Air particulate matter and cardiovascular disease: The epidemiological, biomedical and clinical evidence

Abstract

Air pollution is now becoming an independent risk factor for cardiovascular morbidity and mortality. Numerous epidemiological, biomedical and clinical studies indicate that ambient particulate matter (PM) in air pollution is strongly associated with increased cardiovascular disease such as myocardial infarction (MI), cardiac arrhythmias, ischemic stroke, vascular dysfunction, hypertension and atherosclerosis. The molecular mechanisms for PM-caused cardiovascular disease include directly toxicity to cardiovascular system or indirectly injury by inducing systemic inflammation and oxidative stress in peripheral circulation. Here, we review the linking between PM exposure and the occurrence of cardiovascular disease and discussed the possible underlying mechanisms for the observed PM induced increases in cardiovascular morbidity and mortality.

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© Journal of Thoracic Disease. All rights reserved. J Thorac Dis 2016;8(1):E8-E19www.jthoracdis.com
Introduction
Air pollution has now emerged as a leading problem for
environmental health in the world. Especially in developing
countries, it has become more serious than ever before. The
potentially detrimental to health of air pollution has long
been recognized, and many large epidemiological studies
have clearly demonstrated the strong association between air
pollution exposure and increased morbidity and mortality
(1-3). Air pollutants include gaseous pollutants (e.g., carbon
mono oxide, oxides of nitrogen, ozone and sulfur dioxide)
and particulate matters (PMs). The relationship between
respiratory vulnerability and air pollution has been well
documented, and much attention has now been focused
on the air pollution-induced cardiovascular risk in the
past 15 years (4-6). Of those air pollutants, the ambient
PM has become a major concern for cardiologists and
specialists in environmental medicine. There is a mounting
epidemiological, biomedical and clinical evidence that
indicates the effects of ambient PM on cardiovascular health
(5,7,8). In this review we summarize the main ndings on
the impact of PM particles on cardiovascular system and
discuss the underlying molecular mechanisms of the effects
of PM particles on cardiac muscle and vasculature.
The definition and composition of ambient
particulate matter (PM)
Ambient PM is defined as the material suspended in
the air in the form of minute solid particles or liquid
droplets, which are derived from both human and natural
activities. It is a heterogeneous mixture with varying size
and chemical composition. In terms of their potential
Review Article on Pollutional Haze
Air particulate matter and cardiovascular disease: the
epidemiological, biomedical and clinical evidence
Yixing Du1,2*, Xiaohan Xu3*, Ming Chu1*, Yan Guo1, Junhong Wang1
1Department of Gerontology, 2Department of Neurology, 3Department of Thoracic Surgery, the First Affiliated Hospital of Nanjing Medical
University, Nanjing 210029, China
Contributions: (I) Conception and design: J Wang; (II) Administrative support: Y Guo; (III) Provision of study materials or patients: J Wang, Y Du; (IV)
Collection and assembly of data: M Chu, X Xu; (V) Data analysis and interpretation: Y Du, X Xu, J Wang; (VI) Manuscript writing: All authors; (VII)
Final approval of manuscript: All authors.
*These authors contributed equally to this work.
Correspondence to: Dr. Junhong Wang. Department of Gerontology, the First Afliated Hospital of Nanjing Medical University, Nanjing 210029,
China. Email: cnjjh2000@aliyun.com.
Abstract: Air pollution is now becoming an independent risk factor for cardiovascular morbidity and
mortality. Numerous epidemiological, biomedical and clinical studies indicate that ambient particulate
matter (PM) in air pollution is strongly associated with increased cardiovascular disease such as myocardial
infarction (MI), cardiac arrhythmias, ischemic stroke, vascular dysfunction, hypertension and atherosclerosis.
The molecular mechanisms for PM-caused cardiovascular disease include directly toxicity to cardiovascular
system or indirectly injury by inducing systemic inammation and oxidative stress in peripheral circulation.
