36 nature clinical practice cardiovascular medicine january 2009 vol 6 no 1
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Adverse cardiovascular effects of air pollution
Nicholas L Mills*, Ken Donaldson, Paddy W Hadoke, Nicholas A Boon, William MacNee,
Flemming R Cassee, Thomas Sandström, Anders Blomberg and David E Newby

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Learning objectives
Upon completion of this activity, participants should be
able to:
1 Identify the component of air pollution most associ-
ated with adverse health effects in humans.
2 Describe the distribution of particulate matter.
3
Specify associations between particulate matter and
atherogenesis.

50 years, yet the association between air pollution

S u M M arY
Air pollution is increasingly recognized as an important and modifiable
determinant of cardiovascular disease in urban communities. Acute
exposure has been linked to a range of adverse cardiovascular events
including hospital admissions with angina, myocardial infarction, and
heart failure. Long-term exposure increases an individual’s lifetime
risk of death from coronary heart disease. The main arbiter of these
adverse health effects seems to be combustion-derived nanoparticles that
incorporate reactive organic and transition metal components. Inhalation
of this particulate matter leads to pulmonary inflammation with
secondary systemic effects or, after translocation from the lung into the
circulation, to direct toxic cardiovascular effects. Through the induction
of cellular oxidative stress and proinflammatory pathways, particulate
matter augments the development and progression of atherosclerosis
via detrimental effects on platelets, vascular tissue, and the myocardium.
These effects seem to underpin the atherothrombotic consequences of
acute and chronic exposure to air pollution. An increased understanding of
the mediators and mechanisms of these processes is necessary if we are to
develop strategies to protect individuals at risk and reduce the effect of air
pollution on cardiovascular disease.
KEYWORDS air pollution, atherothrombosis, endothelium, inflammation, risk
NL Mills is a Clinical Lecturer in Cardiology, PW Hadoke is a Senior
Academic Fellow in Pharmacology, NA Boon is a Consultant Cardiologist,
and DE Newby is a British Heart Foundation funded Professor of Cardiology
at the Centre for Cardiovascular Science, Edinburgh University, Edinburgh,
UK. W MacNee is Chair of Respiratory and Environmental Medicine and
K Donaldson is Scientific Director of the ELEGI Colt Laboratory, Edinburgh
University. FR Cassee is Head of the Department of Inhalation Toxicology

10–12
However,
these epidemiologic and observational data are
limited by imprecise measurements of pollution
exposure, and the potential for environmental
and social factors to confound the apparent
associations. For a causal association to have
scientific credence, a clear mechanism must
be defined. In this Review, we discuss potential
pathways through which air pollution mediates
these adverse cardiovascular effects. We also
explore the preclinical and clinical evidence for
the main mechanisms that link air pollution
with cardiovascular disease.
PATHWAY OF EXPOSURE
Causative components
Air pollutants implicated as potentially harmful
to health include particulate matter (PM), nitro-
gen dioxide, ozone, sulphur dioxide, and volatile
organic compounds. We will restrict our discus-
sion to the effects of PM, as this component of
the air pollution ‘cocktail’ has been most consi-
stently associated with adverse health effects.
3

Furthermore, both the WHO and the United
Nations have declared that PM poses the greatest
air pollution threat globally.
Large particles (diameter >10 μm) are mostly
derived from soil and crustal elements, whereas

between 100 and 250
μg/m
3
in industrialized
areas and in the developing world.
Many of the individual components of atmos-
pheric PM are not especially toxic at ambient
levels and some major constituents, such as
sodium chloride, are harmless. By contrast,
combustion-derived nanoparticles carry soluble
organic compounds, polycyclic aromatic hydro-
carbons, and oxidized transition metals on
their surface
13
and can generate oxidative stress
and inflammation.
14
Thus, the toxicity of PM
primarily relates to the number of particles
encountered, as well as their size, surface area,
and chemical composition. Although nano-
particles have a greater surface area and, there-
fore, potency than larger particles, important
effects of the coarse fraction (PM
2.5–10
) should
not be ruled out.
15
Potential effector pathways
The precise pathway through which PM influ-

after inhalation of both concentrated ambient
PM
19
and dilute diesel exhaust.
20
Such expo-
sures led to elevated plasma concentrations of
cytokines such as interleukin (IL)-1β, IL-6, and
granulocyte–macrophage colony-stimulating
factor,
21
all of which could be released as a con-
sequence of interactions between particles, alve-
olar macrophages, and airway epithelial cells.
22

