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Journal of the American Heart Association
J Am Heart Assoc. 2020;9:e014944. DOI: 10.1161/JAHA.119.014944 1
CONTEMPORARY REVIEW
Cumulative Lifetime Burden of Cardiovascular
Disease From Early Exposure to Air Pollution
Juyong Brian Kim , MD, MPH; Mary Prunicki, MD, PhD; Francois Haddad, MD; Christopher Dant, PhD;
Vanitha Sampath, PhD; Rushali Patel; Eric Smith; Cezmi Akdis, MD, PhD; John Balmes, MD;
Michael P. Snyder, PhD; Joseph C. Wu, MD, PhD; Kari C. Nadeau, MD, PhD
ABSTRACT: The disease burden associated with air pollution continues to grow. The World Health Organization (WHO) es-
timates ≈7million people worldwide die yearly from exposure to polluted air, half of which—3.3million—are attributable to
cardiovascular disease (CVD), greater than from major modifiable CVD risks including smoking, hypertension, hyperlipidemia,
and diabetes mellitus. This serious and growing health threat is attributed to increasing urbanization of the world’s populations
with consequent exposure to polluted air. Especially vulnerable are the elderly, patients with pre- existing CVD, and children.
The cumulative lifetime burden in children is particularly of concern because their rapidly developing cardiopulmonary sys-
tems are more susceptible to damage and they spend more time outdoors and therefore inhale more pollutants. World Health
Organization estimates that 93% of the world’s children aged <15years—1.8billion children—breathe air that puts their health
and development at risk. Here, we present growing scientific evidence, including from our own group, that chronic exposure
to air pollution early in life is directly linked to development of major CVD risks, including obesity, hypertension, and metabolic
disorders. In this review, we surveyed the literature for current knowledge of how pollution exposure early in life adversely im-
pacts cardiovascular phenotypes, and lay the foundation for early intervention and other strategies that can help prevent this
damage. We also discuss the need for better guidelines and additional research to validate exposure metrics and interventions
that will ultimately help healthcare providers reduce the growing burden of CVD from pollution.
Key Words: air pollutants, environmental ■ cardiovascular abnormalities ■ cardiovascular disease ■ epithelial barrier
Cardiovascular disease (CVD) is a leading cause of
death worldwide, and evidence suggests that the
disease process can begin early in life.1 Several fac-
tors contribute to the development of CVD; greater than
half of the risk is modifiable, including hypertension, hy-
perlipidemia, diabetes mellitus, and smoking, while the
remaining risks are thought to be heritable.2 A substan-
tial body of epidemiological evidence has demonstrated
significant associations between air pollution exposure
and increased CVD risk.3 Here, we focus on the cumu-
lative lifetime burden of air pollution, especially the ev-
idence of pollution exposure that begins in childhood,
by surveying the association between CVD risk from
exposure to ambient and indoor pollution and discuss
interventional strategies to prevent and mitigate risk.
Every year, >3million people worldwide die of isch-
emic heart disease or stroke attributed to air pollution,
more than from other modifiable cardiac disease risks
such as obesity, diabetes mellitus, or cigarette smok-
ing.4 Both acute and chronic exposures to compo-
nents of air pollution, including fine particulate matter
(PM) and polycyclic hydrocarbons (PAH), have been
associated with increased cardiovascular events
such as ischemic heart disease, heart failure, cardiac
arrhythmias, hypertension, and others.5
The cardiopulmonary systems of children are rapidly
developing, and are therefore more vulnerable to injury
and inflammation caused by pollutants.6 Emerging ob-
servations from the World Health Organization (WHO)
suggest that early exposure to pollution during child-
hood and adolescent years can alter a child’s health
trajectory and result in increased prevalence of risks
for CVD later in life, including obesity, metabolic syn-
drome, and hypertension.7 The most recent WHO
Correspondence to: Juyong Br ian Kim, MD, MPH, 300 Pasteur Drive, Falk CVRC, Stanford, CA 94305. E-mail: kimjb@stanford.edu
For Sources of Funding and Disclosures, see page 15.
© 2020 The Authors. Published on behalf of the American Heart Asso ciation, Inc., by Wiley. This is an open access article under the terms of the Creative
Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited
and is not used for commercial purpose s.