Here, we review the linking between PM exposure and the occurrence of cardiovascular disease and discussed
the possible underlying mechanisms for the observed PM induced increases in cardiovascular morbidity and
mortality.
Keywords: Particulate matter (PM); cardiovascular disease; morbidity; mortality
Submitted Jun 19, 2014. Accepted for publication Oct 28, 2015.
doi: 10.3978/j.issn.2072-1439.2015.11.37
View this article at: http://dx.doi.org/10.3978/j.issn.2072-1439.2015.11.37

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influence on health, they are classified as PM10, PM2.5
and ultrafine particles (UFPs) subgroup according to
their diameter. PM10 includes coarse particles with the
aerodynamic diameter (AD) from 2.5 to 10 μm. The
PM10 particles come from road and agricultural dust, tire
wear emission, construction and demolition works or the
mining operations (8). In addition, the natural activity such
as wildfires and windblown dust are also the sources for
PM10. Compared to PM10, the primary contributors of
PM2.5 mainly come from the trafc and industry includes
fuel combustion from power plant and oil refinery or the
brake emissions of mobile. PM2.5 indicates those fine
particles with AD less than 2.5 μm. Based on numerous
epidemiological studies and large clinical observation,
the PM2.5 has been considered as the main culprit of the
adverse cardiovascular effects of air pollution on human
health (5,6). UFPs include those particles diameters
less than 0.1 μm, and the primary sources of UFPs are
tailpipe emissions from mobile sources. Theoretically,
PM10 particles preferentially deposit in the upper airways,
meanwhile the PM2.5 and UFPs particles are much more
easier to reach the smallest airways and alveoli and UFPs
may further penetrate the alveolar-capillary membrane,
which eventually spread into the systemic circulation. It
has been reported that the UFPs particles can be found in
remote organs (9). This finding may indicate that UFPs
could induce specific organ toxic effects. In addition, the
secondary particular matters, ambient aerosols appear
when ambient particles interact with atmospheric gases
(ozone, sulfur and nitric oxides and carbon monoxide) (8).
Each of those aerosols can have independent and potentially
synergistic or antagonistic effects with each other and with
PM; however, at present, the cardiovascular health impact
of exposure to combinations of those air pollutants is not
well understood (5).
Pathophysiological mechanisms linking
particulate matter (PM) particles and
cardiovascular disease
In the past 15 years, numerous studies and in-depth reviews
have demonstrated that PM particles play a significant role
in the process of cardiovascular disease. Table 1 summarizes
the most recent studies [2014-2015] on PM-induced short-
term and long-term cardiovascular effects. There is a strong
link between the PM particles and the deaths caused due to
cardiovascular diseases (4,21,28,31-33), and several pathways
have recognized that can explain the link between PM particles
and cardiovascular diseases, the rst is the direct pathway. In
this way, PM2.5, in particular UFPs directly translocate into
the blood stream and remote target organ, and the other two
pathways are indirect. For the indirect pathways, the one is
mediated by pulmonary oxidative stress and inflammatory
response, which is less acute and occur after several hours or
days of inhalation (6,34). Interaction on the autonomic nervous
system via specific lung receptors is an another indirect
pathway well documented by many authors (6,8).
Direct actions of ultrane particles (UFPs) on cardiovascular
system
Due to the size, charge, chemical composition of UFPs, it is
much easier to cross the pulmonary epithelium and the lung-
blood barrier than PM10 and other coarse particulate. Thus,
the translocation of UFPs into the blood stream and specic
organ has been documented in animal studies (35-39). This
exposure, even at low concentration, can translocate into
blood steam and remote organ to cause potential cumulative
toxicity (39). The translocation of UFPs to the blood stream
has detrimental effects on cardiovascular system. After
deposit on vascular endothelium, the UFPs can aggravate
the local oxidative stress and inflammation, resulting the
atherosclerotic plaque instability, and finally may lead to
thrombus formation (40). Furthermore, increased ejection
fraction and premature ventricular beats was observed
in rats intravenously injected with UFPs isolated from
ambient air (41). This inotropic effect of UFPs may be
harmful to coronary heart disease patients, which increase
the oxygen demand of the diseased hearts and aggravate the
ischemic symptom. However, the in vitro results of UFPs
on cardiac performance demonstrated that the UFPs have
the cardiac depression effects, which can cause myocardial
stunning and cardiac function deterioration (42). The
seemed contradictable in vivo and in vitro results might be
explained as the difference in circulation-mediated or direct
cardiotoxicity of UFPs in these two models (8). Although not
observed in human beings so far, these studies still indicated
that UFPs has the cardiotoxicity effects and can directly
affect the cardiac performance.
