Background
Fine particulate matter (PM
2.5) 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
PM
2.5 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).
PM
2.5 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/m
3 higher levels of residential
PM
2.5 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/m
3), all of the six areas showed positive
associations. Greater reductions in PM
2.5 over follow-up for a fixed
baseline PM
2.5 were also associated with slowed IMT progression (−2.8
µm/y [95% CI −1.6 to −3.9 µm/y] per 1 µg/m
3 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 PM
2.5
concentrations are associated with increased IMT progression and that greater
reductions in PM
2.5 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
PM
2.5 concentrations and clinical cardiovascular events.
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
...
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.
