Arteriosclerosis, Thrombosis, and Vascular Biology

BRIEF REVIEW

Ambient Air Pollution and Atherosclerosis

Insights Into Dose, Time, and Mechanisms
Graham H. Bevan, Sadeer G. Al-Kindi , Robert D. Brook , Thomas Münzel , Sanjay Rajagopalan

ABSTRACT: Ambient air pollution due to particulate matter ≤2.5 μ is the leading environmental risk factor contributing to global
mortality, with a preponderant majority of these deaths attributable to atherosclerotic cardiovascular disease (ASCVD) causes
such as stroke and myocardial infarction. Epidemiological studies in humans have provided refined estimates of exposure risk,
with evidence suggesting that risk association with particulate matter ≤2.5 levels and ASCVD continues at levels well below
air quality guidelines in North America and Europe. Mechanistic studies in animals and humans have provided a framework
of understanding of the duration and pathways by which air pollution exposure may predispose to atherosclerosis. Although
acute exposure to particulate matter ≤2.5 is associated with oxidative stress and inflammation, system transmission of signals
from the lungs to extrapulmonary sites may involve direct translocation of components, biologic intermediates, and autonomic
nervous system activation. End-organ effector pathways such as endothelial barrier disruption/dysfunction, thrombosis,
vasoconstriction/increased blood pressure, and plaque instability, may contribute to ASCVD. The strength of the association
of air pollution with ASCVD offers an opportunity to mitigate its consequences. Although elimination of anthropogenic sources
of air pollution with a switch to clean energy provides the ultimate solution, this may not be possible in the interim and may
require personal protection efforts and an integrated approach to managing risk posed by air pollution for ASCVD.

GRAPHIC ABSTRACT: A graphic abstract is available for this article.

Key Words: air pollution ◼ atherosclerosis ◼ cardiovascular disease ◼ myocardial infarction ◼ particulate matter
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A
mbient air pollution is the single most important
environmental risk factor globally, contributing to
more deaths than all other known environmental and
common infectious diseases combined.1,2 The strongest
association is for the particulate matter ≤2.5 μ (PM2.5)
component of air pollution.3,4 The preponderant majority
of deaths (57%–76%) due to PM2.5 are a result of ath-
erosclerotic cardiovascular disease (ASCVD). A robust
body of epidemiological evidence supports a consistent
relationship between both short-term (days to weeks)
and chronic (years) air pollution exposure and ASCVD
events, such as myocardial infarction and stroke.5 Given
the large population of asymptomatic yet at-risk indi-
viduals globally, even a small elevation in risk due to an
increase in PM2.5 translates into hundreds of thousands
of lives potentially lost. Although not always consis-
tent, imaging surrogates of atherosclerosis in humans
have provided confirmatory support for epidemiological
observations, whereas mechanistic animal studies and
translational research in humans have provided insights
into pathways by which PM2.5 predisposes to ASCVD
events.6 This review will focus on the epidemiological
links between air pollution and atherosclerosis, dose and
temporal relationships, mechanisms, and finally, the gaps
in our current understanding of air pollution–mediated
ASCVD risk.
COMPOSITION AND DOSE-RESPONSE
RELATIONSHIPS
Air pollution is a heterogeneous mixture of PM and
gaseous components that are released directly into
the atmosphere (primary pollutants) but also generated
through reactions in the atmospheric column or with
other components (ozone and secondary PM2.5) that vary
both spatially and temporally.5,7 The sources of PM are
diverse and include anthropogenic causes (eg, fossil fuel
and power generation), but also natural sources such as

Correspondence to: Sanjay Rajagopalan, MD, University Hospitals, 11100 Euclid Ave, Cleveland, OH. Email sanjay.rajagopalan@uhhospitals.org
For Sources of Funding and Disclosures, see page 635.
© 2020 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at www.ahajournals.org/journal/atvb

628   February 2021 Arterioscler Thromb Vasc Biol. 2021;41:628–637. DOI: 10.1161/ATVBAHA.120.315219
 Bevan et al
Nonstandard Abbreviations and Acronyms
ASCVD atherosclerotic cardiovascular disease
HDL high-density lipoprotein
LDL low-density lipoprotein
MESA Multiethnic Study of Atherosclerosis
MI myocardial infarction
MMP matrix metalloproteinases
PM2.5 particulate matter ≤2.5
PURE Prospective Urban and Rural
Epidemiology
UFP ultrafine PM
volcanic eruptions, dust storms, and wildfires, which are
becoming more prevalent with climate change. The par-
ticles in air pollution range in diameter and are defined
by the following size parameters: coarse PM (PM 2.5–10
μ in diameter; PM10-2.5), fine PM (PM≤2.5 μ in diameter;
PM2.5), and ultrafine PM (UFP, PM≤0.1 μ in diameter;
PM0.1). Notably, PM2.5 contains ultrafine components. The
size fractions demonstrate marked differences in com-
positional chemistry.
The preponderance of epidemiological data has iden-
tified association between PM2.5 and ASCVD. In contrast,
the association between PM10-2.5 and health outcomes
is less consistent.8–10 There is emerging evidence that
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UFP which almost exclusively originate from combustion
sources have important links with ASCVD surrogates
and increased events, compared with PM2.5. However,
the rather unstable nature of UFP, marked regional varia-
tions in composition (within a few meters), and rapidly
changing compositional characteristics, make associa-
tion of ASCVD events with UFP challenging.
The PM2.5 dose-response relationship to mortality and
ASCVD is foundational in understanding the relationship
between concentration level, dose, and risk. In a new expo-
sure-response model (Global Exposure Mortality Model),
based exclusively on studies of ambient air pollution (41
cohorts from 16 countries, including China, allowing a
broad range of exposures), the global burden of mortality
attributable to PM2.5 was found to be 8.9 million deaths,
of which >50% were from ischemic heart disease and
stroke.2 The shape of the response curve for ASCVD was
nearly linear with little evidence of flattening across current
global pollutant levels, and no lower concentration thresh-
old, below which exposures could be considered safe at the
population level (Figure 1). Prior iterations of the integrated
exposure-response included the use of nonoutdoor air pol-
lution exposures such as indoor air pollution and smoking
in the derivation of exposure-response function.2,12,13
The World Health Organization Air Quality Guide-
line recommends that annual average PM2.5 should
not exceed 10 μg/m3, whereas daily levels should not
surpass 20 μg/m3. The National Ambient Air Quality
Arterioscler Thromb Vasc Biol. 2021;41:628–637. DOI: 10.1161/ATVBAHA.120.315219
Ambient Air Pollution and Atherosclerosis
Highlights
Brief Review - VB
• Numerous epidemiological studies conducted
worldwide have established the temporal, composi-
tion, and dose relationships of ambient air pollution
with atherosclerotic cardiovascular disease.
• Mechanistic studies from animal exposure models
and human translational research have identified 3
basic mechanisms by which ambient air pollution
potentiates atherosclerotic cardiovascular disease:
(1) primary initiating responses to pollutant inhala-
tion in the lung, (2) transmission pathways, and (3)
end-organ effector mechanisms.
• Although optimal medical management of traditional
risk factors remains an essential tenet to prevention
of atherosclerotic cardiovascular disease in at-risk
individuals, public policy changes and personal pro-
tection measures such as pollution avoidance and
air filtration may reduce atherosclerotic risk.