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38 nature clinical practice cardiovascular medicine mills et al. january 2009 vol 6 no 1
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Indeed, inhalation of concentrated ambient PM
has been shown to induce the release of bone-
marrow-derived neutrophils and monocytes
into the circulation in both animal models
22
and
clinical studies.
23
Increases in plasma or serum markers of sys-
temic inflammation have been reported after
exposure to PM. In animal studies, plasma

charge, chemical composition, and propensity
to form aggregates. Translocation of inhaled
nanoparticles across the alveolar–blood barrier
has been demonstrated in animal studies for a
range of nanoparticles delivered by inhalation
or instillation.
30–32
Convincing demonstration
of translocation has been difficult to achieve in
humans;
33,34
however, given the deep penetra-
tion of nanoparticulate matter into the alveoli
and close apposition of the alveolar wall and capi-
llary network, such particle translocation seems
plausible—either as a naked particle or after
ingestion by alveolar macrophages (Figure 1).
Once in the circulation, nanoparticles could
interact with the vascular endothelium or have
direct effects on atherosclerotic plaques and
cause local oxidative stress and proinflamma-
tory effects similar to those seen in the lungs.
Increased inflammation could destabilize coro-
nary plaques, which might result in rupture,
thrombosis, and acute coronary syndrome.
35

Certainly, injured arteries can take up blood-
borne nanoparticles,
36

Metals
Capillary
Alveolus
TBTB
AM
PM
2.5
2.5 µm
A
B
Capillary
Classical
pathway
Alternative
pathway
Figure 1 The hypothetical effector pathways through which airborne
particulate matter influences cardiovascular risk. (A) Classical and alternative
pathways through which combustion-derived nanoparticulate matter induces
cardiovascular effects. (B) Transmission electron micrograph of the alveolar-
duct–terminal bronchiolar region that demonstrates the close proximity
between the alveolar wall and capillary network. Particle translocation from
the airways into the circulation may occur directly or after ingestion by alveolar
macrophages. Abbreviations: AM, alveolar macrophages; PM, particulate
matter; RBC, red blood cell; TB, the alveolar-duct–terminal bronchiolar region.
Part B adapted from Lehnert BE (1992) Environ Health Perspect 97: 17–46,
which is published under an open-access license by the US Department of
Health, Education, and Welfare.
69
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increases aortic plaque area and burden,
when compared with filtered air, in apolipo-
protein-E-knockout mice fed a high-fat diet.
37

The ultrafine component of PM
2.5
could have
a greater atherogenic effect than the fine frac-
tion—exposure to ultrafine particulate matter
rich in polycyclic aromatic hydrocarbons pro-
duced more inflammation, systemic oxida-
tive stress, and atheroma formation than the
fine fraction or filtered air in apolioprotein-
E-knockout mice.
38
In the Watanabe hyper-
lipidemic rabbit model, repeated instillation of
ambient PM
10
was associated with the develop-
ment of more-advanced, ‘vulnerable’ coronary
and aortic atherosclerotic plaques than those
seen in control rabbits.
39
Although the precise
role of different fractions of PM requires
further study, taken together these preclinical
data suggest that not only is the atherosclerotic
burden increased by exposure to PM, but that

acute coronary events, ventricular arrhythmia,
stroke, and hospitalizations and death caused by
Figure 2 The mechanisms through which combustion-derived nanoparticulate matter causes acute and
chronic cardiovascular disease.
NCPCM-2008-160-f02.eps
Oxidative stress and inflammation
Endothelium
Atheroma
Plaque rupture
Vasoconstriction
Thrombogenesis
Myocardial ischemia and infarction Arrhythmia
Cardiovascular death
Combustion-derived
nanoparticulate
Plaque
progression
Vasomotor
dysfunction
Fibrinolytic
imbalance
Platelets
Activation and
aggregation
Heart rhythm
Reduced heart
rate variability
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40 nature clinical practice cardiovascular medicine mills et al. january 2009 vol 6 no 1

and accumulation of fibrin and platelets on the
endothelial surface.
45
In addition to altering
the properties of endothelial cells and platelets,
nanoparticles could themselves act as a focus for
thrombus formation. Scanning electron micro-
scopy was used to evaluate explanted temporary
vena caval filters and revealed the presence of
foreign nanoparticulate within the thrombus
itself.
46

In 2008, long-term exposure to particulate air
pollution was linked to an increase in the risk
of venous thromboembolic disease.
47
In pre-
clinical models, overall thrombotic potential is
enhanced by exposure to PM, especially under
circumstances of vascular injury. Intratracheal
instillation of diesel exhaust particles augmented
thrombus formation in a hamster model of
both venous and arterial injury.
48
This increase
in thrombotic potential seems to be mediated,
at least in part, by enhanced platelet activation
and aggregation.
48

