Clinical Science (2008) 115, 175–187 (Printed in Great Britain) doi:10.1042/CS20070444
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Cardiovascular effects of air pollution
Robert D. BROOK
Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48106-0739, U.S.A.
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Air pollution is a heterogeneous mixture of gases, liquids and PM (particulate matter). In the
modern urban world, PM is principally derived from fossil fuel combustion with individual
constituents varying in size from a few nanometres to 10 μm in diameter. In addition to the ambient
concentration, the pollution source and chemical composition may play roles in determining the
biological toxicity and subsequent health effects. Nevertheless, studies from across the world
have consistently shown that both short- and long-term exposures to PM are associated with
a host of cardiovascular diseases, including myocardial ischaemia and infarctions, heart failure,
arrhythmias, strokes and increased cardiovascular mortality. Evidence from cellular/toxicological
experiments, controlled animal and human exposures and human panel studies have demonstrated
several mechanisms by which particle exposure may both trigger acute events as well as prompt
the chronic development of cardiovascular diseases. PM inhaled into the pulmonary tree may
instigate remote cardiovascular health effects via three general pathways: instigation of systemic
inflammation and/or oxidative stress, alterations in autonomic balance, and potentially by direct
actions upon the vasculature of particle constituents capable of reaching the systemic circulation.
In turn, these responses have been shown to trigger acute arterial vasoconstriction, endothelial
dysfunction, arrhythmias and pro-coagulant/thrombotic actions. Finally, long-term exposure has
been shown to enhance the chronic genesis of atherosclerosis. Although the risk to one individual
at any single time point is small, given the prodigious number of people continuously exposed,
PM air pollution imparts a tremendous burden to the global public health, ranking it as the 13th
leading cause of morality (approx. 800 000 annual deaths).
INTRODUCTION
Air pollution is a complex mixture of compounds in
gaseous [ozone, CO and NOx (nitrogen oxides)] and
particle phases [1–4]. In the modern urban and industrial
world, the majority of air pollution is derived from fossil
fuel combustion (e.g. automobiles, power generation and
industry). Cooking and wood burning are additional
significant sources in developing nations. Since the advent
of the industrial revolution, air pollution has become so
omnipresent as to be commonly perceived as a normal or
natural entity, hence the phrase: ‘the hazy, lazy days of
summer’. Nevertheless, it is neither natural nor benign.
Several severe pollution events, such as the infamous
London fog episode of 1952 responsible for thousands
of deaths, helped bring this to public attention [5].
Although particulate and gaseous pollutants co-exist and
may both instigate adverse health effects (e.g. ozone) [6],
the most compelling evidence implicates PM (particulate
matter) as a major perpetrator of human diseases [1–3].
PM itself is a heterogeneous amalgam of compounds
varying in concentration, size, chemical composition,
surface area and sources of origin [1–3]. Although it
may intuitively seem that PM would pose a health risk
mostly to the lungs, the overall evidence indicates that
the majority of the adverse effects of PM are upon the
Key words: air pollution, cardiovascular disease, inflammation, oxidative stress, particulate matter, pulmonary tree.
Abbreviations: CRP, C-reactive protein; CV, cardiovascular; EPA, Environmental Protection Agency; HRV, heart rate variability;
IL-6, interleukin-6; NOx , nitrogen oxides; PM, particulate matter; PSNS, parasympathetic nervous system; SNS, sympathetic
nervous system; TNF-α, tumour necrosis factor-α.
Correspondence: Dr Robert D. Brook (email [email protected]).
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Figure 1 Size, sources and composition of PM air pollution
RBC, red blood cell; SVOC, semi-volatile organic carbons; UFP, ultra-fine particles; VOC, volatile organic carbons.
CV (cardiovascular) system [1–3]. In the present review,
I focus on the role that both acute and chronic exposures
to PM play in causing CV disease. Passive tobacco smoke
is indeed a highly significant source of exposure to
air pollution [2] which, although a critically important
determinant of health, is outside the scope of this review.
CHARACTERISTICS OF PM AIR POLLUTION
Owing to the complexity of its chemistry, historical
precedents and the temporally changing nature of
the compounds within ambient air, PM is broadly
categorized and regulated by aerodynamic diameter (μm)
[2–4]. Figure 1 provides a very general overview of PM
characteristics. It is possible, however, that a classification
based upon chemistry, particle number or relative toxicity
may be more indicative of the health risks. There are
thousands of chemicals and constituents within PM
that may solely, or in combination, impart biological
harm. The actual ‘responsible’ components remain largely
unknown; nonetheless, it is generally believed that the
myriad of compounds that pose intrinsic redox potential
(e.g. metals and organic compounds) and/or those capable
of activating endogenous sources of oxidative stress
within pulmonary tissue (e.g. immune cells) are likely
to be the instigators, rather than inert particles (e.g.