Standards in the United States stipulate levels of <12
and <35 μg/m3 for annual and daily levels, respectively
(Figure 1).12 The population-weighted annual average
PM2.5 over North America decreased from 22±6.4 μg/m3
in 1981, to 12±3.2 μg m3 in 1998, and to 7.9±2.1 μg m3
in 2016. In contrast, global PM2.5 levels increased from
39.6 µg/m3 in 1990 to 49.6 µg/m3 in 2016, largely due
to increasing urbanization/industrialization in Asia and
Africa.4 Over 90% of the world population lives at PM2.5
levels above World Health Organization standards with
annual concentrations exceeding 50 μg/m3 routinely
observed in multiple Asian cities.14
From a compositional standpoint, sulfates, nitrates, and
organic carbon from anthropogenic sources have been
linked strongly with ASCVD events.15–18 Heart failure
hospitalization and death are associated with increases
in carbon monoxide, sulfur dioxide, nitrogen dioxide but
not ozone. In an analysis of 445 860 individuals in the
American Cancer Society Cancer Prevention Study II, the
risk of ASCVD mortality associated with PM2.5 from coal
combustion was five times higher than the risk associated
with overall PM2.5 mass.19 The association between long-
term ozone exposures and cardiovascular mortality are
modest and lower than other causes of mortality, such as
chronic obstructive pulmonary disease.20 Similarly, there
is paucity of data for other gaseous copollutants such as
volatile organics carbons and ASCVD events.6
EPIDEMIOLOGY OF AIR POLLUTION–
MEDIATED ASCVD EVENTS
Numerous studies conducted worldwide have shown
that exposure to PM2.5 is associated with an increased
risk for myocardial infarction, stroke, and cardiovascu-
lar mortality. This relationship is seen across a range of
February 2021   629
 Bevan et al Ambient Air Pollution and Atherosclerosis
Brief Review - VB

Figure 1. Particulate matter size, national distribution, temporal trends, and exposure response estimate.
A, Particulate matter (PM) size fractions. B, Exposure concentrations across the continental United States in 2018 with the colors indicating
locales above and below the National Ambient Air Quality Standards (NAAQS) annual PM ≤2.5 (PM2.5) average. C, Estimates of annual PM2.5
levels in the United States over 2 decades derived from Clay and Muller.11 D, Exposure-response function derived from Burnett et al.2 WHO
indicates World Health Organization.

exposures with no lower or upper limits where the effect CI, 1.09–1.18]). When stratified by country income, PM2.5
estimates attenuate.2 Indeed short-term (hours to days) remained associated with ASCVD events with high or
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time series and case cross-over studies in United States,
Canada, and Europe, at daily levels <35 µg/m3 (Daily
National Ambient Air Quality Standard limit) translate to
a ≈0.25%–1% elevation in relative risk for cardiovascular
mortality. At daily levels >35 µg/m3, a meta-analysis of 7
studies in China showed an increase of 0.35% in risk for
cardiovascular mortality per 10 µg/m3 of PM2.5.21 Chronic
exposure studies have shown stronger estimates, con-
sistent with the concept that cumulative exposure to
PM2.5 may exert effects analogous to classic risk factors
like LDL (low-density lipoprotein) or smoking. The Ameri-
can Cancer Society study in 1.2 million people from 172
metropolitan areas in the United States showed that
after adjustment of 44 variables, each 10 µg/m3 incre-
ment in annual PM2.5 was associated with 15% relative
increase in ischemic heart disease deaths (hazard ratio,
1.15 [1.11–1.20]).22 Even more robust estimates were
in fact seen at lower exposure levels in Canada (mean
PM2.5 of 8.7 µg/m3), with 31% relative increase, in isch-
emic heart disease death (hazard ratio 1.31 per 10 µg/
m3 increment in annual PM2.5).23 Similar estimates were
seen in China, suggesting continuing effects at extreme
doses of PM2.5.6 In analysis of the PURE study (Prospec-
tive Urban and Rural Epidemiology), PM2.5 continued to
associate with cardiovascular events in both rural and
urban communities with larger associations with PM2.5
and stroke in rural communities (hazard ratio, 1.13 [95%
upper middle-income countries demonstrating the stron-
gest associations to cardiovascular events (hazard ratio,
1.14 [95% CI, 1.07–1.21]).24
Both time series and case-crossover studies have
shown an association between PM2.5 exposure and the
risk of nonfatal myocardial infarction (MI; Table I in the Data
Supplement).12 The evidence is stronger for ST-segment–
elevation MI compared with non–ST-segment– elevation
MI, with the risk higher for patients with angiographic evi-
dence of coronary artery disease.25 In a meta-analysis of
34 studies, every 10 µg/m3 of PM2.5 (lag 0 day) was asso-
ciated with a 2.5% relative risk for MI (relative risk, 1.025
[95% CI, 1.015–1.036]) with risk association noted for
other copollutants.26 These associations occur irrespective
of sociodemographic characteristics.27 A 2019 meta-anal-
ysis of 80 studies found a 1% increase in stroke per 10
μg/m3 increment of short-term PM2.5 exposure and a 14%
increase with chronic exposure. Associations were stron-
gest for ischemic and hemorrhagic stroke.28 In a recent
prospective cohort study in China (n=127 840) with
severe chronic elevations in annual PM2.5 (mean level of
67.4±15.1 mg/m3 calculated using satellite approaches)
each 10 μg/m3 increase in mean PM2.5 was associated
with a hazard ratio of 1.39 (95% CI, 1.28–1.52) for isch-
emic heart disease mortality, 1.52 for MI-mortality, and
1.11 for stroke, respectively. The estimates were stronger
at higher concentrations.29 A meta-analysis of 35 studies,

630   February 2021 Arterioscler Thromb Vasc Biol. 2021;41:628–637. DOI: 10.1161/ATVBAHA.120.315219
 Bevan et al
showed a 2.12% increase in risk per 10 μg/m3 (95% CI,
1.42–2.82) of short-term exposure, for the combined out-
come of heart failure hospitalization and death.30 At this
point further understanding of the association between
PM2.5 and the type of heart failure (ischemic versus non-
ischemic and heart failure with reduced ejection fraction
versus heart failure with preserved ejection fraction) is
hampered by lack of studies in this area.
Multiple limitations of PM2.5 epidemiology including
the independent and potentially synergistic contribution
by other environmental coexposures, such as noise, and
other poorly understood socioeconomic variables.
AIR POLLUTION AND ASCVD RISK
SURROGATES
Cross-sectional and prospective longitudinal cohort
studies have demonstrated a positive association
between estimated long-term exposure to PM2.5, as
well as near roadway exposure, to endothelial function
and atherosclerosis burden, when assessed by carotid
intimal media thickness, coronary and abdominal aortic
calcium.31–33 These results have not always been con-
sistent when examined in other cohorts and in some
studies, near roadway distance as a proxy measure for
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traffic air pollution exposure has been a stronger predic-
tor than PM2.5 levels.34,35 The MESA (Multiethnic Study
of Atherosclerosis)-Air cohort (n=6795 across 6 United
States regions) is the largest prospective study to dem-
onstrate an association between progression of coronary
artery calcium with air pollution levels. In MESA, a 5 µg/
m3 increase in long-term PM2.5 was associated with coro-
nary calcium progression (4.1 Agatston units/y).36 Each
40 ppb (parts per billion) increase in NOX resulted in 4.8
Agatston units per year progression in coronary calcium.