Indirect pathways of particulate matter (PM) particulates
on cardiovascular system
Increased oxidative stress and activated inflammatory
pathway in pulmonary due to exposure to PM particulate
play a substantial role in this indirect pathway. Considerable

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Table 1 The representative recent studies [2014-2015] on the short-term and long-term effects of exposure to PMs on cardiovascular system
Studies Study population Main findings
Short-term exposure studies
Li et al. (10) Case-crossover study in eight Chinese large
cities
An increase of 10 μg/m3 in 2-day moving average concentrations of PM10, SO2
and NO2, was significantly associated with increases of daily CHD mortality
MONICA/KORA
study (11)
Case-crossover study of 15,417 MI cases in
Germany
An association between short-term PMs concentration and numbers of MI,
especially for nonfatal and recurrent events
MCAPS (12) 12-year of time series study in USA Daily variation in PM10-2.5 is associated with emergency hospitalizations for
cardiovascular diseases among elderly population (≥65 years)
MED-PARTICLES
project (13)
Case-crossover study in ten southern
European cities
Wildfires and PM10 were associated with increased cardiovascular mortality in
urban residents
Chang et al. (14) Case-crossover study in Taiwan from
2006-2010
Higher levels of PM2.5 enhance the risk of hospital admissions for CVD on
cool days (<25 ℃)
EPHT program (15) Case-crossover study in seven US states
within the CDC EPHT network
Multiple cardiovascular outcomes in addition to AMI may be impacted by
particulate air pollution in state-wide
MINAP (16) Case-crossover study of over 400,000 MI
events in England and Wales
The strong associations with air pollution were observed with selected
non-MI CVD outcomes, while no clear evidence was found for pollution
effects on STEMIs
Zhao et al. (17) Time-series study of 56,940 outpatient in
China
A 10 µg/m3 increase in the present-day concentrations of PM10, SO2, and
NO2 corresponded to increases of 0.56%, 2.07%, and 2.90% in outpatient
arrhythmia visits
Raza et al. (18) Case-crossover study of 5,973 cases in
Stockholm county from 2000-2010
Short-term exposure (in 2 h) to moderate levels of O3 is associated with an
increased risk of out-of-hospital cardiac arrest (OHCA)
Bell et al. (19) Time-series study of aged persons from
four countries in USA
PM2.5 total mass and PM2.5 road dust were associated with increased
cardiovascular hospitalizations, as were the PM2.5 constituent calcium,
black carbon, vanadium, and zinc
Long-term exposure studies
MESA project (20) Time-series study in USA from 2000 to 2012 Long-term exposure to air pollution is related to the markers of inflammation
and fibrinolysis
Qin et al. (21) Cross-sectional study of 24,845 adults in
Northeastern metropolitan China
Being overweight and obese may enhance the effects of air pollution on the
prevalence of CVDs
Wolf et al. (22) Cohort study of 100,166 persons in European
followed on average for 11.5 years
A 100 ng/m³ increase in PM10 and a 50 ng/m³ increase in PM2.5 were
associated with a 6% and 18% increase in coronary events
Wong et al. (23) Cohort study of 66,820 aged persons in
Hong Kong followed for 4 years
Mortality HRs per 10 μg/m3 increase in PM2.5 were 1.22 for cardiovascular
causes and 1.42 for ischemic heart disease
Chan et al. (24) Cross-sectional study of 43,629 women in
USA
Long-term PM2.5 and NO2 exposures were associated with higher blood
pressure (BP)
Pope et al. (25) Cross-sectional study of 669,046
participants in USA
Long-term exposure may contribute to the development or exacerbation
of cardiometabolic disorders, increasing risk of CVD, and cardiometabolic
disease mortality
Kim et al. (26) Cross-sectional study of 5,488 MESA
participants in USA
Long-term concentrations of sulfur and OC, and possibly silicon, were
associated with CIMT
Wilker et al. (27) Cohort study of 5,112 participants in the
Framingham Offsprings.