JAHA is available at: www.ahajournals.org/journal/jaha
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J Am Heart Assoc. 2020;9:e014944. DOI: 10.1161/JAHA.119.014944 2
Kim etal Air Pollution and Cardiovascular Disease
report concluded that the millions of children exposed
to unsafe levels of air pollution suffer a “life sentence”
of illness, pushing them to a “path of chronicity, suf-
fering…and challenge.”8 Furthermore, economically
disadvantaged groups are disproportionally vulnerable
to air pollution and its adverse health effects.9 As such,
there is an urgent need to formulate more effective pol-
icy responses and health guidelines, aimed at protect-
ing the most vulnerable, particularly children and the
elderly.
Air pollution is a complex mixture containing both
particles and gases. The air pollutants for which the
Environmental Protection Agency has set National
Ambient Air Quality Standards include carbon monox-
ide, nitrogen dioxide, sulfur dioxide and ozone, PM, and
lead.5 The most well- researched air pollutant related to
cardiovascular events is fine PM (particles ≤2.5μm in
diameter [PM2.5]), of which a large fraction is comprised
of particles generated by a combustion of fossil fuels,
including black elemental carbon, metals, and a variety
of complex organic molecules.10 These fine particles
penetrate deeply into the small airways and alveoli of
the lungs where they stimulate macrophages and ep-
ithelial cells to release proinflammatory cytokines.4,11,12
The US Environmental Protection Agency regulates air
pollutants such as lead, sulfur dioxide, nitrogen diox-
ides, carbon monoxide, PM, and ozone, all of which
have been associated with cardiovascular events.5
Although the association between exposures to a
pollutant like PM2.5 and CVD risk is now well established,
the specific mechanisms by which these exposures pro-
mote CVD are not completely understood.3 From epi-
demiological studies, one hypothesis argues that upon
entering the lungs, pollutants produce local inflammation
and oxidative stress that leads to subsequent systemic
inflammation, which contributes to endothelial dysfunc-
tion, thrombosis, and enhanced atherosclerosis.13 A
second hypothesis suggests that pollutants activate the
pulmonary autonomic nervous system which can lead
to life- threatening arrhythmias.5 A third hypothesis sug-
gests that PM, particularly, ultrafine particles (<0.1μm
in diameter), enter the blood stream, directly damaging
tissues and cells within the cardiovascular system.5
This paper is meant to be a contemporary review,
rather than a comprehensive review. It focuses on rel-
evant and recent published articles. Using available
evidence, including from our own research, it intends
to inform readers about the complex issue of the cu-
mulative lifetime burden of CVD from exposure to air
pollution. Search terms and keywords included hyper-
tension, obesity, glucose metabolism, and diabetes
mellitus, hyperlipidemia, dyslipidemia, cardiac arrhyth-
mias, stroke, atherosclerosis, cardiac disease, as well
as pollution, PAH, PM2.5, concurrently with keywords
including early exposure, fetal exposure, infants, chil-
dren, or adolescent. We searched for exact phrases
such as “pollution and CVD and children” and included
wildcard searches to find other possible results such
as “cardiovascular disease * pollution”. Finally, to make
our online searches more comprehensive, we con-
ducted citation searches to determine whether articles
have been cited by other authors, and to find more
recent papers on the same or similar subject(s). All ci-
tations were confirmed and entered using EndNote.
GLOBAL AIR POLLUTION: A
GROWING LIFETIME BURDEN
Much of the world’s population lives in places where
air quality exceeds the limits of the health- protective
guidelines set by the WHO (Figure1), making air pol-
lution the largest environmental risk to health world-
wide.14 Here, we discuss the risks from ambient
and indoor air pollution, as well as pollution from to-
bacco smoke, which shares common pathways to air
pollution- induced CVD.
Ambient and Indoor Pollution
Although there are many sources of air pollution, both
natural (eg, volcanic eruptions) and man- made (eg,
cookstoves, power plants, motor vehicles), the latter is
the primary source, because even most catastrophic
wildfires are started by human activities.14,15 Outdoor
air pollution is typically produced by combustion of
fossil fuels and industrial processes while indoor or
household air pollution is produced by smoke from
poorly ventilated domestic cookstoves that burn solid
fuels such as wood, crop waste, dried dung, and coal/
lignite or kerosene mostly in low and middle- income
countries.14 Nearly 3 billion people worldwide are ex-
posed to household air pollution from inefficient cook-
ing and heating stoves,14 and almost the entire global
population is exposed to detectable levels of outdoor
air pollution from traffic, industry, and other sources.
