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Blood First Edition Paper, prepublished online June 10, 2011; DOI 10.1182/blood-2011-04-343111
Thrombogenicity and cardiovascular effects of ambient air pollution
Massimo Franchini,1 Pier Mannuccio Mannucci2
1
Department of Transfusion Medicine and Hematology, Carlo Poma Hospital, Mantova, Italy;
2
Scientific Direction, IRCCS Cà Granda Foundation Maggiore Hospital, Milan, Italy.
Short title: Air pollution and cardiovascular disease
Correspondence:
Pier Mannuccio Mannucci, MD
Scientific Direction, IRCCS Cà Granda Foundation Maggiore Policlinico Hospital
Via Pace 9, 20122 Milan, Italy
Tel: ++ 39 02 5503 5414
Fax: ++ 39 02 54 100 125
e-mail: [email protected]
1
Copyright © 2011 American Society of Hematology
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Abstract
Exposure to air pollution is associated with adverse effects on health. In particular, a strong
epidemiological association is observed between acute and chronic exposure to particulate matter
(PM) and the occurrence of cardiovascular events -- coronary artery disease, cerebrovascular
disease and venous thromboembolism -- especially among older people, people with diabetes and
previous cardiovascular conditions. Multiple mechanisms have been postulated to cause the
increase in atherothrombotic and thromboembolic events, including the activation by PM of
inflammatory pathways and hemostasis factors, production of reactive oxygen species through the
oxidative stress pathway, alterations in vascular tone and decreased heart rate variability (a marker
of cardiac autonomic dysfunction and a predictor of sudden cardiac death and arrhythmias). Current
knowledge on the biological mechanisms and the clinical impact of short- and long-term exposure
to particulate air pollutants is discussed, emphasizing that life expectancy improved significantly in
sites where air pollutants were controlled.
Key words: air pollution, mortality, cardiovascular disease, acute myocardial infarction, venous
thromboembolic disease.
2
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Introduction
Urban air pollution is a leading problem for environmental health.1 Even though much of the early
research focused on respiratory diseases, more recent epidemiological studies demonstrated that air
pollution substantially contributes to the onset and aggravation of cardiovascular diseases, and that
these effects occur at relatively low levels of exposure.2-4 Air pollution definitely increases
morbidity and mortality due to atherothrombotic events, causes more frequent hospitalizations and
worsens pre-existing cardiac diseases (such as congestive heart failure and arrhythmias).5 In
addition, recent preliminary findings suggest an association between air pollution and venous
thromboembolism.3 In line with these observations, the World Health Organization (WHO)
calculates that urban air pollution is an important cause of global mortality, being responsible for at
least 700.000 premature deaths.6 For the individual, the risk of cardiovascular disease triggered by
air pollution is relatively small. However, the public health burden is very important, owing to the
unavoided exposure of large populations to this risk.7
Both gaseous air pollutants (i.e., ozone, sulfur and nitric oxides, carbon monoxide) and particulate
matter (PM) cause adverse effects on health. However, the most serious effects are related to PM,
because particles contain a broad range of toxic substances and are considered reliable indicators of
other pollutants (such as nitric oxides) and hence of the global adverse impact of air pollution.8-10
Ambient PM is distinguished, according to aerodynamic diameter (AD), in coarse (PM10, AD
between 2.5 and <10 μm), fine (PM2.5, AD <2.5 μm) and ultrafine particles (AD <0.1 μm). Upon
inhalation, the coarser particles reach only the nasal cavities and upper airways, but fine particles
reach the lower airways and alveoli. Composition of PM varies greatly and depends on
geographical, meteorological and source-specific variables. In metropolitan areas, primary particles
directly emitted in the ambient are a complex and heterogeneous mixture of solid and liquid
components, including inorganic substances (sulfates, nitrates, ammonium, chloride, metals),
elemental and organic carbon, crustal material and biological components (bacteria, spores,
pollens)11. In addition, chemical conversion of gaseous species to aerosol particles in the
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atmosphere leads to the formation of secondary particles. In metropolitan areas the great majority of
environmental PM is antropogenic and originates from the combustion of fossil fuels, mainly from
automobile traffic and domestic heating.10 There are also soil-related sources of PM that originate
from road dust, smokestacks and windblown soil. The latter source can lead to the phenomenon of
long-range transport and spread of airborne-suspended PM.