Higher levels of spatially PM2.5 at participant residences are associated with
impaired conduit artery and microvascular function in middle-aged and elderly
adults
Weichenthal et al. (28) Cohort study of 83,378 participants in the
USA
Rural PM2.5 may be associated with cardiovascular mortality in men, but not
in women
Beelen et al. (29) A joint analysis of data from 22 European
cohorts consisted of 367,383 participants
Most hazard ratios for the association of air pollutants with mortality from
overall CVD and with specific CVDs were approximately 1.0
Zhou et al. (30) Prospective cohort study of 71,431 middle-
aged Chinese men
Each 10 μg/m3 PM10 was associated with a 1.8% increased risk of
cardiovascular mortality
PM, particulate matter; MI, myocardial infarction.

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evidence has proved that particulate air pollutants can
trigger an inammation related cascade when they deposit
in the lung (43-46). Increased circulating level of pro-
inammatory cytokines such as CRP, IL-6, IL-8 and IL-1β
were observed in healthy subjects when exposure to ambient
PMs (46-50). Similar results have been reported in in vivo
animal models and in vitro cellular models (51,52). Systemic
inammatory is a well-known risk factor for atherosclerosis
progression, and those pro-inflammatory mediators are
close related to increased blood coagulability and endothelial
dysfunction and which finally can exacerbate myocardial
ischemia. In addition, ROS-dependent mechanism was
shown to involved in the PM particulates triggered pro-
inflammatory pathway (47). Increased amounts of ROS
were reported in rat lung and heart by means of in situ
chemiluminescence after exposure to PMs (47). ROS was
shown to be linked to atherosclerosis, vascular dysfunction,
cardiac arrhythmias and myocardial injury (53,54).
Other mechanisms for particulate matter (PM)-induced
cardiovascular disorders
In addition to the sizes of PMs, the quality of PMs
(components) also played an important role in PM-related
harmful effects. The components of PMs varies spatially and
temporally, which includes health hazardous metals, such
as copper, lead, iron, nickel and chromium originate from
industrial combustion processes or trafc combustion. Other
gaseous pollutants (e.g., CO, NO2, NOX, O3 and SO2 etc.)
have also been demonstrated to be close related to the
adverse outcomes of cardiovascular disease (10,17,18,24,26).
Furthermore, PM particulates are thought to stimulate
autonomic nervous system (55), impairing autonomic
balance and favoring sympathetic tone (56). The over
activated sympathetic tone is closely related to increased
cardiovascular risk through induction of pro-hypertensive
vasoconstriction and the predisposition to arrhythmias (56).
Recently, microRNAs (miRNAs) have emerged as
attractive candidates to explore the impact of PM exposures
on cardiovascular system (57,58). Experimental and
clinical studies indicated that PMs can modulate those
miRNAs involved in processes of systemic inflammation,
endothelial dysfunction and atherosclerosis. Meanwhile,
SNPs in miRNA-processing genes may also modify the
associations between ambient pollution and cardiovascular
disease (58,59). However, further work remains need to
be addressed include linking specific PM exposures to
subsequent health outcomes based on established miRNA
expression profiles and experimentally validating putative
downstream targets of the deregulated miRNAs.