Recent data released by WHO show that outdoor
and household air pollution has a vast negative impact
on both adult and child health and survival.14 United
Nations Children's Fund (UNICEF) recently reported
that deaths in Africa from outdoor air pollution increased
from 164 000 in 1990 to 258 000 in 2017–a growth
of nearly 60%–affecting especially the poorest chil-
dren.16 In Asia, deaths attributable to PM2.5 increased
from 3.5million in 1990 to 4.2million in 2015,17 many
of them in children exposed to household air pollution
from unventilated stoves and wood fires.14 In 2010 in
China alone, outdoor air pollution was associated with
>300 000 deaths, 20 million cases of respiratory ill-
ness, and annual healthcare costs >$500 billion, with
children particularly susceptible.18 Especially in children
whose organs are still developing, exposure to PM can
result in adverse cardiopulmonary effects early in life19
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Kim etal Air Pollution and Cardiovascular Disease
and WHO estimates about 93% of the world’s children
aged <15years (1.8billion children) breathe air that is so
polluted it puts their health and development at serious
risk.7 In fact, the damage from air pollution often has al-
ready been inflicted even before birth, as maternal expo-
sure to air pollutants during pregnancy has been shown
to be associated with increased adverse birth outcomes
such as stillbirth, low birth weight, and preterm birth.20–
22 In particular, families living in environments with high
levels of household air pollutants have low child survival
rates23 and increased neonatal morbidity and mortal-
it y. 24 –29 A new, yet- unpublished study from the Cardiff
School of Medicine that followed 8 million live births
in the U.K. and Wales between 2001 and 2012, found
that babies who grow up breathing polluted air—com-
pared with those living in non- polluted regions—have a
higher risk of death as a neonate (38%), between 1 and
12months of age (54%), or during infancy (43%).30
Tobacco Smoke Pollution
Tobacco use significantly increases the risk for many
serious human diseases, but its greatest effect on mor-
bidity and mortality is through promoting CVD31,32 and
the tobacco- related risk for symptomatic atheroscle-
rotic CVD is ≈40%.33 Air pollution- induced CVD shares
common pathways with tobacco- induced CVD, and
air pollution from combustion sources is a complex
mixture of carbon- based particles and gases similar to
tobacco smoke.34 Although a greater body of literature
exists on studies of tobacco smoke exposure, the pre-
cise toxic components and the mechanisms involved
in smoking- related cardiovascular dysfunction are not
completely known, but we know that cigarette smok-
ing increases inflammation, thrombosis, and oxidation
of low- density lipoprotein cholesterol,32 similar effects
produced by pollution exposure. Also, increased hy-
pertension, obesity, and insulin resistance—compo-
nents of metabolic syndrome—have been reported
to be associated with tobacco exposure,35 similar to
what has been reported for ambient pollution expo-
sure (Table). As with indoor and outdoor pollution, we
have seen similar patterns of epigenetic changes in-
cluding increased methylation in newborns and adults
exposed to tobacco smoke.36–38
Particulate Matter Pollution
Both chronic and acute exposure to pollutants like
PM2.5, as well as to tobacco, activate the release of
proinflammatory and vasoactive factors that contrib-
ute to cardiopulmonary pathology4. The pulmonary ef-
fects of PM2.5 and PM10 are well known and include
decreased lung function and increased risks of lung
infection, asthma, bronchitis, disorders for which chil-
dren are particularly vulnerable, as well as chronic
obstructive pulmonary disease and lung cancer in
adults.73–77 Epidemiological and clinical studies have
increasingly shown that air pollution is associated with
not only respiratory diseases but also CVD.6 In fact,
PM2.5 is the pollutant with the most compelling obser-
vational and experimental evidence of association with
increased risk of cardiovascular mortality.78 As we de-
tail in this review, ambient PM2.5 is strongly associated
Fi g u r e 1. Proportion of children aged <5years o f age living in areas in w hich World Health Or ganization air qu ality guidelin es
(particulate matter <2.5μm) are exce eded (by country, 2016).