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elemental carbon). Particle sizes range from clusters of
molecules only nanometres in diameter (ultrafine PM
< 0.1 μm) through the fine PM fraction (< 2.5 μm) and
up to coarse matter close to the visible size range (2.5–
10 μm).
‘Fine PM’ < 2.5 μm (PM2.5 ) has received the majority
of attention from a scientific and regulatory standpoint
[1–3]. Most epidemiological studies report stronger
associations with fine compared with other PM size
fractions (e.g. PM10 ). Moreover, many of the combustionderived compounds thought to possess toxic potential
are contained within PM2.5 . The other size fractions,
including ultrafine particles (PM < 0.1 μm), vary temporally and spatially within the ambient environment often
unrelated to fine PM concentrations. As ultrafine PM
levels do not consistently track with PM2.5 [7,8], it
is unlikely that the consistent epidemiological findings
associated with fine PM [1–3] are simply a surrogate
for ultrafine particles being the underlying culprit. The
nanoparticles within PM0.1 are very short-lived and are
largely found within only a few hundred metres of their
sources (e.g. near roadways). Nonetheless, certain aspects
of ultrafine PM may implicate them as a cause of human
diseases in addition to PM2.5 . Owing to the prodigious
number of particles per volume of air (several orders of
magnitude more than PM2.5 ), ultrafine PM conveys a large
surface area for transporting toxic materials deep within
Cardiovascular effects of air pollution
the pulmonary tree [6,7]. Owing to their minute size,
ultrafine particles may even be capable of translocating
into the systemic circulation and thus directly interact
with multiple organ systems within minutes of exposure
[9–11]. However, this capability, along with the biological
relevance of unknown numbers/character of ultrafine
PM components within the vasculature, remains highly
controversial [11]. The fact that very acute exposure to
traffic for only minutes (a prime source of ultrafine
particles) conveys a particularly large CV health risk
suggests that ultrafine particles may indeed prove to
be important [12,13]. At present, even less is known
about the independent health impact of the coarse PM
fraction [14]. Finally, PM rarely exists by itself within
ambient air pollution. Particles are constantly changing and interacting with gaseous (NOx , SO2 and ozone)
and semi-volatile/volatile compounds (e.g. aldehydes and
polycyclic aromatic hydrocarbons). Many of these
vapour-phase compounds attach to the surface of PM
and/or themselves form secondary aerosol particles.
The individual health risk of these constituents alone,
or interacting together with PM, remains to be better
understood.
Exposure to PM2.5 is measured by the mass of particles
within a volume of air. Average daily and annual levels
of exposure range widely worldwide from < 10 to
> 65 μg/m3 . Most urban cities within North America and
Europe, however, have average annual levels between 5
and 30 μg/m3 . Peak hourly concentrations and personal
levels of exposure within certain micro-environments
can actually reach levels exceeding 200–500 μg/m3 [1–3].
Unfortunately, although air pollution has substantially
decreased throughout much of the United States and
Western Europe, PM concentrations within megalopolis
regions in the developing world (i.e. Asia) are increasing.
Daily particle levels may even exceed 200–500 μg/m3 .
Put into context, these enormous concentrations are
approximately those encountered by passive tobacco
smoking (e.g. smoky bars approx. 500–1500 μg/m3 ).
Owing to the consistency of epidemiological studies
implicating even present-day lower PM concentrations
as a cause of human diseases [3], in 2006 the United
States EPA (Environmental Protection Agency) updated
the North American Air Quality Standards to be
more stringent [4]. Allowable standards for annual
(< 15 μg/m3 ) PM2.5 concentrations remained the same,
whereas 24-h levels were lowered from 65 to 35 μg/m3 .
As no threshold above zero exists below which PM levels
have been found to be consistently safe [1–3], the ideal
target regulations remain unclear.
EPIDEMIOLOGY OF CV DISEASES
ASSOCIATED WITH PM2.5
Since the 1970s, there have been hundreds of
epidemiological studies conducted throughout the world
demonstrating an association between PM2.5 and adverse
health effects [1–3]. During the 1980s, and more clearly
in the 1990s, a growing number of studies reported that
even the decreased levels of present-day of air pollution
concentrations still appear to be linked with excess
mortality. From the mid-1990s onwards, it has become
apparent that CV disease is the single leading cause of
air-pollution-mediated morbidity and mortality (in terms
of absolute risk). Although dozens of studies of varying
types conducted throughout widely different parts of
the world report associations between PM2.5 and excess
CV event [1–3], not all studies have been positive [15].