In a recent study performed in South Korea in patients
who underwent serial coronary computed tomographic
angiography at an interval of >2 years, an increase in 1
μg/m3 of PM2.5 was associated with a 62% increased
incidence of high-risk plaque (plaque with low attenua-
tion, spotty calcium, and positive remodeling) at follow-
up.37 Although findings from surrogate measures of
atherosclerosis provided a mechanistic basis to epide-
miological findings, results from surrogate studies should
be interpreted with caution, given the many limitations
inherent to these studies including cross-sectional analy-
sis (eg, unadjusted confounding variables, multiple colin-
ear factors, multiple testing, air pollution measures, such
as PM2.5 not being the primary variable of interest, etc;
Table II in the Data Supplement).
Arterioscler Thromb Vasc Biol. 2021;41:628–637. DOI: 10.1161/ATVBAHA.120.315219
Ambient Air Pollution and Atherosclerosis
TIME FRAMES OF EXPOSURE AND ASCVD
EVENTS
Brief Review - VB
A key question in air pollution research is what time
frames of exposure are most relevant in mediating
ASCVD events. Time series and case cross-over studies
attest to the close relationship between acute variation
in PM2.5 and ASCVD events and is supportive evidence
that PM2.5 plays a potential etiologic role.5 In this case, a
susceptible individual who is high-risk for ASCVD, may
experience an event when exposed to high levels of air
pollution, often in concert with other poorly understood
stressors. This is consistent with the available evidence
that patients who are older, those with multiple risk fac-
tors, or prior cardiovascular or pulmonary disease, experi-
ence most of the risk posed by air pollution.6,12 Although
exposure over years may promote anatomic progression
of the burden of atherosclerosis plaque commonly used
in surrogate studies, this is ultimately not the process
responsible for an acute ASCVD event. Progression of
plaque with chronic exposure may, however, facilitate the
development of vulnerable plaque features that may pre-
cipitate an acute coronary event (plaque inflammation,
weakening of fibrous cap, and lipid content).37 Thus it is
easy to see how years of PM2.5 exposure may facilitate
a vulnerable state that may then confer risk to acute
variations in PM2.5 levels. The epidemiological studies are
indeed consistent with this notion, where attributable risk
to PM2.5 is related to exposures in the short- and inter-
mediate-term (hours to 1–2 years). Larger but progres-
sively smaller relative increases in health effects (ie, in
a less-than-additive fashion) are induced by prolonging
the exposure window or follow-up period beyond 1 to 2
years (Figure 2). It is important not to overlook statisti-
cal artifacts that could serve as potential explanations
for this observation. For instance, ASCVD risk in the first
year of exposure is likely highly correlated with exposure
over many years, and this may help explain why only a
short period of PM2.5 exposure assessment is required to
understand the risk of longer-term exposure.
Mendelian Randomization studies have been quite
helpful in understanding time scales of exposure to risk
factors in ASCVD. Analogous to the findings from these
studies, where cumulative exposure to risk factors, such as
LDL or blood pressure (through genetic polymorphisms in
the LDL-receptor or pathways that regulate blood pres-
sure) over decades, magnifies the impact of these risk
factors on ASCVD events; it is possible that a lifetime of
exposure may promote even larger health effects. The
risks associated with decades of exposure have yet to be
fully captured and cohort studies could potentially under-
estimate the totality of ASCVD risk due to PM2.5 exposure.
It is unclear at present if the prospective studies which
typically associate only 1 to 10 years of exposure suffice
to quantify this lifetime excess risk, complicated by varia-
tion in PM2.5 levels and individual mobility.
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Figure 2. Conceptual model illustrating how long-term particulate matter ≤2.5 (PM2.5) exposure enhances cardiovascular risk
through plaque progression leading to an increased risk for cardiovascular events and plaque rupture, which itself may be
precipitated by acute variations in PM2.5 exposure.

system (sympathetic or hypothalamic pituitary adrenal

AIR POLLUTION AND ATHEROSCLEROSIS:
BIOLOGIC MECHANISMS
Mechanistic studies have shown that many distinct
yet interrelated processes mediate the cardiovascu-
lar effects of PM2.5 and underscore important parallels
with other conventional risk factors (Table III in the Data
Supplement).38 Furthermore, such pathways may pro-
vide clues for how PM2.5 may be a risk factor for plaque
progression and ASCVD events. ASCVD mechanisms
in response to air pollution may be broadly divided into
(1) primary initiating responses to pollutant inhalation in
the lung, (2) transmission pathways, and (3) end-organ
effector mechanisms. The initiating pathways in the lung
include (1) exogenous/pollutant or endogenous oxi-
dative stress, (2) pulmonary inflammation, and (3) ion
channel/receptor activation. The transmission pathways
include generation of biologic intermediates (eg, oxidized
lipids, cytokines, activated immune cells, microparticles,
microRNA, vasoconstrictors), autonomic imbalance/
afferent neurological circuits leading to central nervous
axis activation), and finally, nanoparticle constituents
reaching the circulation, or transmitted via neurological
pathways. These pathways, in turn, lead to end-organ
effector mechanisms responsible for ASCVD events,
among which 6 are most studied: (1) endothelial barrier
disruption or dysfunction; (2) tissue/organ inflammation;
(3) heightened coagulation-thrombosis; (4) vasocon-
striction/increased blood pressure (5) secondary tissue
damage/responses (plaque instability; Figure 2).12
An important aspect to consider when evaluating the
mechanistic evidence on air pollution and ASCVD vari-
ables, is the inherent variation in compositional charac-
teristics, routes/duration of exposure, and experimental
animal models. Although intratracheal/nasal exposures
are not physiological, they have been useful in elucidating
mechanistic pathways. Particle concentrators (for PM2.5)
and exposure systems for diesel exhaust emissions
have been used widely in experimental animal models
and humans. The limitations of the particle concentra-
tors are that the effects of gaseous constituents and

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 Bevan et al
Figure 3. Biologic mechanisms of particulate matter ≤2.5 (PM2.5)–induced atherosclerosis.