From World Health Organization report on air pollution.14 PM2.5 indicates particulate matter <2.5μm.
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J Am Heart Assoc. 2020;9:e014944. DOI: 10.1161/JAHA.119.014944 4
Kim etal Air Pollution and Cardiovascular Disease
with increased CVD such as myocardial infarction (MI),
cardiac arrhythmias, ischemic stroke, vascular dys-
function, hypertension and atherosclerosis78 (Ta b l e ).
Ambient PM2.5 exposure is among the leading causes
of world- wide mortality, particularly from CVD79 and
exposure to PM2.5 increases the risk of hospitalizations
from CVD.80 Accordingly, reducing exposure to PM2.5
would benefit public health by decreasing both imme-
diate and long- term CVD risk.4,12,79,81–83
Pollution in the Disadvantaged
In addition, economically disadvantaged groups are dis-
proportionately vulnerable to air pollution and its nega-
tive health effects.84 An underprivileged environment is
clearly linked to increased risks for CVD and other dis-
eases.2 This is because low- income residents in urban
settings often live closer to major roadways, power
plants, and industrial facilities, and in neighborhoods with
other environmental risk factors (noise, crime, little green
space, food deserts) and poor- quality housing com-
pared with those living under better conditions.85 Indoor
pollution caused by cooking with fires burning solid fuels
or dirty stoves fueled by kerosene is of particular con-
cern for children living in such households.85 In poorly
ventilated houses with families living in low- and middle-
income countries, the burning of solid fuels, kerosene,
incense, and mosquito coils increases indoor PM, irri-
tating respiratory tract, eyes, and skin86,87 and, accord-
ing to WHO, is responsible for around nearly 4 million
deaths from serious cardiopulmonary diseases.15
CVD RISK FROM POLLUTION: FROM
BIRTH TO ADULTHOOD
The large and growing body of scientific evidence points
to a causal relationship between elevated air pollution
and cardiovascular morbidity and mortality.3 Such evi-
dence places nearly 2billion children at serious lifetime
CVD risk.7,14 These children are disproportionately in
low- socioeconomic- status households, with little con-
trol over their home and social environment. Further,
maternal exposures to pollution during pregnancy has
also been linked to increased propensity towards devel-
oping future CVD risk.88 The published evidence about
the adverse effects of pollution exposure on major
CVD risks and cardiovascular phenotypes in pregnant
women, neonates, children, and adults is summarized
in Table and discussed in detail below.
Hypertension
Children with high systolic blood pressures are at in-
creased risk of hypertension and the metabolic syn-
drome later in life.89 Recent evidence suggests that
air pollution exposure in pregnancy may also portend
increased risk for the next generation. In the prospec-
tive Boston Birth Cohort of 1200 mothers, Zhang
et al39 found that PM2.5 exposure during pregnancy
was associated with elevated blood pressure in chil-
dren ages 3 to 9 years; further, in another study, these
authors found long- term exposure to ambient PM was
also associated with higher prevalence of hypertension
in children and adolescents.40 In addition, exposure to
PM2.5 during late pregnancy was positively associ-
ated with systolic hypertension in newborns41 and in
a cohort of 1131 mother- infant pairs exposed to PM2.5,
newborn infants showed systolic hypertension,41 an
association also seen in smoking mothers.90 Children
attending school on days with higher concentrations of
PM (diameter <100nm) had higher systolic blood pres-
sures.42 In addition, children aged 6 to 12years ex-
posed to ultrafine PM or PM2.5 in combination with NO2
demonstrated increased systolic and diastolic blood
pressures.42,4 3 Curto et al44 found that adult women
aged 18 to 84years living in India exposed to PM2.5
had increased systolic blood pressure. Finally, even
short- term exposure to air pollution from cookstoves
elicited increases in systolic blood pressure in adults.45
Obesity
Airborne polycyclic aromatic hydrocarbons (PAHs) is a
family of pollutants that have been most strongly asso-
ciated with obesity, although PM2.5 and NO2 have been
linked with obesity as well. PAH are created during in-
complete combustion processes and are known to have
endocrine disrupting effects, and alter the behavior of
adipocytes, promoting obesity.91–95 Alderete etal46 found
pregnant women exposed to traffic- related air pollution
had higher cord blood levels of leptin and high- molecular-
weight adiponectin, which were associated with in-
creased infant weight gain, which may have implications
for future obesity risk. Adolescents exposed to air pollu-
tion and PAH during the pre- term/neonatal period had
increased prevalence of obesity and diabetes mellitus.47
In 1 study, Jerrett etal48 examined traffic pollution around
family homes in the United States and found that higher
levels of vehicular traffic and pollution were associated
with higher attained body mass index in children aged 10
to 18years, particularly females aged 18years. In 1 com-
munity of Southern California, pollution from automobiles
was positively associated with higher body mass index
in children aged 5 to 11 years.49 Infants exposed to black
carbon and PM2.5 emissions from traffic pollution in early
life exhibited rapid postnatal weight gain.50 Wang etal51
found a positive association between several pollutants
and obesity in a meta- analysis of 35 studies.