This review focuses on the relationship between ambient air pollution, thrombogenicity and
cardiovascular diseases through the analysis of the putative biological mechanisms and the strength
of the epidemiological evidence.
Biological mechanisms
Even though the mechanisms by which air pollutants influences the risk of cardiovascular events
are still under investigation, a number of plausible explanations are available.10 One possible
pathway involves the finest particles (<2.5 nm) that upon inhalation penetrate beyond the upper
respiratory tract into the parenchymal region of the lung, where they may be translocated into the
circulating blood via interstitium, macrophage phagocytosis as well as epithelial cell endocytosis.12
Following PM inhalation, the lung releases locally and into the systemic circulation pro-oxidative
(i.e., reactive oxygen species) and/or pro-inflammatory mediators (i.e., cytokines as interleukin-6
and tumor necrosis factor-α ) and such vasoactive hormones such as endothelins.13-20 Acute phase
reactions take place and lead to the increase in plasma of such reactants as C-reactive protein and
fibrinogen. In the lung the secretion of adhesion molecules by inflamed endothelial cells results in
binding and activation of leukocytes and platelets, formation of platelet-leukocyte conjugates and
generation of hemostatically active, tissue factor-bearing microparticles.21-23
A series of studies conducted in animals have demonstrated that acute exposure to proxies of
particulate air pollutants leads to the activation of platelets and coagulation enzymes.23 Nemmar et
al24 found that in hamsters the intratracheal instillation of ultrafine polystyrene particles enhanced
thrombus formation, mainly through a mechanism involving platelet activation. In subsequent
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experiments that employed diesel exhaust as proxy of ambient PM heightened thrombus formation
did follow particle penetration into the circulating blood.25 In another study a persistent increase in
thrombosis susceptibility to diesel exhaust particles was seen as long as after 24 hours. This
prolonged effect was mitigated by pretreatment with sodium cromoglycate (a stabilizer of mast cells
and basophil degranulation), suggesting that thrombosis was secondary to histamine release.26
These data provided evidence for a direct link between diesel exhaust, particle-induced release of
histamine and pulmonary inflammation, which in turn caused thrombosis through systemic
inflammation and platelet activation. However, pulmonary inflammation and thrombosis appeared
to be associated events only at the latest time points, because histamine was increased in plasma
only 6 and 24 hours after exposure to diesel exhaust and diphenhydramine (a histamine H1-receptor
antagonist) mitigated thrombosis at 6 and 24 hours but not at 1 hour.27 It was hypothesized that
direct effects of PM constituents reaching the circulation may be responsible for the earlierst
prothrombotic effects. Pulmonary instillation of carbon nanotubes triggered neutrophil lung influx
and circulating platelet-leukocyte conjugates were elevated 6 hours after exposure, whereas
procoagulant microvesicular tissue factor activity and the peripheral thrombotic potential were
increased 24 hours later.27 Inhibition of P-selectin (which mediates the adhesion of activated
platelets to circulating leukocytes) abrogated these responses, demonstrating that rapid activation of
circulating platelets by the pulmonary deposition of PM plays a crucial role.28
This series of experimental studies suggests that the delayed release in the lung of cell–derived
mediators (eg, histamine), together with the earlier activation of circulating platelets by lung
inflammation via P-selectin-dependent mechanisms, may mediate the prothrombotic effects of the
proxies of particulate air pollution. It must be emphasized that the particles used in these studies do
reproduce the situation of exposure to ambient PM in terms of size, but not in composition, because
ambient PM contains an array of toxic substances that cause adverse effects well beyond their size.
For instance, the content of transition metals like iron may be particular toxic through the oxidative
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stress pathways, because they yield highly reactive oxygen species, including the hydroxyl radical
through the Fenton reaction.