However, it is extremely unlikely that publication bias
explains the overall consistency, coherence and strength
of the associations demonstrated worldwide, as suggested
by large reviews of the entire literature [1–2]. A specific
investigation of the possible impact of publication bias
found that it had no significant effect upon the accuracy of
the positive risk estimates reported for mortality in shortterm time series studies [15a]. Several comprehensive
reviews have recently been published on this topic [1–2],
including the most recent Criteria Document by the U.S.
EPA [3]. Therefore only a concise summary of the critical
epidemiological findings will be provided.
The published observations can be broadly categorized
into short-term (time series analyses over a few days of
exposure), ultra-acute (case cross-over studies related to a
few hours of exposure) and longer-term (cohort survival
analyses over years of exposure) studies. There have been
many more short-term studies, which in general associate
numbers of events (e.g. deaths and hospitalizations) with
changes in daily (or a few days) averages of PM2.5 within
different regions (e.g. cities). Case cross-over studies can
investigate the effect of ‘ultra-acute’ exposures (e.g. 1–
2 h) on the risk of CV events. The longer-term studies
typically compare survival, or time to event, of individuals
living within areas of chronically differing levels of PM2.5
concentrations.
Short-term exposure studies
Table 1 shows the results of some of the largest short-term
studies. From the many studies available [12,13,16–25],
Pope and Dockery [1] have summarized that CV death
increases by approx. 1 % for every 10 μg/m3 short-term
daily increase in PM2.5 concentration. Although presentday levels of air pollution probably have a minimal impact
upon the mortality rate of completely healthy individuals
(i.e. some degree of sensitivity or underlying disease must
be present to be clinically affected) [24], the acute increase
in death rate is not due solely to a mortality elevation only
among critically ill people, who would have imminently
died regardless of exposure (harvesting) [25]. This risk of
CV disease appears to be linear without evidence of a safe
PM threshold, even down to levels < 3–5 μg/m3 [26,27].
Studies have also shown excess CV morbidity related
to higher levels of PM: myocardial infarctions [24,28],
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Table 1 Selected epidemiological studies linking short-term air pollution exposure with CV events
NMMAPS, National Morbidity, Mortality, and Air Pollution Study; APHEA2, Air Pollution and Health: A European Approach 2; COMEAP, Committee on the Medical Effects
of Air Pollutant; IHCS, Intermountain Heart Collaborative Study; AMIR, Augsburg Myocardial Infarction Registry.
Study
Reference
Major findings
NMMAPS
[16]
APHEA2
[18]
COMEAP
[23]
Medicare population
[30]
IHCS
[24]
AMIR
[12]
Time series study. In approx. 50 million adults from 20 to 100 U.S. cities, it was found
in an updated re-analysis that daily cardiopulmonary mortality increases significantly
by 0.6 % per 20 μg/m3 increase in PM10 .
Time series study. In approx. 43 million adults in 29 European cities there was a 1.5 %
significant increase in daily CV mortality per 20 μg/m3 increase in PM10 .
Meta-estimates from the U.K. A 10 μg/m3 increase in PM2.5 significantly increases the
risk of daily CV mortality by 1.4 %.
Time series study. For 204 U.S. urban counties with approx. 11.5 million Medicare
enrolees older than 65 years of age, there were short-term increases in
hospitalizations for all types of CV health outcomes (ischaemic heart disease,
cerebrovascular disease, heart rhythm, heart failure and peripheral vascular disease).
Case cross-over study. Among 12 865 patients in Utah who had a heart catheterization,
an ambient PM2.5 increase of 10 μg/m3 was associated with a daily increase of
4.5 % in acute ischaemic coronary events; air pollution effects were largest on the
concurrent day of event and only significant among patients with one coronary
vessel(s) with pre-existing atherosclerosis (70 % stenosis).
Case cross-over study. Among 691 patients with a myocardial infarction, transient
exposure to traffic 1 h before the event was associated with an increase in risk for a
heart attack (odds ratio of 2.92).
Table 2 Selected cohort studies linking longer-term air pollution exposure with CV events
Study
Reference
Major findings
Harvard Six Cities (extended analysis)
[45]
American Cancer Society II (extended analysis)
[39]
Woman’s Health Initiative
[41]
Cohort survival analysis. The extended 28-year follow-up in approx. 8096 people living in
six U.S. cities showed that the relative risk for a CV death was increased significantly
by 1.28 per 10 μg/m3 increase in long-term PM2.5 . The decrease in PM2.5 over the
study period resulted in a significant reduction in CV mortality (relative risk of 0.69).