51
Vascular dysfunction
Epidemiologic and observational clinical studies
indicate that exposure to air pollution could
worsen symptoms of angina,
52
exacerbate exercise-
induced myocardial ischemia,
53
and trigger acute
myocardial infarction.
6
Many of these effects
could be mediated through direct effects on the
vasculature.
Both preclinical and clinical assessments
have demonstrated alterations in vascular vaso-
motor function after controlled exposures to
air pollution. In their proatherogenic mouse
model, Sun and colleagues reported enhanced
vasoconstriction and reduced endothelium-
dependent vasodilatation in the aorta after
chronic exposure to concentrated ambient
PM.
37
Similar vasoconstrictor effects of PM have
been reported by Brook and colleagues in clini-
cal studies of forearm conduit vessels, although
they observed no effects on endothelium-


www.nature.com/clinicalpractice/cardio
Abnormalities of vascular function are not only
restricted to vasomotion. In a series of double-
blind, randomized crossover studies, healthy men
and patients with stable coronary artery disease
were exposed to dilute diesel exhaust (300
μg/m
3

PM concentration) or filtered air for 1 h during
intermittent exercise.
55,62
In these studies, the
acute release of tissue plasminogen activa
-
tor, a key regulator of endogenous fibrinolytic
capacity, was reduced after diesel exhaust inha-
lation. This effect persisted for 6 h after initial
exposure,
55
and the magnitude of this reduc-
tion is comparable with that seen in cigarette
smokers.
63
This antifibrinolytic effect further
underscores the prothrombotic potential of air
pollution, especially under circumstances of

vascular injury.
The clinical effect of these alterations in vas-

65
Liao and colleagues were the first to report an
association between PM
2.5
and heart rate vari-
ability in a panel of elderly individuals (mean
age 81 years).
66
Although the authors considered
their finding somewhat exploratory, the analysis
revealed an inverse correlation between same-
day PM
2.5
concentrations and cardiac auto-
nomic control response. They hypothesized that
the association between inhaled PM and adverse
cardiovascular outcomes might be explained by
the effect of PM exposure on the autonomic
control of heart rate and rhythm. How inhaled
5*7*4MLWZ
100
90
80
70
60
50
0
10 15 20 25 30 35 40
10
0

A
C
Figure 3 Clinical consequences of diesel exhaust inhalation in patients with
coronary heart disease. Electrocardiographic ST-segment depression occurs
during exercise in patients with coronary heart disease exposed to filtered air
(solid line) or dilute diesel exhaust (dashed line). (A) Average change in heart rate
and ST-segment in lead II. (B) Maximal ST-segment depression (P = 0.003, diesel
exhaust versus filtered air), and (C) total ischemic burden (P <0.001, diesel exhaust
versus filtered air) as an average of leads II, V2, and V5. Reproduced from Mills NL
et al. (2007) Ischemic and thrombotic effects of dilute diesel-exhaust inhalation
in men with coronary heart disease. N Engl J Med 357: 1075–1082. Copyright ©
2007 Massachusetts Medical Society. All rights reserved.
62
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42 nature clinical practice cardiovascular medicine mills et al. january 2009 vol 6 no 1
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PM would modulate autonomic functions
remains unclear, but some investigators have
postulated that deposited particles could stimu-
late irritant receptors in the airways and directly
influence heart rate and rhythm via reflex activa-
tion of the nervous system.
35
Numerous panel
studies have since explored this mechanistic
hypothesis and have studied the associations
between levels of different air pollutants and
changes in heart rate variability or incidence
of cardiac arrhythmia. The current literature is,

challenge by the automotive industry. The mech-
anisms that underlie this association have yet to
be definitively established, but clear evidence
exists that many of the adverse health effects
are attributable to combustion-derived nano-
particles. Either through direct translocation
into the circulation or via secondary pulmonary-
derived mediators, PM augments atherogenesis
and causes acute adverse thrombotic and vas-
cular effects, which seem to be mediated by pro-
inflammatory and oxidative pathways. Improving
air quality standards, reducing personal expo-
sures, and the redesign of engine and fuel tech-
nologies could all have a role in reducing air
pollution and its consequences for cardiovascular

morbidity and mortality.
KEY POINTS
■ Exposure to air pollution is associated with
increased cardiovascular morbidity and deaths
from myocardial ischemia, arrhythmia, and
heart failure
■ Fine particulate matter derived from the
combustion of fossil fuels is thought to be the
most potent component of the air pollution
cocktail
■ Particulate matter upregulates systemic
proinflammatory and oxidative pathways, either
through direct translocation into the circulation
or via secondary pulmonary-derived mediators

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Foundation.
Charles P Vega, University
of California, Irvine, CA,
is the author of and is
solely responsible for the
content of the learning
objectives, questions and
answers of the Medscape-
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Competing interests
The authors declared no
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