In humans, increased exposure to air pollution is associated with the increase in plasma of several
hemostasis components. For instance, in 3256 randomly selected people plasma viscosity increased
markedly during an air pollution episode that lasted 13 days.29 Healthy volunteers experimentally
exposed to concentrated PM had increased plasma levels of fibrinogen, an acute-phase
inflammatory protein, an important determinant of increased viscosity and an established risk factor
for venous and arterial thrombosis.18 Another marker of thrombophilia such as plasma
homocysteine is positively associated with exposure to traffic-related pollutants, especially PM and
black carbon.30 A study conducted in 1218 healthy individuals found that the degree of chronic
exposure to air pollution was associated with the shortening of such a global coagulation test as the
prothrombin time.31 The same study confirmed that homocysteine increases in proportion to the
degree of exposure to gaseous and particulate air pollutants, albeit only in smokers.32 Bonzini et al
demonstrated heightened thrombin formation in workers from a steel-production plant exposed to
high concentrations of inhalable particles.33 In these workers the link between inflammation and
hypercoagulability was emphasized by the concomitant increase in C-reactive protein.33
The fibrinolytic system is an important regulator of thrombus formation, propagation and vascular
occlusion. In a series of double-blind experiments carried out by Mills et al.,34-36 healthy people as
well as patients with stable coronary artery disease were randomly exposed to filtered air or high
concentrations of diesel exhaust (300 μg/mm3) while performing intermittent exercise. The release
from endothelial cells of tissue plasminogen activator, a key player in the regulation of endogenous
fibrinolysis, was reduced upon exposure to diesel exhaust. This antifibrinolytic effect persisted for
at least 6 hours after exposure, and was of similar magnitude to that seen in heavy smokers.
On the whole, these findings in humans indicate that secondary pulmonary inflammation and/or
microparticles penetrating directly into the blood cause a hypercoagulable state and
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hypofibrinolysis, that in turn may trigger thrombotic cardiovascular events owing to heightened
thrombus formation in blood vessels.37
Another mechanism for the occurrence of cardiovascular disease is perhaps related to the alterations
induced by PM to the autonomic control of the heart.38,39 Animals exposed to diesel exhaust had
reduced heart rate variability.40,41 These experimental data were substantiated by a number of
clinical studies showing an inversely proportional relationship between PM concentration and heart
rate variability.42-48 Decreased heart rate variability indicates the existence of a state of cardiac
autonomy dysfunction and is a risk factor of sudden cardiac death due to arrhythmias. The adverse
effects of particulate pollutants on the cardiac autonomic balance have also been documented
through their effects on vascular tone and reactivity, leading to increased blood pressure.49-52 The
underlying mechanisms responsible for the increase of the sympathetic drive remain unclear, but
may involve activations of pulmonary neural reflex arcs and direct effects of pollutants on cardiac
ion channels.53
In addition to these mechanisms, several studies in humans and animals have shown that exposure
to PM results in the progression of atherosclerotic lesions through pro-inflammatory mechanisms.54
For instance, intratracheal administration of ambient PM10 in hyperlipidemic rabbits55 or long-term
exposure to PM2.5 of genetically susceptible mice (apolipoprotein E-deficient) enhanced
atherosclerotic plaque growth.56,57 ApoE-null mice exposed to ultrafine particles exhibited
significantly more and larger atherosclerotic lesions than mice exposed to filtered air, through prooxidative effects and the inhibition of the anti-inflammatory capacity of plasma high-density
lipoprotein.58
Thus, the forementioned experimental and clinical studies suggest that heightened thrombus
formation over atherosclerotic plaques is likely to be an important mechanistic player in the
occurrence of cardiovascular events, as supported by the close temporal relationship existing
between short-term peaks of pollutants and concomitant increases in atherothrombotic events such
as acute myocardial infarction (AMI) and ischemic stroke (see below). Figure 1 summarizes the
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mechanism and pathways that are likely to be involved in the cardiovascular effects of ambient air
pollution.