The air pollution levels during 1 year prior to death predicted mortality equally well
compared with the entire duration of the study, suggesting relatively rapid health
effects of pollution and that only the annual level prior to mortality is required to
predict death rate.
Cohort survival analysis. The extended 16-year follow-up performed in approx. 500 000
adults demonstrated a 12 % increase in risk for death from CV causes per 10 μg/m3
increase in long-term PM2.5 exposure. Death from ischaemic heart disease (18 %
increase) was the single largest cause of mortality, with smaller absolute numbers of
people (although with similar relative risk elevations) dying from arrhythmias and
heart failure.
In 65 893 healthy post-menopausal women in 36 U.S. cities, an increase of 10 μg/m3 in
long-term PM2.5 exposure was associated with a 24 and 76 % increase in risk of a CV
event and CV mortality respectively.
cardiac ischaemia [29], heart failure [30–33], arrhythmias
and sudden cardiac death [30], stokes [34,35], peripheral
arterial disease [30] and excess hospitalizations for various
CV conditions [30]. Even as little as a few hours of exposure to PM2.5 can trigger CV events. The risk of
myocardial infarctions has been shown to increase by
48 % following exposure to only a 2-h-long elevation
of PM2.5 by 25 μg/m3 [28]. Heart attack risk may be
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increased by 2.73-fold only 1 h after exposure to traffic
[12].
Longer-term exposure studies
Chronic exposure to airborne PM increases the risk CV
diseases as well (Table 2). It remains unclear whether
there is an incremental health risk conveyed by longterm exposure that is totally independent from the
Cardiovascular effects of air pollution
summation of acute effects that occur over days-toweeks. For example, are there synergistic health effects
(e.g. development of clinically overt coronary artery
atherosclerosis due to PM exposure that leads to a
CV event years later) that are beyond the additive
accumulation of all the PM-attributable acute events
(e.g. triggering of plaque rupture and acute myocardial
infarction) during the chronic time period [36,37]? Some
evidence suggests that weeks-to-months of exposure
captures the majority of the risk estimate size [38]. It
is possible that repeated exposures over days-to-weeks,
not just 1 day, in a susceptible person may be required
to trigger an acute event. It may also be that subchronic
exposures over weeks may alter plaque stability and/or
enhance blood thrombogenecity leading to a CV event in
those with underlying coronary artery disease, whereas
a single day’s exposure is insufficient. It is also possible
that a vulnerable plaque could be ruptured by even 1 h
of PM exposure, but the clinically overt event might not
actually become apparent until days, or even weeks, later.
Differences in risk estimations between short- and longerterm studies may also be related to variations in statistical
and study designs, as well as cohort studies being capable
of capturing the entirety of the temporal–risk relationship
during the years of follow-up. On the other hand, it may
also be that chronic air pollution exposure in fact does
cause additively greater amounts of adverse health effects
than acute or subacute (weeks) of exposure. Regardless,
the relative risk of CV mortality estimated by the longerterm exposure cohort studies over years tends to be
higher than seen in the acute few days setting [39–41].
A summary of the effect of chronic exposure to PM2.5
suggests CV risk elevations ranging from 9.3 to 95 % per
10 μg/m3 increase in particle concentration [1].
From these studies, the WHO (World Health
Organization) has estimated outdoor PM as the 13th
leading cause of mortality worldwide, responsible for
approx. 800 000 deaths/year [42]. CV deaths explain
the largest portion of this excess mortality [1,39,43–
45]. Although it is difficult to accurately compare the
adverse health burden posed by PM upon the CV
system compared with the pulmonary system, several
studies provide insight that, contrary to what was once
thought, heart diseases account for the largest single
portion of absolute mortality risk. In the American
Cancer Society study, when cardiopulmonary risk was
separated into individual components it was found that
CV mortality increased by 12 %, whereas death from
respiratory diseases was actually reduced by a 10 μg/m3
increase in long-term PM2.5 exposure [39]. In a similar
fashion, the Harvard Six City follow-up analysis found
that chronic PM exposure significantly increased CV but
not pulmonary mortality risk [45]. This is not to state
that air pollution does not prompt respiratory diseases.
Rather, over a long-term time course, many more people
in a population die due to CV diseases (i.e. much larger
at-risk population and higher basal event rate) than lung
diseases and, thus, the modestly larger relative risk of
death posed by PM for heart diseases translates into a
substantially larger absolute mortality risk. Moreover, air
pollution exposure may shift the type of mortality from
pulmonary to an earlier CV death even among the smaller
number of individuals that are at risk of dying from
lung diseases (e.g. those with chronic obstructive pulmonary disease). Short-term exposure findings also show
that admission rates increase acutely to a greater extent
for CV than pulmonary diseases in terms of absolute
numbers of hospitalizations [30].