Insulin Resistance and Diabetes Mellitus
Animals exposed to air pollutants during pregnancy
show an increased risk of metabolic syndrome, birth
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Kim etal Air Pollution and Cardiovascular Disease
Tab l e. CVD Risks From Pollution Exposure in Pregnant Women, Neonates, Children, and Adults
Cardiovascular
Risk Timing of Exposure Exposure Effect Reference
Hypertension Neonatal PM2.5 Increased blood pressure in ages 3 to 9 y Zhang M (2018)39
Children 1 to 10 y;
Adolescents 10 to
19 y
PM2.5 Increased blood pressure Zhang M (2019)40
Newborns PM2.5 Increased systolic blood pressure Van Rossem L (2015)41
School children, 6
to 12y
Ultrafine particles (<100nm) Increased systolic blood pressure Pieters N (2015)42
12y Long- term exposure to NO2
and PM2.5
Increased diastolic blood pressure Bilenko N (2015)43
Women 18 to 84y PM2.5 Increased blood pressure Curto A (2019)44
adults Pollution f rom cookstoves Increased systolic pressure Fedak KM (2019)45
Obesity Pregnant women Traffic- related air pollution Higher cord blood levels of leptin and high
molecular weight adiponectin, adipokines
associated with increased infant weight
change in female infants.
Alderete TL (2018)46
5 to 14y Polycyclic aromatic
hydrocar bons and f ine PM
The prevalence of obesity was 20.6% at age
5 y and incre ased across follow- ups until age
11 y when it was 33.0%
Rundle A (2019)47
10 to 18y Traffic- related pollution Increased BMI, mostly in females at age 18y Jerrett M (2010)48
5 to 7y Traffic- related air pollution A 13.6% increase in the rate of average
annual BMI growth between the children
exposed to the lowest to the highest tenth
percentile of air pollution
Jerrett M (2014)49
Birth to 6mo Black carbon, PM2.5 Infants exposed to higher traffic- related
pollution in early life may exhibit more rapid
postnatal weight gain and reduced fetal
growth in mothers exposed to PM2.5
Fleisch AF (2015)50
Adults, meta- analysis Chemical pollutants
(polychlorinated biphenyls,
others)
Positive associations between pollutants and
obesity
Wang Y (2016)51
Glucose
metabolism
abnormalities,
Diabetes
mellitus
Pregnant women NO2, PM2.5 Gestation diabetes mellitus in first and
second trimester
Choe S (2019)52
8 to 18y Ambient and traf fic- related
ambient pollution
Higher insulin resistance and secretion,
which was observed in conjunction w ith
higher glycemia
Toledo- Corral C
(2018)53
6 to 13y Medium- term exposure to
ambient PM2.5 and PM10
Higher fasting blood glucose levels Cai L (2019)54
5y Traffic- related exposure to
ozone and PM10.