Population studies
The relationships between ambient air pollution and cardiovascular events are usually represented
by dose-response exposure functions that express the relative risk of adverse events for a specified
increase in air pollutants. The clinical studies can be broadly divided into short-term and long-term
studies. This artificial distinction is justified by the fact that the former investigate the effects of
acute transient peaks of exposure to air pollution with emphasis on mortality and hospitalization,
and includes mostly time series analyses over a few days of increased PM exposure (changes
generally ranging from 10 to 30 μg/mm3). The long-term studies, comprising cohort survival
analyses over many years of exposure, evaluate the chronic, persistent impact of exposure to air
pollutants on the risk of cardiovascular events.59-61 In terms of putative mechanisms, while shortterm exposure affects mainly endothelium-mediated processes (impaired vasodilation, greater
vasoconstriction and hemostasis activation in the specific pulmonary bed) owing to an increase of
the sympathetic drive, more systemic mechanisms (such as oxidative stress, inflammation and
hypercoagulability) are likely to be predominant pertaining to long-term effects, through an
acceleration of atherosclerosis and a heightened thrombotic tendency.62
Short-term effects
Several epidemiological studies have unequivocally shown a strong association between acute
peaks of particulate air pollutants and the occurrence of cardiovascular events.63-79 The National
Morbidity, Mortality and Air Pollution Study (NMMAPS), that involved 50 million people in the
20 largest cities in the USA, found that total mortality rates were independently associated with
particle concentrations and that, on the day before death, each 20 μg/m3 rise in PM10 was associated
with a 0.6% increase for cardiopulmonary mortality.64 A stronger association between adverse
health outcomes and air pollution was demonstrated by the Air Pollution and Health European
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Approach (APHEA-2) study.67 For 43 million people living in 29 European cities, the estimated
daily increase in cardiovascular mortality was 1.5% for each 20 μg/m3 rise in PM10. A recent update
of the Meta-analysis of Italian Studies on the short-term effects of Air pollution (MISA),66 that
collected data from 9 million people from 15 Italian cities through the period 1996-2002, has shown
an increased daily rate of cardiorespiratory mortality associated to increased levels of several air
pollutants (NO2, CO, SO2 and PM10).
Other studies have analyzed the adverse cardiovascular effects of air pollution in terms of morbidity
(i.e., coronary artery disease, arrhythmias and heart failure) rather than mortality. For instance, in a
case-crossover study conducted in 691 German patients who had developed AMI, the time spent in
cars, public transport, motorcycles or bicycles was consistently linked to the time of onset of
symptoms, thus indicating that exposure to air pollution due to road traffic is a risk factor for AMI
(odds ratio 2.92).65 The increased risk was somewhat greater in cyclists (odds ratio 3.94) than is
automobile users (odds ratio 2.60), suggesting an adverse interaction between physical activity and
traffic-related air pollution. In a case-crossover study a 25 μg/mm3 PM2.5 rise within the two hours
preceding the event was associated with a 48% increased risk of AMI.63 The acute effect of fine
particulate air pollution on elderly people was analyzed by Dominici and colleagues,64 who studied
between 1999 and 2002 a U.S. population of 11.5 million individuals aged more than 65 years in
order to evaluate whether or not there was an association between daily concentrations of PM2.5 and
changes in hospital admissions for cardiovascular and respiratory diseases. The largest association
was for congestive heart failure, with a 1.3% increased risk per 10 μg/m3 rise in same day PM2.5
concentration. From 1986 to 1999 the relationship between particulate air pollution and hospital
admissions for congestive heart failure was investigated in 7 U.S. cities: a 10 μg/m3 rise in PM10
was associated with a 0.7% increase in the rate of admission with this diagnosis on the same day. In
the Intermountain Heart Collaborative Study (IHCS), a rise by 10 μg/m3 of short-term exposure to
PM2.5 was associated with a 4.5% increased rate of acute coronary events.70 The association
between traffic-borne air pollutants and AMI is also supported by the European HEAPSS (Health
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Effects of Air Pollution among Susceptible Subpopulations) study,71 air pollution being associated
with an increased risk of cardiac readmission to hospital in patients with pre-existing AMI.72 In a
study on the relationship between air pollution and emergency room admissions in Boston, a
positive association was found between NO2, PM2.5 and the risk of hospitalization for AMI.73
A higher incidence of ischemic and hemorrhagic stroke has also been reported, with higher
mortality and more hospital admissions related to short-term increases in airborne PM.74 For
instance, in the US Medicare population of elderly patients, there was an increase in hospitalization
for stroke on the same day of exposure to higher PM2.5 levels.68 A study in nine US cities of people
aged 65 or more confirmed this association, with a daily rise of 1.03% in hospital admissions for
ischemic stroke for every 23 μg/m3 increase in PM10.75 A positive association between stroke
mortality and daily concentrations of fine particles was also found in individuals aged 65 years or
more from Helsinki.76 A more recent study conducted in Denmark confirmed also for ultrafine
particles the association with hospital admissions for stroke.77
While all the forementioned epidemiological studies provide solid and unequivocal evidence of a
positive relationship between short-term peaks of air pollution and atherothrombotic disease, the
evidence for an effect on venous thromboembolism is more preliminary and less established.78
Dales et al reported that the short-term increase in hospital admissions for venous thrombosis and
pulmonary events in Santiago (the capital city of Chile) was proportional to the concentration of
particulate and gaseous air pollutants.79 These findings are not surprising, because there is evidence
that venous and arterial thromboses are not distinct entities but share a number of common risk
factors.80 Thus, given that acute peaks of exposure to air pollution contribute to pulmonary and
systemic inflammation and hypercoagulability, an epidemiological link between short-term PM
peaks and changes in venous thrombosis events is plausible, but additional evidence is warranted.