Very importantly, a reciprocal association between
air pollution levels and CV diseases appears to hold
true as well. Even relatively short-term reductions in air
pollution levels over several months to a few years greatly
decreases the rate of CV mortality [43–45]. Thus, at the
very least, even if air pollution acts mostly as a triggering
event (over hours-to-months) in susceptible patients,
such as those with pre-existing (even silent) coronary
atherosclerosis, avoiding exposure at a vulnerable time
point might prevent a myocardial infarction that may not
have occurred until years later or never. On the other
hand, it remains entirely possible that a portion of the
CV risk conveyed by long-term PM exposure is also
explained by chronic adverse health effects superimposed
upon the acute.
Geography and sources of pollution
CV admissions are most strongly related to PM in the
Northeast, Midwest and Southern U.S. regions, whereas
exposure in Northwestern U.S. regions may not be
associated with any excess risk [15,30]. Small differences
in geographic locations, and pollution characteristics,
within a single city have been shown to be stronger
determinants of CV risk than inter-city risks [46]. Longterm exposure to traffic-related air pollution (living close
to a major roadway) is also a particularly strong predictor
of myocardial infarction risk [13]. This may be due to the
fact that the composition (e.g. sulfate content) and sources
of (e.g. automobiles) PM, along with the co-pollutants
(e.g. gases and vapour-phase compounds), vary across
differing regions. Ambient meteorology may also play a
major role in determining exposure characteristics. Thus
the role of PM constituents (e.g. specifically transition
metals and organic carbon compounds), sources (e.g.
specifically traffic pollution) and the impact in regional
meteorology requires further investigation.
BIOLOGICAL MECHANISMS
Dozens of human panel and controlled exposures, animal
exposures, toxicological and basic science/molecular
studies have now illustrated a variety of mechanisms
whereby PM exposure may be capable of mediating CV
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Figure 2 Broad biological pathways whereby PM may cause CV events
AT2, angiotensin II; CVA, cerebrovascular accident; CHF, congestive heart failure; ET, endothelins; MI, myocardial infarction; ROS, reactive oxygen species; UFP, ultra-fine
particles; WBC, white blood cells.
events [1–3]. A major issue has been to determine how
the inhalation of PM into the lungs could be capable of
affecting remote CV territories. There are three putative
‘general’ pathways: (1) autonomic mechanisms [e.g. PSNS
(parasympathetic nervous system) withdraw and/or SNS
(sympathetic nervous system) activation]; (2) the release
of circulating pro-oxidative and/or pro-inflammatory
mediators from the lungs (e.g. cytokines and activated
immune cells) into the systemic circulation following
PM inhalation that, in turn, indirectly mediate CV
responses; and (3) nano-scale particles and/or soluble PM
constituents translocating into the systemic circulation
after inhalation that then directly interact with the CV
system (Figure 2). Pathway 1 may be partially, whereas
pathway 3 may be entirely, initiated without requiring
the generation of lung inflammation. PM deposited
in the pulmonary tree can directly stimulate lung
nerve reflexes via irritant receptors and, consequently,
alter systemic autonomic balance (i.e. change PSNS
and/or SNS activities or baroreceptor settings). Soluble
compounds and/or nanometer-sized PM may rapidly
enter the pulmonary vasculature and, subsequently, be
transported throughout the systemic circulation. Prooxidative PM constituents might thus directly interact
with the vasculature and promote harmful CV responses.
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Most end points pertaining to pathway 2 share a single
common aetiology: pulmonary tissue oxidative stress
induced by PM inhalation [47–59]. Numerous studies
confirm that an initial lung oxidative stress may stem from
chemicals within the PM mixture (e.g. metals and redoxactive compounds) and/or from activation of endogenous
lung-based cellular defences (leucocytes or pulmonary
cells) in response to deposition of PM. However, some
important mediators of CV disease (e.g. endothelins)
might be able to be released from the pulmonary tissue
without overt lung inflammation or oxidative stress
[60].
Regarding pathway 2, pulmonary oxidative stress
may be responsible for instigating the systemic CV
pro-oxidative [61–68] and pro-inflammatory [69–83]
chain reaction observed after PM exposure. Cardiac
tissue oxidative stress increases within hours of PM2.5
inhalation [61], whereas footprints (e.g. myeloperoxidase,
nitrotyrosine and inducible nitric oxide synthase) of
elevated free radical generation are found in remote nonpulmonary animal vessels hours to days later [68,84,85].
