM2.5 may be associated with the progression of atherosclerosis, even at levels below existing regulatory standards. Such a pathway would lend further support to reported associations between air pollution and the incidence of clinical cardiovascular disease.



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