Left, Initiating, transmission, and effector mechanisms. Right, Cellular mechanisms of atherosclerosis. LDL indicates low-density lipoprotein;
ROS, reactive oxygen species; TLR4, Toll-like receptor 4; and VCAM, vascular cell adhesion molecule.
multipollutant interactions are typically absent, whereas
with diesel exhaust engine exposures, the lack of other
sources of PM2.5 and the resultant formation of second-
ary pollutants is largely absent. Nonetheless, these model
systems have been very useful in refining our mechanis-
tic understanding of exposure in atherosclerosis. Due to
a lack of appropriate animal model systems of unstable
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plaque, mechanistic understanding of triggered events is,
however, limited. In an early study of chronic exposure
over 6 months (5 days a week of exposure), ApoE−/−
mice exposed intermittently to 85 μg/m3 for 6 hours a
day 5 days a week developed more aortic plaque, lipid
content, vascular inflammation, and oxidant stress com-
pared with filtered air counterparts. Additionally, plaque
progression was accompanied by decreased endothelial
function and heightened vasoconstriction.39 Other expo-
sures including ultrafine and diesel exhaust have also
demonstrated progression of atherosclerosis.40,41 Con-
centrated UFP appears to be even more robust when
compared with concentrated PM2.5 in accelerating ath-
erosclerosis. In an important experiment in ApoE−/− mice
using a concentrator adjacent to the 110 freeway in Los
Angeles, ApoE−/− mice were exposed for 40 days (75
hours of cumulative exposure) to concentrated PM2.5 or
UFP, and compared with filtered air.41 PM2.5 concentra-
tion by mass was higher than UFP mass (438 versus
113 μg/m3), while particle numbers were lower (≈44%
greater in the UFP chamber), consistent with the smaller
size of UFP (and hence mass), and larger surface area
attributable to high particle numbers. Exposure to UFP
resulted in 55% greater aortic atherosclerosis versus
filtered air control. Although exposure to concentrated
PM2.5 resulted in increased atherosclerosis, it was of a
lower magnitude.29 Diesel exhaust particles have been
Arterioscler Thromb Vasc Biol. 2021;41:628–637. DOI: 10.1161/ATVBAHA.120.315219
Ambient Air Pollution and Atherosclerosis
Brief Review - VB
shown to increase atherosclerosis lesion severity.40 At
least for diesel, increased lipid peroxidation products and
diminished antioxidant function of HDL (high-density
lipoprotein) may be important etiologic mechanisms.42
In combined clinical and experimental studies that
have directly tested translocation of nanoparticles in
the ultrafine range (gold nanoparticles), particles been
shown to directly leach into the circulation and penetrate
atherosclerotic plaque.43 Gold was detected in the blood
and urine of volunteer humans within 15 minutes, with
small concentrations detected 3 months after expo-
sure. Translocation was markedly greater for particles
<10 nm with gold nanoparticles preferentially accumu-
lating in inflammation-rich vascular lesions of ApoE−/−
mice. Following inhalation studies in humans awaiting
carotid endarterectomy, gold particles could be detected
in surgical specimens of carotid artery plaque.43These
experiments suggest that nanoparticles are perfectly
capable of penetration with the systemic effects ulti-
mately depending on the chemical composition and
reactivity of these particles.
In a short-term study of gasoline emissions, ApoE−/−
mice were exposed by inhalation to filtered air or gas-
oline engine exhaust (1:12 dilution) 6 hours per day
for 1 or 7 days.44 Gasoline engine exhaust exposure
increased aortic content of MMP (matrix metallopro-
teinase)-2/9, endothelin-1, tissue inhibitor of metal-
loproteinases-2 mRNA, and reactive oxygen species
at 7 days. Antagonism of oxidant stress with endothe-
lin-1 using BQ-123 ameliorated expression of MMP-9
and MMP-2. In a parallel study in human subjects of
2-hour diesel exhaust exposure (100 μg/m3), sig-
nificant increase in plasma endothelin-1 and MMP-9
expression and activity were noted. These results are
February 2021   633
 Bevan et al
suggestive but not conclusive of oxidative stress–medi-
ated alteration in vulnerability characteristics in plaque
Brief Review - VB
with exposure to anthropogenic emissions.45–47
The role of the innate immune system in orchestrating
initiation and progression of atherosclerosis is common
to multiple traditional cardiovascular risk factors such as
diabetes and hyperlipidemia including ambient air pollu-
tion. Both coarse and fine PM, and likely UFP, stimulate
migration of monocyte populations from the bone mar-
row and spleen into atherosclerotic lesions.48 The trans-
mission of inflammatory signals from lung to circulation
and ultimately atherosclerotic plaques, likely involves oxi-
dative stress pathways and the generation of oxidized
intermediates, such as oxidation products of phospholip-
ids, cholesterol, and fatty acids.42,49,50 These intermediate
compounds may facilitate inflammation and CCL2/CCR2
(chemokine ligand 2/chemokine receptor 2) mediated
Ly6chi monocyte release from bone marrow.51Additional
biologic modifications of cholesterol to 7-ketocholesterol
has also been described in experimental atherosclerosis
in response to PM2.5 exposure.52 7-ketocholesterol is the
most abundant modified sterol in human atherosclero-
sis, exerting oxidant stress via NADPH oxidase activa-
tion and endothelial dysfunction; 7-ketocholesterol is
formed in response to experimental concentrated PM2.5
exposure, migrates in the plasma compartment in the
LDL fraction, and is avidly taken up by monocytes/mac-
rophages.52 Exposure to diesel exhaust enhanced lipid
peroxidation in mice with increased oxidized arachidonic
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acid and linoleic fatty acid products in both plasma and
bronchiolar fluid.42
PM2.5 exposure has also been shown to be associ-
ated with abnormalities in reverse cholesterol transport,
hyperlipidemia, and HDL dysfunction suggesting that
modification of HDL cholesterol could hypothetically
contribute to potentiation of atherogenesis.53,54
Endothelial dysfunction and alterations in systemic
microvascular and macrovascular tone occurs rapidly not
only in response to PM2.5 and UFP (eg, diesel exhaust)
but also coarse particles, and have been noted in ran-
domized trials in humans.31,55–57 Although it is likely true
that systemic effects may develop in the absence of
substantial pulmonary toxicity, it is also true that there is
a paucity of high-quality comparative studies that have
thoroughly investigated vascular and pulmonary toxicity
in animal models. Many of the studies have examined
one compartment vigorously, but not the other. Thus, the
evidence is at best inconclusive. However, it is indeed
safe to say that rapid alterations in vascular function and
blood pressure that occur within a matter of hours in
humans with acute exposure and may not involve sub-
stantial pulmonary inflammation. Several mechanisms
have been invoked as causal factors of rapid vascular
dysfunction, including release of reactive oxygen and
nitrogen species, degradation of nitric oxide, enhanced
release of vasoconstrictors, and finally inflammatory
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Ambient Air Pollution and Atherosclerosis
cytokines each of which individually and collectively may
impact vascular function.31,58 Heterogeneity in design
of human studies has sometimes yielded incongruent
results with vascular function and redox parameters,
most likely as a result of differences in chemical com-
position of air pollutants, associated copollutants, clini-
cal trial design, and host susceptibility.59 Nevertheless, in
several short-term studies, antecedent exposure to PM2.5
is associated with inflammatory and oxidant stress mea-
sures, that reverse on reducing exposure or moving to
a cleaner area.60 Higher air pollutant levels have been
associated with decrease in tissue inhibitor of MMP-1
and 2, heightened thrombogenicity (increase in soluble