Pro-inflammatory mediators {cytokines [e.g. IL-6
(interleukin-6)], acute-phase reactants [e.g. fibrinogen
and CRP (C-reactive protein)], vasoactive hormones
(e.g. endothelins) and activated leucocytes} released from
Cardiovascular effects of air pollution
the pulmonary into the system vasculature may then
secondarily trigger a variety of adverse CV reactions. It is
important to note, however, that some studies have also
reported negative findings (i.e. no signal of a systemic
inflammatory response) [1,83]. It is likely that the
specific pollution constituents, co-pollutant levels (e.g.
gases), the duration of exposure and patient susceptibility
play important roles in determining the subsequent
responses (or lack thereof). It is also important to note
that even the repeated observation of higher levels of
pro-inflammatory mediators found within the systemic
circulation following PM inhalation does not necessarily
prove that their original source is a spillover from
pulmonary cells. Hypothetically, immune cells (e.g.
monocytes) that remain entirely within the pulmonary
vessels as they circulate through the lungs to the rest of the
body could become ‘activated’ (if appropriately primed)
by the local inflammatory/oxidative signal derived from
resident lung cells given their extreme proximity to
each other. The initial source of the systemic proinflammatory reaction and the detailed mechanisms by
which it is conveyed throughout the body following PM
exposure require much more investigation.
The three general pathways are not mutually exclusive.
They may overlap temporally and/or be principally
activated at differing time points. Hyperacutely (within
minutes to hours), autonomic imbalance and direct prooxidative/inflammatory vascular actions of circulating
PM constituents are the most plausible dominant
pathways leading to CV events. Acute to subacute
responses (hours to days) may be prompted by the former
means (pathways 1 and 3) and also by secondarily induced
systemic oxidative stress and inflammation (pathway 2).
Finally, the chronic actions of PM upon the CV system,
such as the enhancement of atherosclerosis, are most
likely to be induced by the generation of a chronic proinflammatory state (pathway 2). The types and sizes of
pollutants inhaled may also determine their toxicity and
the relative importance of the pathways. Larger fine or
coarse PM cannot be transported into the circulation
and will require secondary neural or pro-inflammatory
responses to mediate extrapulmonary actions, whereas
ultrafine PM (or soluble constituents of larger particles)
might directly enter the blood stream. A PM mixture
rich in pro-oxidative combustion particles (e.g. organic
carbon compounds and metals) might trigger more robust
responses in a more rapid fashion which differs from
less toxic inert PM. These underlying general ‘mediating’
pathways can, in turn, act alone or together to instigate
several different types of manifest CV diseases. Air
pollution has been shown to cause CV morbidity and
mortality due to arrhythmias and sudden death, ischaemic
events (e.g. myocardial infarctions and strokes), heart
failure, the progression of underlying atherosclerosis and
possibly the development of conventional CV risk factors
(e.g. hypertension and diabetes).
Arrhythmias
Air pollution has been associated with ventricular
arrhythmias, implantable defibrillator discharges, atrial
fibrillation and ECG repolarization abnormalities
[1,2,29,86–89]. In agreement with these observations, a
sizeable portion of the CV morbidity and mortality
stemming from PM exposure has been shown to be
due to cardiac arrhythmias and sudden death [30,39–
41,45]. The mechanism responsible is likely to be that
the inhalation of particles into the pulmonary tree can
alter neural reflexes (general pathway 1), which then
disrupt cardiac autonomic balance and lead to myocardial
electrical instability [90–93]. Inhaled particles irritate a
wide range of pulmonary nerve endings, which generally
leads to subsequent PSNS withdrawal [90]. Indeed, PM
inhalation has repeatedly been shown to alter HRV (heart
rate variability), a marker of cardiac autonomic tone,
within minutes to hours [1,2,82,90–93]. Most, but not
all, studies show a reduction in overall time domain HRV,
indicting a blunted PSNS activity [1]. This has been linked
to an adverse CV prognosis and an increased risk of
sudden death and ischaemic events [94,95]. Nevertheless,
several question remain including the importance of
gaseous co-pollutants (e.g. NOx and SO2 ) [93,97], the role
of pollution source (e.g. traffic) [98], patient susceptibility
[99,100], whether the altered HRV is a causal mediator of
events compared with an epiphenomenon and whether
altered HRV actually reflects changes in central nervous
system autonomic outflow (and in what pattern to
different organs).
Previous observations demonstrate that patients with
reduced capacities to defend against oxidative stress (e.g. a
glutathione S-transferase M1 polymorphism) have a more
robust alteration in HRV [101,102]. This is important
as it demonstrates further the central role of ‘oxidative
stress’ as a fundamental core pathway whereby PM
imparts biological harm. However, the question now
arises whether the generation of oxidative stress (perhaps
in pulmonary tissue) is somehow required to trigger
the neural reflex/reduced HRV and that the presence
of particles within the pulmonary tree is not adequate.