In all, these findings demonstrate that short-term elevations in ambient PM (that are also a proxy for
gaseous pollutants) are capable of triggering atherothrombotic events and perhaps also clinical
manifestations of venous thromboembolism such as deep vein thrombosis and pulmonary
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embolism. Table 1 shows the detailed results of the largest short-term studies. It must be
emphasized that the degree of elevation in ambient PM that, according to these studies, causes a
substantial increase in mortality and morbidity for cardiovascular disease may indeed occur very
frequently in metropolitan areas, especially where and when there is a combination of intense
automobile traffic, high atmospheric pressure and air stagnation.
Long-term effects
Also chronic exposure to airborne PM enhances the risk of cardiovascular diseases or mortality.81 In
more than 8000 adults from six USA cities (HSCS, Harvard Six Cities Study) followed for 14-16
years, overall mortality was 1.26 times higher in the most polluted than in the least polluted cities.82
In an extended follow-up of this study for eight additional years,83 a significant increase in risk of
death was found for every 10 μg/m3 rise in PM2.5, with a relative risk (RR) of 1.28 for
cardiovascular death. The American Cancer Society (ACS) who conducted a study between 1982
and 1989 in order to investigate individual health risks for 552,138 residents of 151 U.S. cities in
relation to local ambient air quality, found a RR of 1.17 for all-cause mortality owing to increased
levels of PM2.5.84 The extended 16-year follow-up of the ACS study demonstrated that each rise of
10 μg/m3 in the mean PM2.5 daily concentration was associated with a 12% increased risk of death
from cardiovascular causes,85 and that death from coronary artery disease was the single largest
cause of mortality (18%). Mortality from long-term exposure to air pollution was also investigated
through the follow-up of 22,905 subjects residing in the Los Angeles urban area during the years
1982-2000.86 Cardiopulmonary mortality and deaths for coronary artery disease increased by 20%
and 49% per 10 μg/m3 rise in PM2.5 exposure. A study conducted in Sweden on 176,309 male
construction workers exposed to PM and compared with 71,778 unexposed workers found that their
occupational PM exposure was associated with an increased RR for coronary artery disease
(1.13).87 A large Dutch cohort study showed that living near a major road was associated with total
mortality (RR 1.41), an even more significant relationship being found for cardiopulmonary
mortality (RR 1.95).88 Miller et al89 reported that exposure to air pollution over a 6-year period
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increased the risk of cardiovascular events by 24% and cardiovascular-related death by 76% for
every 10 μg/m3 PM2.5 rise. Similarly, the same PM2.5 rise was associated with a 35% and 83%
increase in risk for stroke and stroke-related mortality, respectively. In the frame of a retrospective
cohort study carried out in residents of South London who survived a first stroke,90 a positive
association was seen between estimated exposure to ambient air pollution and subsequent poststroke mortality.