CD40 ligand, soluble P-selectin, and fibrinogen/fibrin
degradation products) and elevation in interleukin-1β,
and other inflammatory markers.61 Recent double-blind
cross-over studies have demonstrated rapid changes in
microvascular function coupled with increase in inflam-
matory and oxidative stress parameters in healthy adults
that were reversible by reduction in particle numbers and
concentrations.31 Collectively, this supports the concept
that air pollution exposure through changes in oxidative
stress and likely downstream inflammatory mediators
causes endothelial dysfunction, rendering the exposed
individual more susceptible to chronic progression of
atherosclerosis. Endothelial progenitor cell–mediated
rescue of arterial injury has been shown to be impaired
in PM2.5 exposed mice. This effect was reversed with
lung overexpression of superoxide dismutase, illustrating
the causal nature of oxidative stress in the impairment of
endothelial function.50 Decreased endothelial progenitor
cells have also been noted in humans following episodes
of high air pollution levels.6 Exposure to PM2.5 has been
shown to enhance thrombogenicity and thrombosis in
humans and experimental models, suggesting a mech-
anism by which atherothrombotic events may occur in
vulnerable plaque following acute exposure.62–64 Hypoth-
esized pathways in animal models include lung macro-
phage release of interleukin-6 via mitochondrial reactive
oxygen species, as well as opening of endoplasmic retic-
ulum calcium channels and β adrenergic pathways.62 In
humans with a history of myocardial infarction, exposure
to diesel exhaust reduced endothelial tissue plasminogen
activator and increased ST-segment depression during
exercise, suggesting a direct mechanism by which acute
events may occur following an episode of ambient air
pollution.63 Platelet activation seems to be another hall-
mark of air pollution exposure in humans.64 Finally, it is
important to mention that air pollution appears to worsen
several traditional risk factors known to be strongly asso-
ciated with atherosclerosis, including increase in blood
pressure, insulin resistance, and myocardial hypertrophy.6
 Bevan et al
INTERVENTIONS TO REDUCE ASCVD RISK
POSED BY PM2.5 EXPOSURE
The Lancet Commission on Pollution and Public Health
stresses governmental regulation, legislation, resources,
and a clear roadmap as requirements for successful
air pollution regulation.1 Indeed legislative mandates to
reduce PM2.5 levels, result in demonstrable and immediate
benefits in ASCVD events. Urban planning, green belts,
relocation of sources (including major roadways and air-
ports), avoidance of mixed-use areas (such as industrial–
residential areas), and clean energy transportation can
all help reducing events in response to exposure through
multiple direct and indirect pathways. Although clean
energy solutions and social engineering approaches to
reduce exposure are permanent measures, these are not
immediate solutions. Coronavirus disease 2019 (COVID-
19) has provided an opportunity to accelerate a transi-
tion to a clean energy future by 2035.7 In the interim,
personal protection to mitigate PM2.5 exposure offers a
unique opportunity to reduce risk.6,12 Intervention trials
with N95 filtration masks have shown that reduction of
PM2.5 exposure lowers systolic blood pressure by 2 to 7
mm Hg and improves heart rate variability within hours.12
Multiple studies using home air filtration, when used over
days to weeks, have been shown to improve endothelial
function, reduce blood pressure and inflammation and
thrombotic biomarkers.6,12 Preliminary studies involving
Downloaded from http://ahajournals.org by on March 26, 2024
dietary fish oil supplementation (2.5 g/day) has been
shown to prevent PM2.5-mediated increase in inflamma-
tion, coagulation, endothelial function, oxidative stress,
and neuroendocrine stress response.65 Further research
is, however, needed to identify whether additional dietary
supplements, diets, or drugs can attenuate or prevent
the direct cardiovascular effects of air pollution. In the
interim, optimal medical management of traditional risk
factors remains an essential tenet to primary and sec-
ondary prevention of atherosclerosis and concomitant
exposure PM2.5 in at-risk individuals. The incorporation
of PM2.5 as a risk factor for ASCVD in national guide-
lines would be an important step towards acknowledg-
ment of the global impact of air pollution and directly
involving the medical community in targeting it.
CURRENT KNOWLEDGE GAPS AND
FUTURE DIRECTIONS
The strength of the epidemiological association between
PM2.5 and ASCVD across a range of concentrations and
recent insights into mechanisms including timing have
provided a refined understanding of the role exposure
plays in precipitating ASCVD. Even so, additional research
can facilitate further understanding into ASCVD events,
including promotion of unstable plaque syndromes,
and provide insights into exposure dose, duration, and
Arterioscler Thromb Vasc Biol. 2021;41:628–637. DOI: 10.1161/ATVBAHA.120.315219
Ambient Air Pollution and Atherosclerosis
response. In particular, further mechanistic understand-
ing of atherosclerosis with the use of state of art lineage
Brief Review - VB
tracking and vulnerable models may provide clarity on
cell-specific contributions and temporal changes asso-
ciated with short- and long-term air pollution exposure,
with opportunities for therapeutic modulation. In humans,
randomized, controlled clinical trials on the efficacy of
personalized intervention on hard outcomes can provide
definitive evidence of the efficacy of such measures
while we transition to complete elimination of fossil
fuels.66 Intervention trials would be of greatest relevance
and be most effective in heavily polluted countries, where
a reduction in inhaled PM2.5 would likely translate to a
substantial decrease in events, but could also be relevant
in vulnerable groups or hot spots in countries with low
levels of air pollution. Ultimately, the integration of exter-
nal environmental factors such as air pollution to tradi-
tional risk factors can provide an important opportunity
to address risk factors across the internal and external
environmental spectrum and help eliminate ASCVD risk.
ARTICLE INFORMATION
Received June 28, 2020; accepted November 11, 2020.
Affiliations
Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical
Center and School of Medicine, OH (G.H.B., S.G.A.-K., S.R.). Case Western Re-
serve University, Cleveland, OH (G.H.B., S.G.A.-K., S.R.). Division of Cardiovascu-
lar Diseases, Wayne State University, Detroit, MI (R.D.B.). Center for Cardiology,
Cardiology I, Angiology and Intensive Care Medicine, University Medical Center of
Johannes Gutenberg University, Mainz, Germany (T.M.). German Center for Car-
diovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany (T.M.).
Sources of Funding
This work was funded by National Institute of Environmental Health Sciences and
National Institute of Health Grants 5R01ES019616-07 and 1R01ES026291.
Disclosures
None.
REFERENCES
1. Landrigan PJ, Fuller R, Acosta NJR, Adeyi O, Arnold R, Basu NN,
Baldé AB, Bertollini R, Bose-O’Reilly S, Boufford JI, et al. The Lancet
Commission on pollution and health. Lancet. 2018;391:462–512. doi:
10.1016/S0140-6736(17)32345-0
2. Burnett R, Chen H, Szyszkowicz M, Fann N, Hubbell B, Pope CA III, Apte JS,
Brauer M, Cohen A, Weichenthal S, et al. Global estimates of mortality asso-
ciated with long-term exposure to outdoor fine particulate matter. Proc Natl
Acad Sci USA. 2018;115:9592–9597. doi: 10.1073/pnas.1803222115
3. Lelieveld J, Evans JS, Fnais M, Giannadaki D, Pozzer A. The contribution
of outdoor air pollution sources to premature mortality on a global scale.
Nature. 2015;525:367–371. doi: 10.1038/nature15371
4. Cohen AJ, Brauer M, Burnett R, Anderson HR, Frostad J, Estep K,
Balakrishnan K, Brunekreef B, Dandona L, Dandona R, et al. Estimates and
25-year trends of the global burden of disease attributable to ambient air pol-
lution: an analysis of data from the Global Burden of Diseases Study 2015.