Alternatively, these findings could be explained if the
reduced HRV is an illustration of impaired cardiac ion
channel function induced by systemic oxidative stress
after PM inhalation and not necessarily that it reflects
changes in autonomic balance. Despite uncertainties,
environmentally relevant levels of PM do appear capable
of rapidly altering HRV, potentially reflecting alterations
in autonomic balance and/or cardiac electrical stability,
which may cause arrhythmias and sudden death.
Atherosclerotic and ischaemic events
Exposure to air pollution and automobile traffic has
been shown to trigger myocardial ischaemia [29,103,104]
and infarctions [12,28] within hours following exposure.
The risks of strokes [34,35] and hospitalizations for
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ischaemic events increase as well [30]. A central
cause of these ischaemic events could be PM-induced
vascular dysfunction and vasoconstriction. Endothelial
dysfunction, impaired smooth muscle dilation and/or
both findings have been reported at the resistance
and conduit artery level in humans [104–109] and in
animal/basic science ex vivo studies [84,85,111–120].
Gaseous pollutants such as SO2 may also be linked to
endothelial dysfunction [110]. PM2.5 can also cause a prohypertensive response in humans and animals [121–123].
Subsequently, endothelial dysfunction, vasoconstriction
and increased blood pressure could each (or in
conjunction) trigger atherosclerotic plaque instability,
leading to myocardial infarctions and stokes and/or
promote myocardial ischaemia in susceptible people.
All three general pathways may play roles in causing
this vascular dysfunction. The systemic oxidative stress
and inflammation following air pollution exposure can
decrease the bioavailability of NO in the vasculature
[85,112–114], tipping the balance toward vasoconstriction. Several of the circulating pro-inflammatory factors
[e.g. IL-6, TNF-α (tumour necrosis factor-α) and CRP]
[81] and mediators of oxidative stress (e.g. H2 O2 ) [59]
shown to increase after PM inhalation blunt vascular NO
activity [1]. Relative SNS hyperactivity could also impair
endothelial function by reducing NO bioavailability
[124] and/or by promoting vasoconstriction via α-adrenergic receptor activation. Even without pulmonary
inflammation, PM inhalation may also enhance the release
into the systemic circulation of direct vasoconstrictors
such as endothelins [120], augment the bioactivity of
the vasoconstrictor AngII (angiotensin II) [116] and/or
directly augmenting smooth muscle contractile responses
(e.g. alter Rho kinase activity or myosin light-chain
kinases) via oxidative stress mechanisms [85,115]. Certain
PM constituents (e.g. metals and organic compounds)
might also reach the systemic circulation and, thus,
directly instigate pro-oxidative stress reactions within
the vasculature, leading to catabolism of NO and the
release of vasoconstrictors [125]. However, this final
pathway remains highly controversial. Finally, several
studies in both humans and animals suggest that chronic
PM exposure may enhance the progression and instability
of underlying atherosclerosis by pro-inflammatory
mechanisms, thus promoting further future ischaemic
events [126–129].
Enhanced thrombosis
PM inhalation can also enhance arterial thrombosis
and coagulation [130–138]. As with other biological
mechanisms, not all studies have been positive [139].
Nonetheless, with underlying vulnerable atherosclerotic
plaques, the generation of a pro-thrombotic milieu
could trigger arterial thrombosis and subsequent acute
ischaemic events. After air pollution exposure, studies
have suggested that these effects could be caused by
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increases in fibrinogen and blood viscosity, elevated
CRP, increased platelet reactivity, altered coagulation
factors (e.g. tissue factor), histamine, enhanced IL-6dependent pathways, expression of microvascular surface
adhesion molecules and reduced release of fibrinolytic
factors (e.g. tissue plasminogen activator) [104,105,130–
138]. The relative roles of systemic inflammation, altered
autonomic balance and direct effects of PM constituents
acting upon blood-borne mediators of thrombosis remain
largely unknown.
Heart failure
PM air pollution is linked to an increased risk of heart
failure exacerbations and hospital admissions [30–33]. It
is possible that both the pro-ischaemic and arrhythmic
effects of PM exposure could be responsible; however,
a recent study in mice has also shown that pulmonary
PM deposition can impair the ability of lung alveoli
to clear fluid due to reduced membrane Na,K-ATPase
activity [140]. This effect was prevented by antioxidant
defences, suggesting once again that oxidative stress plays
an important role.