In addition to the forementioned strong and consistent evidence that long-term exposure to air
pollution is associated with an increase in atherothrombotic clinical events, markers of subclinical
atherosclerosis are more frequently found in communities chronically exposed to high levels of
ambient air pollution. For instance, Künzli and colleagues measured carotid intima–medial
thickness in 800 residents of Los Angeles.91 Personal air pollution exposures were estimated with a
geostatistical model that mapped their area of residence to PM values recorded by local pollutionmonitoring stations. For every 10 μg/m3 rise in PM2.5, intima-media thickness increased by 4% after
adjustment for potential confounding variables. The same authors reported an association between
air pollution and progression of atherosclerosis (measured as the annual rate of increase in the
carotid artery intima-media thickness) following the analysis of 5 double-blind randomized trials.92
Similar effects have also been reported for coronary artery calcium content, a biomarker of
coronary atherosclerosis. In a prospective cohort study of 4,494 individuals, living close to a major
urban road increased coronary artery calcium scores by 60%.93
The strong evidence supporting the association between atherothrombosis and air pollution is
complemented by fewer studies on venous thromboembolism. Baccarelli et al94 examined the
relationship between exposure to PM10 and venous thrombosis in a case-control study of 870
patients and 1210 healthy individuals, and found that for each 10 μg/mm3 rise in PM10 there was a
70% increase of venous thrombosis, independently of other clinical and environmental variables.95
In the same study, exposure to PM was associated with a shortened prothrombin time, extending
previous observations based upon a shorter time window of exposure to pollution.31 The increased
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risk of venous thrombosis was nearly linearly associated with living in proximity to major traffic
roads, extending findings by other investigators who had shown the same association for arterial
cardiovascular events.96 However, these results on the risk of venous thromboembolism were not
replicated by two prospective cohort studies, indicating the need of further studies in this field.97,98
Table 2 summarizes the findings of the largest studies on long-term cardiovascular effects of
particulate air pollution. Taken together, they demonstrate that prolonged exposure to particulate air
pollution is associated with adverse cardiovascular events, even when PM10 concentrations become
only modestly higher than the thresholds established as target by regulatory agencies (for instance,
20 μg/mm3 by the World Health Organization). 99
Conclusions
From an array of experimental, epidemiological and clinical studies it emerges that air pollution is
an important acquired cardiovascular risk factor that adds to the traditional ones. Alterations
induced by exposure to particulate air pollution contribute in the long-term to the development and
progression of atherosclerosis and, in the frame of short-term exposures, to triggering thrombosis
and acute cardiovascular events. The two most frequent cardiovascular diseases (i.e., coronary
artery disease and cerebrovascular disease) are definitely and consistently increased by particulate
exposure. There is preliminary evidence that PM exposure may be a risk factor also for venous
thromboembolism. A recent evaluation of the public health relevance of triggers of acute
myocardial infarction found that exposure to automobile traffic had the greatest population effect on
this event, being an ongoing factor to which a huge number of individuals are exposed.7
Further studies on the mechanisms of cardiovascular effects related to air pollution are necessary
and changes in the hemostatic system warrant special attention. For instance, the role of platelets in
thrombus formation has been relatively poorly studied in humans,100 at variance with the evidence
gained in animal models, that however were based upon artificial proxies of ambient air pollutants.
The many toxic substances contained in the anthropogenic PM (such as, for instance, metals) may
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cause oxidative stress and platelet hyperactivity. Of the other components of hemostasis,
coagulation and fibrinolysis are more thoroughly investigated, but more adequate models of PM
exposure in humans and animals are needed, because the different particles used in these models
failed to mimic the complex composition of PM that are present in the urban ambient owing to
traffic and domestic heating.