Lancet. 2017;389:1907–1918. doi: 10.1016/S0140-6736(17)30505-6
5. Brook RD, Rajagopalan S, Pope CA III, Brook JR, Bhatnagar A, Diez-Roux AV,
Holguin F, Hong Y, Luepker RV, Mittleman MA, et al; American Heart Asso-
ciation Council on Epidemiology and Prevention, Council on the Kidney
in Cardiovascular Disease, and Council on Nutrition, Physical Activity and
Metabolism. Particulate matter air pollution and cardiovascular disease: an
February 2021   635
 Bevan et al
update to the scientific statement from the American Heart Association. Cir-
culation. 2010;121:2331–2378. doi: 10.1161/CIR.0b013e3181dbece1
Brief Review - VB
6. Al-Kindi SG, Brook RD, Biswal S, Rajagopalan S. Environmental determi-
nants of cardiovascular disease: lessons learned from air pollution. Nat Rev
Cardiol. 2020;17:656–672. doi: 10.1038/s41569-020-0371-2
7. Newby DE, Mannucci PM, Tell GS, Baccarelli AA, Brook RD, Donaldson K,
Forastiere F, Franchini M, Franco OH, Graham I, et al; ESC Working Group
on Thrombosis, European Association for Cardiovascular Prevention and
Rehabilitation; ESC Heart Failure Association. Expert position paper on air
pollution and cardiovascular disease. Eur Heart J. 2015;36:83–93b. doi:
10.1093/eurheartj/ehu458
8. Kan H, London SJ, Chen G, Zhang Y, Song G, Zhao N, Jiang L, Chen B. Differ-
entiating the effects of fine and coarse particles on daily mortality in Shang-
hai, China. Environ Int. 2007;33:376–384. doi: 10.1016/j.envint.2006.12.001
9. Peng RD, Chang HH, Bell ML, McDermott A, Zeger SL, Samet JM,
Dominici F. Coarse particulate matter air pollution and hospital admissions
for cardiovascular and respiratory diseases among Medicare patients.
JAMA. 2008;299:2172–2179. doi: 10.1001/jama.299.18.2172
10. Zanobetti A, Schwartz J. The effect of fine and coarse particulate air pollution
on mortality: a national analysis. Environ Health Perspect. 2009;117:898–
903. doi: 10.1289/ehp.0800108
11. Clay K, Muller NZ. Recent Increases in Air Pollution: Evidence and Implica-
tions for Mortality. NBER Program(s), Environment and Energy Economics;
2019. National Bureau of Economic Research Working Paper No. 26381.
12. Rajagopalan S, Al-Kindi SG, Brook RD. Air pollution and cardiovascular
disease: JACC state-of-the-art review. J Am Coll Cardiol. 2018;72:2054–
2070. doi: 10.1016/j.jacc.2018.07.099
13. Pope CA III, Burnett RT, Krewski D, Jerrett M, Shi Y, Calle EE, Thun MJ. Car-
diovascular mortality and exposure to airborne fine particulate matter and
cigarette smoke: shape of the exposure-response relationship. Circulation.
2009;120:941–948. doi: 10.1161/CIRCULATIONAHA.109.857888
14. van Donkelaar A, Martin RV, Brauer M, Boys BL. Use of satellite obser-
vations for long-term exposure assessment of global concentrations of
fine particulate matter. Environ Health Perspect. 2015;123:135–143. doi:
10.1289/ehp.1408646
15. Annex BH, Denning SM, Channon KM, Sketch MH Jr, Stack RS, Morrissey
JH, Peters KG. Differential expression of tissue factor protein in directional
atherectomy specimens from patients with stable and unstable coronary syn-
Downloaded from http://ahajournals.org by on March 26, 2024
dromes. Circulation. 1995;91:619–622. doi: 10.1161/01.cir.91.3.619
16. Ostro B, Lipsett M, Reynolds P, Goldberg D, Hertz A, Garcia C, Henderson
KD, Bernstein L. Long-term exposure to constituents of fine particulate air
pollution and mortality: results from the California Teachers Study. Environ
Health Perspect. 2010;118:363–369. doi: 10.1289/ehp.0901181
17. Ostro B, Hu J, Goldberg D, Reynolds P, Hertz A, Bernstein L, Kleeman MJ.
Associations of mortality with long-term exposures to fine and ultrafine par-
ticles, species and sources: results from the California Teachers Study Cohort.
Environ Health Perspect. 2015;123:549–556. doi: 10.1289/ehp.1408565
18. Atkinson RW, Mills IC, Walton HA, Anderson HR. Fine particle components
and health—a systematic review and meta-analysis of epidemiological time
series studies of daily mortality and hospital admissions. J Expo Sci Environ
Epidemiol. 2015;25:208.
19. Thurston GD, Burnett RT, Turner MC, Shi Y, Krewski D, Lall R, Ito K, Jerrett M,
Gapstur SM, Diver WR, et al. Ischemic heart disease mortality and long-term
exposure to source-related components of U.S. fine particle air pollution.
Environ Health Perspect. 2016;124:785–794. doi: 10.1289/ehp.1509777
20. Lim CC, Hayes RB, Ahn J, Shao Y, Silverman DT, Jones RR, Garcia C, Bell ML,
Thurston GD. Long-term exposure to ozone and cause-specific mortality
risk in the United States. Am J Respir Crit Care Med. 2019;200:1022–
1031. doi: 10.1164/rccm.201806-1161OC
21. Lu F, Xu D, Cheng Y, Dong S, Guo C, Jiang X, Zheng X. Systematic review
and meta-analysis of the adverse health effects of ambient PM2.5 and
PM10 pollution in the Chinese population. Environ Res. 2015;136:196–
204. doi: 10.1016/j.envres.2014.06.029
22. Krewski D, Jerrett M, Burnett RT, Ma R, Hughes E, Shi Y, Turner MC,
Pope CA III, Thurston G, Calle EE, et al. Extended follow-up and spatial analy-
sis of the American Cancer Society study linking particulate air pollution and
mortality. Res Rep Health Eff Inst. 2009;140:5–114; discussion 115-136.
23. Crouse DL, Peters PA, van Donkelaar A, Goldberg MS, Villeneuve PJ,
Brion O, Khan S, Atari DO, Jerrett M, Pope CA, et al. Risk of nonaccidental
and cardiovascular mortality in relation to long-term exposure to low con-
centrations of fine particulate matter: a Canadian national-level cohort study.
Environ Health Perspect. 2012;120:708–714. doi: 10.1289/ehp.1104049
24. Hystad P, Larkin A, Rangarajan S, AlHabib KF, Avezum Á, Calik KBT,
Chifamba J, Dans A, Diaz R, du Plessis JL, et al. Associations of outdoor fine
636   February 2021 Arterioscler Thromb Vasc Biol. 2021;41:628–637. DOI: 10.1161/ATVBAHA.120.315219
Ambient Air Pollution and Atherosclerosis
particulate air pollution and cardiovascular disease in 157 436 individuals
from 21 high-income, middle-income, and low-income countries (PURE): a
prospective cohort study. Lancet Planet Health. 2020;4:e235–e245.