Instigation of traditional risk factors
Short-term air pollution exposure can trigger an increase
in arterial blood pressure within hours to days [120–
123]. Many of the pro-inflammatory/oxidative reactions,
the vascular dysfunction and the autonomic imbalance
instigated by PM may prompt the chronic development
of overt hypertension [123]. However, whether longterm exposure can promote a sustained elevation in blood
pressure remains unknown at present. Moreover, it is also
possible that PM exposure could also promote insulin
resistance, thereby increasing the risk of future diabetes
mellitus and the metabolic syndrome [141]. In support
of this hypothesis, a recent study has demonstrated that
NO2 , a marker of traffic exposure, was independently
correlated with the prevalence diabetes in women
[142]. Owing to the enormous number of individuals
exposed continuously worldwide, even small effects of air
pollution on chronic levels of blood pressure and glucose
would have tremendous public health importance.
In summary, the experimental findings provides ample
evidence to demonstrate the plausibility that air pollution
can actually cause CV disease. It is clear that exposure to
PM can trigger acute CV events via many mechanisms in
susceptible individuals. Although long-term air pollution
exposure may enhance underlying atherosclerosis and
could conceivably increase the risk for hypertension
and diabetes, the clinical significance of these putative
chronic effects remains unclear.
FUTURE RESEARCH
Our knowledge from both an epidemiological and
mechanistic standpoint regarding the association between
Cardiovascular effects of air pollution
PM and CV health has expanded greatly in the past
decade. Although a host of finer biological details remain
to be fully understood, there is no question that the
original penultimate goal for studying the mechanisms
involved (i.e. to provide an overall plausibility for the
epidemiology) has been reached. Thus future research
providing a more detailed mechanistic understanding
would mostly serve the quest to enhance human scientific
knowledge in general and perhaps better our overall
understanding of biology. Not that these noble aims
are not important; however, the main point is that no
more mechanistic details are required in order to provide
a fundamental ‘plausibility’ for the epidemiological
findings (and thus to act by reducing air pollution). It
is my humble suggestion that the priority of air pollution
research should now be re-focusing on means to achieve
the ‘ultimate’ goal: how to best save lives and improve the
overall human condition.
In this context, there are several areas where future
research could be particularly helpful. Foremost is a
greater understanding of the most ‘responsible’ pollutants
for causing the greatest disease burden. For example,
identifying the most toxic/harmful to health sources
(e.g. traffic), specific chemical compounds (e.g. metals,
organic species and gaseous co-pollutants) and vulnerable
places/times of exposure. In this fashion, the most critical
pollutants can be most effectively targeted for reduction.
Alternatively, it may be found that the health effects
from the pollution mixture is too non-specific to target
individual chemicals or that they occur in response
to a host of different PM subtypes and sources and
that only an overall reduction in most/all components
can adequately assure a decrease in the associated CV
mortality. Identifying individuals at greatest risk or those
most susceptible, along with practical mechanisms to
feasibly reduce the risks of exposure and/or subsequent
health problems once exposed, are warranted. Finally,
a comprehensive assessment of the health benefits from
these measures is important.
From a biological standpoint, a key remaining
uncertainty is the mechanism(s) and/or pathway(s)
whereby the original insult to the lungs induced by
PM inhalation is conveyed to the systemic vasculature
and the heart (where a host of adverse responses have
already been shown to occur that could feasibly trigger
CV events). What are the specific signalling mediators
(e.g. cytokines, inflammatory cells, mediators of oxidative
stress and soluble PM components) and how can they
be therapeutically mitigated? Finally, understanding the
pertinence (e.g. relative importance) among the large
host of different responses shown to be triggered
by air pollution (e.g. vascular dysfunction, enhanced
thrombosis and autonomic imbalance), or alternatively
the lack of any one single predominant factor, in actually
causing the observed human CV mortality is critically
important to investigate.
CONCLUSIONS
PM air pollution exposure over both the short- and longterm is associated with an increased risk of CV morbidity
and mortality. Even PM2.5 inhalation over a few minutes
to hours can trigger myocardial infarctions, cardiac
ischaemia, arrhythmias, heart failure, strokes and sudden
death. More long-term exposures may also enhance the
risk of developing chronic CV diseases. A multitude
of plausible mechanistic explanations have now been
demonstrated that could alone or together explain the
observational findings. Although the finer details of all of
the responsible mechanisms and pollutants are not fully
described, this should not stop the medical and scientific
communities from supporting efforts to maintain optimal
air quality in order to protect their patients and the public
health at large (information for healthcare providers at:
http://www.airnow.gov/). To paraphrase an aphorism:
you do not need to know every last detail about the archer
who shot you with a poison arrow, before you know that
you need to pull the arrow out.
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Received 12 December 2007/25 January 2008; accepted 7 February 2008
Published on the Internet 12 August 2008, doi:10.1042/CS20070444
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