The linking between ambient particulate matters
(PMs) and cardiovascular disease
Cardiovascular (CV) mortality and particulate matter
(PM) particulates exposure
The positive relationship between CV mortality and PM
particulates exposure has been proved in many large time-
series and case-crossover studies. Even a 10 μg/m3 increase
in short-term (<24 h) PM2.5 level increases the relative
risk (RR) of daily cardiovascular mortality by ~0.4% to
1.0% (60). In addition, several landmark time-series studies
have been conducted worldwide in recent years to address
the daily PM-related CV and all-cause mortality. One
of the largest was the National Morbidity, Mortality and
Air Pollution Study (NMMAPS) (61,62). The APHEA
(Air pollution and Health: A European Approach) and
APHEA-2 projects investigated the relationship between
short-term PM exposure and CV mortality in multiple
European cities (63,64). Those large studies revealed that
PM particulates including the coarse particulates, PM10,
were significantly associated with daily all-cause and CV
mortality. Similar time-series studies conducted in Asia
countries (China, Thailand and Indian) further conrmed
the relationship between the daily PM-exposure and CV
mortality (65-67).
In addition to the short-term exposure of PM
particulates, the longer-term exposure may have more
deleterious effects on healthy and cardiovascular mortality
giving the more accumulated PM exposure during the
extended periods of time. Miller et al. revealed that long-
term exposure to ne particulate air pollution was associated
with the incidence of cardiovascular disease and death
among postmenopausal women based on the data from 36
USA metropolitan areas (33). Many large prospective cohort
studies and ne meta-analysis have further provided us with
clear answers on the correlation between longer-term PM-
exposure and CV mortality (29,68,69). However, a most
recent large cohort study performed by Beelen et al. (29) did
not found any association between PM and cardiovascular
mortality. The explanation for the difference between this
study and those of previous studies may be because of the
changes in cardiovascular risk prole (e.g., reduced smoking
and increased medication and medical treatment). And the
changed risk prole nally altered the relationship between

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air pollution and cardiovascular mortality. The extended
reanalysis of the two large cohort studies—the Harvard Six
Cities and ACS Studies further emphasized the notorious
effects of PM2.5 on CV mortality (2,32,70). Furthermore,
studies demonstrated that signicantly reduction of PM2.5
level was associated with reduced mortality risk (70,71).
However, unlike the results observed in short-term exposure
studies, the reanalysis of ACS study demonstrated that the
coarse particles (PM10) were generally not significantly
related to CV mortality (32).
Ischemic heart disease (IHD) and particulate matter (PM)
particulates exposure
An earlier hospital-based study (72) demonstrated that
the incidence of myocardial infarction (MI) and angina
was found to associate with atmospheric gases and/
or black smoke. Another studies conducted in USA
(4-year in 204 counties) and European (10-year in
five major cities) indicated that hospital admission for
IHD were positively associated with increased level
of fine PM particulates (73,74). Furthermore, a very
recent large prospective cohort study and meta-analysis
in 11 European cohorts from the ESCAPE project
confirmed that long term exposure to PM is associated
with incidence of coronary events, and this association
persists at levels of exposure even below the current
European limit values (25 μg/m3 for PM2.5, 40 μg/m3
for PM10) (75). They concluded that with a 5 μg/m3
increase in estimated annual mean PM2.5 was associated
with a 13% increased risk of coronary events (HR 1.13,
95% confidence interval 0.98 to 1.30), and a 10 μg/m3
increase in estimated annual mean PM10 was associated
with a 12% increased risk of coronary events (1.12, 1.01
to 1.25). In California teachers cohort study (76), Lipsett
et al. provided evidence linking long-term exposure to
PM2.5 with increased risks of incident IHD mortality,
particularly among postmenopausal women. Meanwhile,
exposure to nitrogen oxides was also associated with
elevated risks for IHD and all cardiovascular mortality. In
addition to the long-term effects of PM on IHD, short-
term elevated ambient ne PM concentrations has also been
reported to increase the IHD hospital admission, which was
further proved by numerous time-series, case-crossover and
meta-analysis studies (69,77,78). Recently a large cohort
study investigated the relationship between occupational
particle exposure and the incidence of IHD in Swedish
workers. They found that either exposure to a small job-
exposure matrix (<1 μm) or large (>1 μm) was associated
with an increased HR for acute MI, and the association was
somewhat stronger for those exposed to small particles for
more than 5 years (79).