25. Pope CA III, Muhlestein JB, May HT, Renlund DG, Anderson JL,
Horne BD. Ischemic heart disease events triggered by short-term expo-
sure to fine particulate air pollution. Circulation. 2006;114:2443–2448. doi:
10.1161/CIRCULATIONAHA.106.636977
26. Mustafic H, Jabre P, Caussin C, Murad MH, Escolano S, Tafflet M, Périer MC,
Marijon E, Vernerey D, Empana JP, et al. Main air pollutants and myocardial
infarction: a systematic review and meta-analysis. JAMA. 2012;307:713–
721. doi: 10.1001/jama.2012.126
27. Weaver AM, McGuinn L, Neas L, Mirowsky J, Devlin RB, Dhingra R,
Ward-Caviness C, Cascio WE, Kraus WE, Hauser ER, et al. Neighborhood
sociodemographic effects on the associations between long-term PM2.5
exposure and cardiovascular outcomes and diabetes. Environ Epidemiol.
2019;3:e038.
28. Fu P, Guo X, Cheung FMH, Yung KKL. The association between PM2.5
exposure and neurological disorders: a systematic review and meta-
analysis. Sci Total Environ. 2019;655:1240–1248. doi: 10.1016/j.
scitotenv.2018.11.218
29. Liang F, Liu F, Huang K, Yang X, Li J, Xiao Q, Chen J, Liu X,
Cao J, Shen C, et al. Long-term exposure to fine particulate matter and
cardiovascular disease in China. J Am Coll Cardiol. 2020;75:707–717. doi:
10.1016/j.jacc.2019.12.031
30. Shah AS, Langrish JP, Nair H, McAllister DA, Hunter AL, Donaldson K,
Newby DE, Mills NL. Global association of air pollution and heart failure: a
systematic review and meta-analysis. Lancet. 2013;382:1039–1048. doi:
10.1016/S0140-6736(13)60898-3
31. Münzel T, Gori T, Al-Kindi S, Deanfield J, Lelieveld J, Daiber A, Rajagopalan S.
Effects of gaseous and solid constituents of air pollution on endothelial func-
tion. Eur Heart J. 2018;39:3543–3550. doi: 10.1093/eurheartj/ehy481
32. Wilker EH, Ljungman PL, Rice MB, Kloog I, Schwartz J, Gold DR, Koutrakis P,
Vita JA, Mitchell GF, Vasan RS, et al. Relation of long-term exposure to air
pollution to brachial artery flow-mediated dilation and reactive hyperemia. Am
J Cardiol. 2014;113:2057–2063. doi: 10.1016/j.amjcard.2014.03.048
33. Provost EB, Madhloum N, Int Panis L, De Boever P, Nawrot TS. Carotid
intima-media thickness, a marker of subclinical atherosclerosis, and par-
ticulate air pollution exposure: the meta-analytical evidence. PLoS One.
2015;10:e0127014. doi: 10.1371/journal.pone.0127014
34. Wang Y, Wellenius GA, Hickson DA, Gjelsvik A, Eaton CB, Wyatt SB. Resi-
dential proximity to traffic-related pollution and atherosclerosis in 4 vascular
beds among African-American adults: results from the Jackson Heart Study.
Am J Epidemiol. 2016;184:732–743. doi: 10.1093/aje/kww080
35. Dorans KS, Wilker EH, Li W, Rice MB, Ljungman PL, Schwartz J, Coull BA,
Kloog I, Koutrakis P, D’Agostino RB, et al. Residential proximity to major
roads, exposure to fine particulate matter and aortic calcium: the Fram-
ingham Heart Study, a cohort study. BMJ Open. 2017;7:e013455. doi:
10.1136/bmjopen-2016-013455
36. Kaufman JD, Adar SD, Barr RG, Budoff M, Burke GL, Curl CL,
Daviglus ML, Diez Roux AV, Gassett AJ, Jacobs DR Jr, et al. Association
between air pollution and coronary artery calcification within six metropoli-
tan areas in the USA (the Multi-Ethnic Study of Atherosclerosis and Air
Pollution): a longitudinal cohort study. Lancet. 2016;388:696–704. doi:
10.1016/S0140-6736(16)00378-0
37. Yang S, Lee SP, Park JB, Lee H, Kang SH, Lee SE, Kim JB, Choi SY, Kim YJ,
Chang HJ. PM2.5 concentration in the ambient air is a risk factor for the
development of high-risk coronary plaques. Eur Heart J Cardiovasc Imaging.
2019;20:1355–1364. doi: 10.1093/ehjci/jez209
38. Münzel T, Sørensen M, Gori T, Schmidt FP, Rao X, Brook FR, Chen LC,
Brook RD, Rajagopalan S. Environmental stressors and cardio-metabolic
disease: part II-mechanistic insights. Eur Heart J. 2017;38:557–564. doi:
10.1093/eurheartj/ehw294
39. Sun Q, Wang A, Jin X, Natanzon A, Duquaine D, Brook RD, Aguinaldo JG,
Fayad ZA, Fuster V, Lippmann M, et al. Long-term air pollution exposure and
acceleration of atherosclerosis and vascular inflammation in an animal model.
JAMA. 2005;294:3003–3010. doi: 10.1001/jama.294.23.3003
40. Miller MR, McLean SG, Duffin R, Lawal AO, Araujo JA, Shaw CA, Mills NL,
Donaldson K, Newby DE, Hadoke PW. Diesel exhaust particulate increases
the size and complexity of lesions in atherosclerotic mice. Part Fibre Toxicol.
2013;10:61. doi: 10.1186/1743-8977-10-61
41. Araujo JA, Barajas B, Kleinman M, Wang X, Bennett BJ, Gong KW, Navab M,
Harkema J, Sioutas C, Lusis AJ, et al. Ambient particulate pollutants in the
ultrafine range promote early atherosclerosis and systemic oxidative stress.
Circ Res. 2008;102:589–596. doi: 10.1161/CIRCRESAHA.107.164970
 Bevan et al
42. Yin F, Lawal A, Ricks J, Fox JR, Larson T, Navab M, Fogelman AM,
Rosenfeld ME, Araujo JA. Diesel exhaust induces systemic lipid peroxida-
tion and development of dysfunctional pro-oxidant and pro-inflammatory
high-density lipoprotein. Arterioscler Thromb Vasc Biol. 2013;33:1153–
1161. doi: 10.1161/ATVBAHA.112.300552
43. Miller MR, Raftis JB, Langrish JP, McLean SG, Samutrtai P, Connell SP,
Wilson S, Vesey AT, Fokkens PHB, Boere AJF, et al. Inhaled nanoparticles
accumulate at sites of vascular disease. ACS Nano. 2017;11:4542–4552.
doi: 10.1021/acsnano.6b08551
44. Lund AK, Lucero J, Lucas S, Madden MC, McDonald JD, Seagrave JC,
Knuckles TL, Campen MJ. Vehicular emissions induce vascular
MMP-9 expression and activity associated with endothelin-1-mediated
pathways. Arterioscler Thromb Vasc Biol. 2009;29:511–517. doi: 10.1161/
ATVBAHA.108.176107
45. Loftus IM, Naylor AR, Goodall S, Crowther M, Jones L, Bell PR,
Thompson MM. Increased matrix metalloproteinase-9 activity in unsta-
ble carotid plaques. A potential role in acute plaque disruption. Stroke.
2000;31:40–47. doi: 10.1161/01.str.31.1.40
46. Zeiher AM, Goebel H, Schächinger V, Ihling C. Tissue endothelin-1 immuno-
reactivity in the active coronary atherosclerotic plaque. A clue to the mech-
anism of increased vasoreactivity of the culprit lesion in unstable angina.