What can be done to control these adverse effects of air pollution? The American Heart Association
has recently delivered the following statement:39 “the overall evidence is consistent with a causal
relationship between PM2.5 exposure and cardiovascular morbidity and mortality”. A large number
of metropolitan areas around the world have PM concentrations well above the WHO target of 20
μg/mm3, especially in Eastern and Southern Europe and Asia. PM exposure is a modifiable risk
factor.39 It has been calculated that a reduction by only 10 μg/mm3 in the daily mean concentration
of PM10 would decrease by 1.6% the incidence of new cases of myocardial infarction, the decrease
being as large as 4.8 % if PM10 concentration were decreased by as much as 30 μg/mm7. Because it
has been shown that the decrease of air pollution clearly leads to a parallel increase in life
expectancy,83,101 it is a community responsibility to adopt the necessary measures. Efforts directed
to manage local air quality should aim to reduce not only PM from anthropogenic but also from soil
sources, even if anthropogenic particles appear to have a higher impact on cardiovascular events
due to their stronger production of pro-inflammatory cytokines. Yet, also the single citizen can
adopt simple measures to reduce his /her individual risk, such as to avoid walking in the most
trafficked roads, performing strenuous outdoor exercise in busy roads and exposing small children
to the high concentration of air pollutants that are present next to the ground.
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Acknowledgments
This works was supported in parte by grants to PMM by the Lombardy Region. Drs. Baccarelli and
Bertazzi are thanked for helpful discussion and advice.
Conflict of interest
The authors declare no conflict of interest.
Legend to Figure 1.
Adverse effects of air pollution exposure: possible mechanisms of action of cardiovascular events.
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Table 1. Summary of the largest population studies on short-term cardiovascular effects of ambient air pollution.
First author, year (study
Population
Many findings
Reference
Peters, 2001
Case cross-over study of 772 patients with AMI
A PM2.5 increase of 25 μg/m3 within the 2 hours preceding the event was
63
associated with a 48% increased risk of AMI
Dominici, 2003 (NMMAPS) Time series study including 50 million people from 20 U.S. cities
0.6% daily increase of cardiorespiratory deaths for each 20-μg/m3 PM10
64
increase
Peters, 2004 (AMIR)
Case cross-over study of 691 patients with AMI
Increased risk of AMI (OR 2.92) associated with acute exposure to car traffic
65
one hour before the event
Biggeri, 2004 (MISA)
Meta-analysis of 9 million people from 15 Italian cities
0.4% daily increase of cardiovascular deaths for each 10 μg/m3 increase in
66
NO2, of 0.9%, for each 1mg/m3 increase in CO, of 1.1%, for each 10 μg/m3
increase in SO2,, and of 0.5% for each 10 μg/m3 increase in PM10
Analitis, 2006 (APHEA-2)
Dominici, 2006
Wellenius, 2006
Pope, 2006 (IHCS)
Time series study of 43 million people from 29 European cities
1.5% daily increase in cardiovascular deaths for each 20 μg/m3 PM10 increase
67
Time series study of 11.5 million U.S.
1.3% daily increase in the risk of congestive heart failure, and 1.2% increase in
68
people aged more than 65 years
the risk of stroke for each 10 μg/m3 PM2.5 increase.
Time series study on 292,918 admissions for congestive heart
0.7% increase in the rate of admission for heart failure for each 10 μg/m3 PM10
failure in 7 U.S. cities
increase
Case cross-over study on 12,865 U.S. patients undergoing
4.5% daily increase of acute coronary events for each 10 μg/m3 PM2.5 increase
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acronym)
69
70
26
coronary arteriography
Lanki, 2006 (HEAPPS)
26,854 cases of first AMI in 5 European cities
A positive association with AMI of the same day CO (RR 1.021) per 0.2
71
von Klot, 2005 (HEAPPS)
22,066 AMI survivors in 5 European cities
Rate ratio for cardiac readmissions was 1.021 for each 10 μg/m3 in PM10
72
increase
Zanobetti, 2006
Wellenius, 2005
Kettunen, 2007
Andersen, 2010
Dales, 2010
15,578 admission for cardiovascular and respiratory diseases in
Significant association between NO (12.7% increase) and PM2.5 (8.6%
Boston
increase) and the risk of emergency hospitalization for AMI
155,503 ischemic and 19,314 hemorrhagic stroke admissions in
One interquartile range increase in PM10 was associated with a 1.03% daily
people aged 65 years or more from 9 US cities
increase in hospitalization for ischemic stroke
3265 deaths from stroke among people aged 65 years or more
Daily stroke mortality was positively associated with current and previous day
from Finland
PM2.5 levels
Case cross-over study on 7485 admissions for hemorrhagic and
Exposure to ultrafine particles led to a 21% increase in hospitalization for
ischemic stroke in Denmark
ischemic stroke
Times series study on a population of 5.4 million residents in
The relative risk of hospitalization for venous thrombosis was 1.05 for a 20
Santiago (Chile)
μg/m3 PM2.5 increase
73
75
76
77
79
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mg/m3 and particle number concentration (RR 1.058) per 10,000 particles/cm2
PM, particulate matter; OR, odds ratio; RR, relative risk; NMMAPS, National Morbidity, Mortality and Air Pollution Study; APHEA, the Air Pollution and HealthEuropean Approach; MISA, Meta-analysis of Italian Studies on the short-term effects of Air pollution; IHCS, Intermountain Health Collaborative Study; AMIR,
Ausburg Myocardial Infarction Registry; CHF, congestive heart failure; HEAPSS, Health Effects of Air Pollution among Susceptible Subpopulations; AMI, acute
myocardial infarction
27
Table 2. Summary of the largest population studies on long-term cardiovascular effects of particulate air pollution.