Increased ozone exposure may be a
contributory factor to the increased incidenc e
of type 1 diabetes mellitus. PM10 may be
associated with development of type 1
diabetes mellitus before 5y of age
Hathout E (20 02)55
10y Traffic- related air pollution Insulin resistance increased by 17% for every
2 SD of increase in ambient PM and NO2
Thiering E (2013)56
12 to 19y Tobacco smoke Environmental second- hand tobacco smoke
exposure was independently associated with
the metabolic syndrome and t ype 2 diabetes
mellitus
Weitzman M (2005)57
Dyslipidemia 45 to 84y PM2.5 and black carbon
exposure 2wk, 3 mo, 1 mo
Air pollution is adversely associated with HDL Bell G (2017)58
18 to 29y (23±5y) PM2.5, black carbon, NO2, CO High ambient air pollution concentrations
associated with impairments in HDL
functionality from systemic inflammation and
oxidative stress
Li J (2019)59
Children and adults PM10 PM10 associated with elevated triglycerides,
apolipoprotein B, and reduced HDL
Chuang K (2010)60
Adults PM2.5 Long- term PM2.5 exposure associated with
lipoprotein increases
McGuinn L (2019)61
(Continued)
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Kim etal Air Pollution and Cardiovascular Disease
defects, and diabetes mellitus.96 Animal studies have
also demonstrated that PM2.5 exposure enhances in-
sulin resistance and visceral inflammation/adiposity,
providing a strong link between air pollution and type 2
diabetes mellitus.97 This has been borne out in human
studies. In a large cohort of singleton births in New
York City, mothers’ exposure to NO2 in the first trimes-
ter and PM2.5 in the second trimester were associated
with higher odds of gestational diabetes mellitus.52 In
a cohort of 429 overweight and obese minority chil-
dren in Los Angeles, increased prior- year exposure to
traffic- related air pollution adversely affected type 2
diabetes mellitus- related pathophysiology.53 Further, in
4234 children aged 6 to 13years, Cai etal54 found ex-
posure to ambient PM2.5 and PM10 was associated with
higher fasting blood glucose levels. Hathout etal55 re-
ported that exposure to fine particulates such as PM10
was a specific contributing factor for type 1 diabetes
mellitus in children aged <5 years. In another study,
insulin resistance and type 2 diabetes mellitus were
greater in 10- year- old children exposed to high levels
of traffic- related air pollution compared with those chil-
dren exposed to lower levels.56 Finally, indoor exposure
from second- hand tobacco smoke was associated
with an increase in metabolic syndrome and type 2
diabetes mellitus in adolescents aged 12 to 19years.57
Dyslipidemia
In Chinese men and women, Bell etal58 found that ex-
posures to PM2.5 and black carbon (2 weeks, 3months,
and 1year) was associated with lower concentrations
of high- density lipoprotein. In a 2- year study, 73 young
adults (23±5years) exposed to traffic- related pollution
(PM2.5, black carbon, NO2, CO) had significant reduc-
tions in high- density lipoprotein and apolipoprotein
A-I (ApoA1) indicating impairments in lipoprotein func-
tionality as a result of systemic inflammation and oxi-
dative stress.59 In a cohort of Taiwanese children and
adults, Chuang etal60 found that individuals exposed
to PM10 over time had elevated triglycerides, apolipo-
protein B, and reduced high- density lipoprotein levels,
Cardiovascular
Risk Timing of Exposure Exposure Effect Reference
Cardiac
arrhythmias
Adults Second- hand smoke Exposure during gestational development
and during childhood was associated with
having atrial fibrillation later in life
Dixit S (2016)62
Adults PM2.5 and PM10 Increased ris k of atrial f ibrillation Liu X (2018)63
Older adults (median
71y)
PM2.5 and PM10 In patients exposed to PM10 and PM2. 5
followed for 1y, ventricular tachycardia and
ventricular fibrillation correlated significantly
with PM2.5 but not PM10
Folino F (2017)64
Young adults Ultrafine particles (5–
560nm), black carbon, NO2
and CO, SO2, and O3
Significant increases in QTc, indicating
cardiac repolarization abnormalities
particularly in males overweight/obese and
with higher C- reactive protein levels
Xu H (2019)65
Stroke Post- menopausal
women
NO2 and NOx In a large cohort of postmenopausal women,
strong association between daily NO2 and
NOx exposure and hemorrhagic stroke more
pronounced among non- obese participants
Sun S (2019)66
Adults PM2.5 and PM10, NO2, NOx,
SO2, and O3
Air pollutants are significantly associated with
ischemic stroke mortality
Hong YC (2002)67
Adults PM10, NO2, NOx, SO2, and O3 All pollutants associated with primary
intracerebral hemorrhage and ischemic
stroke patients
Tsai SS (2003)68
Atherosclerosis Adults PM2.5 In older men and women (>60y), signif icant
associations between PM2. 5 and carotid
thickness
Kunzil N (2005)69
Adults 45 to 84y PM2.5 Conce ntrations of PM2.5 and traffic- related air
pollution within metropolitan cities associated
with coronary calcification, consistent with
acceleration of atherosclerosis
Kaufman JD (2016)70
Adults PM2.5 PM2.5 exposure associated with increased
likeliho od of having mild and especially
severe coronary atherosclerosis
Hartiala J (2016)71
Adults PM2.5 Exposure to higher concentrations of PM2.5 in
ambient air was significantly associated with
development of high- risk coronary plaques
Yang S (2019)72
BMI indicates body mass index; HDL, high- density lipoprotein; and PM, particulate matter.