Circulation. 1995;91:941–947. doi: 10.1161/01.cir.91.4.941
47. Rajagopalan S, Meng XP, Ramasamy S, Harrison DG, Galis ZS. Reactive
oxygen species produced by macrophage-derived foam cells regulate
the activity of vascular matrix metalloproteinases in vitro. Implications for
atherosclerotic plaque stability. J Clin Invest. 1996;98:2572–2579. doi:
10.1172/JCI119076
48. Suwa T, Hogg JC, Quinlan KB, Ohgami A, Vincent R, van Eeden SF. Particu-
late air pollution induces progression of atherosclerosis. J Am Coll Cardiol.
2002;39:935–942. doi: 10.1016/s0735-1097(02)01715-1
49. Haberzettl P, O’Toole TE, Bhatnagar A, Conklin DJ. Exposure to fine par-
ticulate air pollution causes vascular insulin resistance by inducing pulmo-
nary oxidative stress. Environ Health Perspect. 2016;124:1830–1839. doi:
10.1289/EHP212
50. Haberzettl P, Conklin DJ, Abplanalp WT, Bhatnagar A, O’Toole TE. Inhalation
of fine particulate matter impairs endothelial progenitor cell function via pul-
monary oxidative stress. Arterioscler Thromb Vasc Biol. 2018;38:131–142.
doi: 10.1161/ATVBAHA.117.309971
Downloaded from http://ahajournals.org by on March 26, 2024
51. Kampfrath T, Maiseyeu A, Ying Z, Shah Z, Deiuliis JA, Xu X, Kherada
N, Brook RD, Reddy KM, Padture NP, et al. Chronic fine particulate mat-
ter exposure induces systemic vascular dysfunction via NADPH oxi-
dase and TLR4 pathways. Circ Res. 2011;108:716–726. doi: 10.1161/
CIRCRESAHA.110.237560
52. Rao X, Zhong J, Maiseyeu A, Gopalakrishnan B, Villamena FA, Chen LC,
Harkema JR, Sun Q, Rajagopalan S. CD36-dependent 7-ketocholesterol
accumulation in macrophages mediates progression of atherosclerosis in
response to chronic air pollution exposure. Circ Res. 2014;115:770–780.
doi: 10.1161/CIRCRESAHA.115.304666
53. Li J, Zhou C, Xu H, Brook RD, Liu S, Yi T, Wang Y, Feng B, Zhao M,
Wang X, et al. Ambient air pollution is associated with HDL (High-Density
Lipoprotein) dysfunction in healthy adults. Arterioscler Thromb Vasc Biol.
2019;39:513–522. doi: 10.1161/ATVBAHA.118.311749
Arterioscler Thromb Vasc Biol. 2021;41:628–637. DOI: 10.1161/ATVBAHA.120.315219
Ambient Air Pollution and Atherosclerosis
54. Gaio V, Roquette R, Dias CM, Nunes B. Ambient air pollution and lipid
profile: systematic review and meta-analysis. Environ Pollut. 2019;254(pt
Brief Review - VB
B):113036. doi: 10.1016/j.envpol.2019.113036
55. Wauters A, Dreyfuss C, Pochet S, Hendrick P, Berkenboom G,
van de Borne P, Argacha JF. Acute exposure to diesel exhaust impairs
nitric oxide-mediated endothelial vasomotor function by increasing endo-
thelial oxidative stress. Hypertension. 2013;62:352–358. doi: 10.1161/
HYPERTENSIONAHA.111.00991
56. Lucking AJ, Lundbäck M, Barath SL, Mills NL, Sidhu MK, Langrish JP,
Boon NA, Pourazar J, Badimon JJ, Gerlofs-Nijland ME, et al. Particle traps
prevent adverse vascular and prothrombotic effects of diesel engine
exhaust inhalation in men. Circulation. 2011;123:1721–1728. doi:
10.1161/CIRCULATIONAHA.110.987263
57. Brook RD, Brook JR, Urch B, Vincent R, Rajagopalan S, Silverman F.
Inhalation of fine particulate air pollution and ozone causes acute arterial
vasoconstriction in healthy adults. Circulation. 2002;105:1534–1536. doi:
10.1161/01.cir.0000013838.94747.64
58. Langrish JP, Unosson J, Bosson J, Barath S, Muala A, Blackwell S,
Söderberg S, Pourazar J, Megson IL, Treweeke A, et al. Altered nitric oxide
bioavailability contributes to diesel exhaust inhalation-induced cardio-
vascular dysfunction in man. J Am Heart Assoc. 2013;2:e004309. doi:
10.1161/JAHA.112.004309
59. Rao X, Zhong J, Brook RD, Rajagopalan S. Effect of particulate matter air
pollution on cardiovascular oxidative stress pathways. Antioxid Redox Signal.
2018;28:797–818. doi: 10.1089/ars.2017.7394
60. Lin Y, Ramanathan G, Zhu Y, Yin F, Rea ND, Lu X, Tseng CH, Faull KF, Yoon AJ,
Jerrett M, et al. Pro-oxidative and proinflammatory effects after traveling from
Los Angeles to Beijing: a biomarker-based natural experiment. Circulation.
2019;140:1995–2004. doi: 10.1161/CIRCULATIONAHA.119.042054
61. Xu H, Wang T, Liu S, Brook RD, Feng B, Zhao Q, Song X, Yi T, Chen J, Zhang Y,
et al. Extreme levels of air pollution associated with changes in biomarkers of
atherosclerotic plaque vulnerability and thrombogenicity in healthy adults. Circ
Res. 2019;124:e30–e43. doi: 10.1161/CIRCRESAHA.118.313948
62. Soberanes S, Misharin AV, Jairaman A, Morales-Nebreda L, McQuattie-
Pimentel AC, Cho T, Hamanaka RB, Meliton AY, Reyfman PA, Walter JM,
et al. Metformin targets mitochondrial electron transport to reduce air-
pollution-induced thrombosis. Cell Metab. 2019;29:503. doi: 10.1016/j.
cmet.2018.12.001
63. Mills NL, Törnqvist H, Gonzalez MC, Vink E, Robinson SD, Söderberg
S, Boon NA, Donaldson K, Sandström T, Blomberg A, et al. Ischemic and throm-
botic effects of dilute diesel-exhaust inhalation in men with coronary heart dis-
ease. N Engl J Med. 2007;357:1075–1082. doi: 10.1056/NEJMoa066314
64. Lucking AJ, Lundback M, Mills NL, Faratian D, Barath SL, Pourazar J,
Cassee FR, Donaldson K, Boon NA, Badimon JJ, et al. Diesel exhaust inha-
lation increases thrombus formation in man. Eur Heart J. 2008;29:3043–
3051. doi: 10.1093/eurheartj/ehn464
65. Lin Z, Chen R, Jiang Y, Xia Y, Niu Y, Wang C, Liu C, Chen C, Ge Y, Wang W,
et al. Cardiovascular benefits of fish-oil supplementation against fine par-
ticulate air pollution in China. J Am Coll Cardiol. 2019;73:2076–2085. doi:
10.1016/j.jacc.2018.12.093
66. Brook RD, Newby DE, Rajagopalan S. Air pollution and cardiometabolic dis-
ease: an update and call for clinical trials. Am J Hypertens. 2018;31:1–10.
February 2021   637