Although few direct evidence for the induction of cardiac
ischemia by exposure to ambient level of PM has been
documented in real patient world, the experimental MI
model provided more evidence linking PM exposure and
increased infarct size and/or potential myocardial ischemia
(80-82). The mechanisms for PM exposure induced
myocardial ischemic injury can be attributed to increased
systemic inflammation, altered endothelial function and
enhanced thrombotic tendency (80,83). In addition, the
PM exposure was found to be associated with a small
but significant decrease in myocardial flow, especially in
ischemic area in a conscious canine myocardial ischemic
model (82). Moreover, traffic-related PM in patients with
coronary artery disease was found to be strongly related to
the incidence of ST-segment depression during 24-hour
Holter monitoring.
Cardiac arrhythmias, out-of-hospital cardiac arrest (OHCA)
and particulate matter (PM) particulates exposure
Several studies have observed a positive association between
exposure to ambient PM and the incidence of ventricular
arrhythmias in patients implanted with automatic
defibrillators (84,85). A 5-year prospective study (86) in
Taipei demonstrated that increased numbers of emergency
room cardiac arrhythmia visits were signicantly associated
with PM2.5 on both warm days (>23 ℃) and cool days
(<23 ℃), with an interquartile range rise associated with a
10% and 4% elevation in number of ER visits for cardiac
arrhythmias, respectively. Very recently, another prospective
follow-up study evaluated the association of air pollution
with the onset of atrial brillation (AF) in 176 patients with
dual chamber implantable cardioverter-debrillators (ICDs).
The authors revealed that PM2.5 is an acute trigger of AF,
which was associated with increased odds of AF onset [26%
(95% CI: 8-47%) increase for each 6.0 mg/m3 increase in
PM2.5 concentration] within hours following exposure in
patients with known cardiac disease (87). Similarly, PM2.5
or ne PM-exposure has been reported to be associated with
OHCA in Melbourne (88), Houston (89), New York (90),
and many other cities or countries but not in Demark (91)
and Seattle (92). These seemed inconsistent results may
reect different PM compositions due to different sources
among the cities and countries. Furthermore, the lower

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exposure levels in Demark and Seattle than in New York
and Houston should also be considered.
In general, the incidence of sudden cardiac death
and cardiac arrhythmias is closely related to the activity
of the autonomic nervous system, and its activity in
susceptible patients can be evaluated by measuring the
changes in heart rate variability (HRV). HRV is mediated
by a balance between sympathetic and parasympathetic
branches of autonomous nervous system (34), which is
recognized as a marker for prognosis the incidence of
ventricular arrhythmia. Reduced HRV often predict the
likelihood of developing ventricular arrhythmias in post-
MI and heart failure patients (93,94). The reductions in
HRV were observed on exposure to ambient, household
or occupational PMs in healthy volunteer, susceptible
patients, housewives and workers (95-97). In the studies
in Beijing, the authors demonstrated an increase in
HRV in healthy volunteers and CHD patients when
exposure to ambient PM particles. On the contrary, the
protective effects were observed when the participants
used the highly efficient facemask (98,99). Although the
mechanisms for PMs induced HRV and other changes in
ECG remain largely unknown, some studies demonstrated
that PM-induced cardiac electrophysiological changes
can be prevented by inhibiting the transient receptor
potential vanilloid receptor 1 (TRPV1) in the lungs (100).