Tab l e. Continued
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Kim etal Air Pollution and Cardiovascular Disease
indicating a link between air pollution and progression
of atherosclerotic disease. In a recent 9- year study of
6587 adults in the United States, long- term exposure
to PM2.5 was associated with increased lipoprotein
concentrations.61
Cardiac Arrhythmias
Arrhythmia is another potential manifestation of air
pollution exposure that could lead to cardiovascular
morbidity and mortality.98 Adults having had a smok-
ing parent during gestational development and those
living with a smoker during childhood were each signifi-
cantly associated with atrial fibrillation, which was more
pronounced among adults without risk factors for atrial
fibrillation.62 In a study of 100 adults exposed over to
PM2.5 and PM10 over several months, an increased risk
of atrial fibrillation was seen.63 In another study of 281
patients (mean 71years) exposed to PM10 and PM2.5
followed for 1 year,64 ventricular tachycardia and ven-
tricular fibrillation correlated significantly with PM2.5
(P<0.001) but not PM10. In these older adults, an analy-
sis of the ventricular fibrillation episodes alone corre-
lated significantly with higher PM2.5 and PM10 exposure.
Finally, Xu etal65 followed 73 healthy young adults liv-
ing in China under continuous pollution (particulates
5–560nm diameter, black carbon, NO2, CO, SO2, and
O3) using 24- hour electrocardiographic recordings,
and found that the young participants showed cardiac
repolarization abnormalities (increased QTc interval),
which were most strongly associated with nano- sized
PM, with traffic- related pollutants (black carbon, NO2,
and CO), and with SO2, and O3. The associations were
stronger in males who were overweight and had higher
levels of C- reactive protein levels.
Stroke
Evidence from epidemiological studies has demon-
strated a strong association between air pollution
and stroke.99 Among 5417 confirmed strokes in 5224
women between 1993 and 2012 in Asia exposed
daily to particulate matter (PM2.5 and PM10), NO2, NOx,
SO2, and O3, Sun etal66 found a positive association
between risk of hemorrhagic stroke and NO2 and
NOx but not with the other pollutants in the 3days
before a stroke. A 7- year study in Korea showed sig-
nificant associations between PM2.5 and PM10, NO2,
NOx, SO2, and O3 and the incidence of ischemic but
not hemorrhagic stroke mortality, suggesting clini-
cally significant alterations in the cerebrovascular
system induced by air pollution.67 Finally, in a study
of 23179 stoke admissions in Taiwan between 1997
and 2000, Tsai et al68 reported significant positive
associations between levels of PM10, NO2, SO2, O3,
and CO and primary intracerebral hemorrhage as
well as ischemic stroke.
Atherosclerosis
In mice prone to developing atherosclerotic lesions,
chronic exposure to concentrated ambient PM pro-
duced aortic plaques that were significantly more ad-
vanced compared with non- exposed mice, indicating
long- term exposure to PM can produce adverse cardi-
ovascular effects by enhancing atherosclerosis.100 The
atherosclerotic disease process begins early as sug-
gested by human autopsy studies that have found fatty
streaks, indicating the early stages of atherosclerosis,
in coronary arteries of teenagers.1 In fact, fatty streaks
have been observed in children as young as 3years
of age with coronary involvement identified at adoles-
cence.101 Several studies confirm that the risk factors
observed in adults (eg, elevated low- density lipopro-
tein, obesity, hypertension, tobacco exposure, and
diabetes mellitus) also contribute to atherosclerosis in
children.102,103 In particular, pollution has been shown
to induce the progression of atherosclerosis and CAD.