First author, year (Study)
Key findings
Reference
Increase in cardiovascular death (RR 1.28) for each 10 μg/m3 PM2.5 increase
83
Prospective cohort of 500,000 residents
12% increased risk of cardiovascular deaths and 18% increased risk of
85
in 150 U.S. cities followed for 16 years
coronary artery disease for each 10 μg/m3 increase in long-term PM2.5
Prospective cohort of 8,111 people from
6 U.S. cities followed for 28 years
Pope, 2004 (ACS)
exposure
Jerrett, 2005
Prospective cohort of 22,905 residents in the Los Angeles area
20% and 49% increase in the risk for cardiopulmonary and coronary artery
86
disease deaths for each 10 μg/m3 increase in long-term PM2.5 exposure
Toren, 2007
Hoek, 2002 (NLCS)
Prospective cohort of 176,309 PM exposed construction workers
Increased risk for coronary artery disease (RR 1.13) associated with
and 71,778 PM unexposed construction workers
occupational exposure to particulate air pollution
4492 Dutch participants
Increased risk of cardiopulmonary mortality (RR 1.95) associated with
87
88
living near a major traffic road
Miller, 2007
Prospective cohort of 65,893 postmenopausal women in 36 U.S.
24% and 76% increase in the risk for cardiovascular events and
cities followed for 6 years
cardiovascular mortality for each 10 μg/m3 increase in long-term PM2.5
89
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
Laden, 2006 (HSCS)
Population
exposure.
Maheswaran, 2010
Retrospective cohort study on 3320 patients with stroke residents
Each 10 μg/m PM10 increase was associated with a 52% increase
3
90
28
in south London between 1995 and 2005
Kunzli, 2005
Measurement of carotid intima-media thickness in 798 resident in Each 10 μg/m3 PM2.5 increase was associated with a 5.9% increase
Los Angeles
of carotid intima–media thickness
4494 German study participants
Compared with participants living more than 200 m away from a major
Nixdorf Recall Study)
91
93
road, participants living within 50, 51 to 100, and 101 to 200 m had odds
ratios of 1.63, 1.34, and 1.08, respectively, for a high coronary artery
calcium content
Baccarelli, 2008
Baccarelli, 2009
870 patients with deep-vein thrombosis and 1210 controls in
Each 10 μg/m PM10 increase was associated with a 70% increase in
Northern Italy
the risk of venous thrombosis
663 patients with deep vein thrombosis and 859 controls in
The risk of venous thrombosis was increased (OR 1.47) for subjects living
Northern Italy
near a major traffic road
3
94
95
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Hoffmann, 2007 (Heinz
post-stroke mortality
PM, particulate matter; HSCS, Harvard Six Cities Study; RR, relative risk; ACS, American Cancer Society; WHI, Woman’s Health Initiative; NLCS, Netherlands
Cohort Study; DVT, deep vein thrombosis.
29
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Prepublished online June 10, 2011;
doi:10.1182/blood-2011-04-343111
Thrombogenicity and cardiovascular effects of ambient air pollution
Massimo Franchini and Pier Manuccio Mannucci
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