In addition, there have been relatively few researchers
studied on the gene-PM exposure interactions, and
most have done on a small number of loci for genetic
polymorphisms. Some authors indicated that the
associations between PM2.5 and HRV can be modified
by gene polymorphisms of apolipoprotein E (APOE),
lipoprotein lipase (LPL), vascular endothelial growth
factor (VEGF) and glutathione S-transferase (GST) in
general population, and the biological metabolism for PM
related HRV changes might be related to the action on
autonomic function via the lipid/endothelial metabolism
and oxidative stress pathways (101,102).
Vascular function, blood pressure (BP), atherosclerosis and
particulate matter (PM) particulates exposure
Experiments demonstrated that PM particulates can cause
excess ROS formation thus leading to impairment of
nitric oxide-dependent vascular dilation and enhancing
vasoconstrictor in ex vivo and in vivo studies (5,103).
Furthermore, exposure to PM has found to be associated with
an increase in plasma concentration of endothelin-1 (ET-1),
which is a putative potent endogenous vasoconstrictor to
cause vascular endothelial dysfunction (104,105). Although
the PM-related vascular dysfunction is documented in many
articles, the results for BP response to acute PM exposure
is inconsistent. Some controlled studies reported that PM
exposure cause no changes among healthy adults, while other
recent findings suggested that actual period of exposure to
concentrated ambient particulate (CAP) signicantly increase
the diastolic BP (106), whereas no changes was observed with
longer time of exposure (24 h) to PM (107). In that, those
results suggested that this CAP induced BP changes might
be more related to the PM-induced ANS imbalance which
favored sympathetic over parasympathetic cardiovascular tone.
Although a recent meta-analysis from four European
cohort studies in the ESCAPE study only nd a positive but
not signicant associations between CIMT and long-term
exposure to the PM2.5 (108), many epidemiological and
animal evidences still documented that exposure to PMs
plays a role in the development of atherosclerosis. Sun and
his colleague demonstrated that exposure to environmentally
relevant PM2.5 (regional northeastern of US) in
conjunction with a high-fat chow diet in ApoE−/− mice for
6 months can cause endothelial dysfunction, increase the
vascular plaque burden and accelerate the progression
of atherosclerosis (109). The same results were reported
in Beijing, Los Angeles and many other places when the
ApoE−/− mice were exposure to the local ambient particle
(110,111). To investigate the relation between individual-
level estimates of long-term air pollution exposure and
the progression of subclinical atherosclerosis, a large
prospective, multicenter study named Multi-Ethnic
Study of Atherosclerosis and Air Pollution (MESA Air)
was initiated in 2004. That study demonstrated that
long-term PM2.5 exposure was significantly associated
with decreased endothelial function with increased
IMT progression even over a relatively short follow-up
period, which add to the literature on air pollution and
the progression of atherosclerotic processes in humans
(112,113). Even more, the authors observed that the
slower IMT progression was related to greater reductions
in PM2.5. A very recent study recalled the data [2000-2003]
from the German Heinz Nixdorf Recall Study, which
included a population-based cohort of 4,814 randomly
selected participants. The study used a reliable indice,
the thoracic aortic calcification (TAC), to evaluate the
subclinical atherosclerosis. Their results demonstrated that
long-term exposure to ne PM is independently associated
with subclinical atherosclerosis (114). Taken together,

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these findings may elucidate important pathways linking
air pollution to the development of atherosclerosis.
Thrombus formation, blood coagulation and particulate
matter (PM) particulate exposure
In vivo as well as in vitro studies demonstrated that PM
particulates can induce pro-thrombotic effects by producing
inflammatory mediators in the lungs and releasing into
the blood circulation or directly translocation of small
particulates from lung to the circulation. Nemmar et al.
revealed that exposure of hamster to the diesel exhaust
particles after photochemical injury resulted in platelet
function abnormalities and thrombus formation both in
arteries and veins (115). Mutlu GM and his colleague
using IL-6 knockout (KO) mouse model demonstrated
that IL-6 and its downstream signaling pathway plays
a pivotal role in PM-induced prothrombotic state by
increasing the expression of fibrinogen, factor VIII and
tissue factor (TF), thus increasing the risk of both venous
and arterial thrombosis (34,116). Furthermore, they also
found that the prothrombotic effect of PM was further
mitigated in macrophage-depleted mice (116). Those
results may suggest that IL-6, macrophage and pulmonary
inflammation are the necessary initial steps for PM-
induced prothrombotic changes. Kilinç et al. documented
the possible mechanisms for early and chronic exposure
of PM (UFPs)-driven procoagulant activity in genetically
modied mice [FXII(−/−)]. They revealed that PM promotes
its early procoagulant actions mostly through the TF-
driven extrinsic pathway of coagulation, whereas PM-
driven long lasting thrombogenic effects are predominantly
mediated via formation of activated FXII. Hence, they
concluded that FXII-driven thrombin formation may be
relevant to an enhanced thrombotic susceptibility upon
chronic exposure to PM in humans (40). In addition to
increasing the inammatory mediators and prothrombotic
proteins, particulate nanoparticles and other UFPs
themselves could reach the circulation and directly enhance
thrombus formation as analyzed by scanning electron
microscopes (117). In real-world studies, the MONICA
survey indicated that plasma viscosity was increased in both
men and women when exposure to air pollutions (118).
Recently, researchers studied the effects of short-term
changes in exposure to UFPs on stroke, separately for
ischaemic and hemorrhagic strokes, and ischaemic strokes
with (likely embolic) and without (likely thrombotic) AF.
Their results demonstrated that exposure to UFPs lead to a
21% increase in hospital admissions (per interquartile range
of 5-day averages; 95% CI: 4-41%) for mild ischaemic
stroke of without AF (likely thrombotic origin), which may
further indicate the thrombotic and procoagulant actions of
PM particles (119).
Conclusions
In summary, a wide array of experimental and epidemiological
studies have unequivocally provided persuasive evidences
on the negative impact of PMs on cardiovascular events
and outcomes. In addition, numerous findings indicate
that even a few hours to weeks of short-term exposure to
PM particulates can trigger CVD-related mortality and
events, especially among the susceptible individuals at great
risk including the elderly or the patients with preexisting
coronary artery disease. The underlying mechanisms for
PM-caused cardiovascular disease include directly insults
by UFPs translocating to the circulations and remote
localization to the heart or indirectly injury by inducing
systemic inflammation and oxidative stress in circulation,
thus leading to cardiovascular damage. However, even the
epidemiology and the biomedical studies will possibly help us
better understand the underlying mechanisms and increase
the effectiveness of our efforts to reduce the risk of air
pollution—related cardiovascular disease, the major strategy
in decreasing the harmful effects of air pollution is to reduce
the air pollutants themselves. As the air pollution is becoming
an ecological and social dilemma in the world, especially
in developing countries like China, the social movements
backed up by medical doctors, medias and government,
therefore, might be great needed to combat with the
deteriorating air pollution problem and nally to lower the
associated cardiovascular risk.
Acknowledgements
Funding: This work was supported by the National Natural
Science Foundation of China (NSFC 30900602, J Wang)
and National Natural Science Foundation of Jiangsu
Province (BK2012879 to J Wang and BK2011382 to Y
Guo); Dr. Wang was also supported by the “Sixth-Peak
Talent” of Jiangsu Province (2013WSN-036).
Footnote
Conicts of Interest: The authors have no conicts of interest
to declare.

E15Journal of Thoracic Disease, Vol 8, No 1 January 2016
© Journal of Thoracic Disease. All rights reserved. J Thorac Dis 2016;8(1):E8-E19www.jthoracdis.com
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Cite this article as: Du Y, Xu X, Chu M, Guo Y, Wang J.
Air particulate matter and cardiovascular disease: the
epidemiological, biomedical and clinical evidence. J Thorac Dis
2016;8(1):E8-E19. doi: 10.3978/j.issn.2072-1439.2015.11.37