In a study of 798 adults in 2 clinical trials, among older
participants (≥60 years), women, never smokers, and
those reporting lipid- lowering treatment at baseline,
showed significant associations between PM2.5 and
carotid intimal- media thickness, with the strongest as-
sociations found in women aged ≥60years.69 In a pro-
spective, 10- year cohort study of 6795 adults aged 45
to 84years living in metropolitan cities, it was found that
increased concentrations of PM2.5 and traffic- related air
pollution commonly encountered worldwide, were as-
sociated with the progression of coronary calcification,
consistent with acceleration of atherosclerosis.70 In a
longitudinal study of 6575 adults undergoing coronary
angiography, exposure to PM2.5 was associated with
increased likelihood of having coronary atherosclerosis
that was mild to severe.71
MECHANISMS OF CVD FROM
POLLUTION EXPOSURE
Currently available evidence has demonstrated that
systemic inflammation and immunological responses—
derived from pollutants coming into contact with the
epithelial lung lining and entering the systemic circula-
tion—initiate a cascade of events leading to the acute
and chronic effects of pollution on CVD.104 Based on
our current knowledge, plausible pathophysiological
mechanisms linking exposure to pollutants (primarily
PM2.5) and CVD include: (1) increased systemic inflam-
mation, which produce cardiovascular stress105,106;
(2) activated platelets in the bloodstream, increasing
the risk of acute thrombosis, as in MI and ischemic
stroke107,108; (3) alterations of the autonomic nervous
system and the autorhythmic cells in the sinoatrial
node, which leads to decreased heart rate variability,
a prognostic risk factor for heart disease109,110; and
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Kim etal Air Pollution and Cardiovascular Disease
(4) direct changes in the vascular cell types, including
macrophages, endothelial and smooth muscle cells,
thereby increasing CVD risk.106 However, because of
the lack of a standard modeling platform, the mecha-
nisms underlying PM- induced cardiopulmonary tox-
icity in humans are still not well understood, making
clinical management of air pollution- related cardiovas-
cular risks difficult and impeding the development of
effective preventive approaches.111
Improving our understanding of the specific molecu-
lar or immunological pathways underpinning pollution-
driven CVD will allow us to develop targeted therapies
for individuals living in areas of high pollution or those
genetically predisposed to pollution- driven CVD.
Increased Systemic Inflammatory Burden
of Pollution: Interleukin- 1β and the
Inflammasome
Exposure to pollutants generates airway oxidative
stress and inflammation.112 Furthermore, these local
lung responses spill over, and ultrafine PM can cross
the alveolar capillary membrane to the blood stream
and produce systemic inflammatory and immuno-
logical responses by activating circulating immune
cells.113 Multiple studies indicate an increase in the
systemic inflammatory burden in response to air pol-
lution exposure as measured by biomarkers, including
interleukin (IL)- 6, IL- 8, C- reactive protein, IL- 1β, and
monocyte chemoattractant protein-1 (MCP-1).11 3 –115
Gruzieva etal measured a panel of blood inflamma-
tory markers from 8- year- old children (n=670) who
had been exposed to traffic NO2 and PM10 in early life
and also examined gene data from 16- year- olds that
had been exposed to traffic NO2 and PM10. In this co-
hort, a 10μg/m3 increase of NO2 exposure during their
infancy was associated with a 13.6% increase in IL- 6
levels, as well as with a 27.8% increase in IL- 10 levels,
which was limited to children with asthma. Results
were similar using PM10, which showed a high cor-
relation with NO2 exposure. The functional analysis of
16- year- olds in this study identified several differen-
tially expressed genes in response to air pollution ex-
posure during infancy, including IL10, IL13, and tumor
necrosis factor (TNF). In a group of healthy young
adults, episodic PM2.5 exposure was associated with
increased levels of circulating monocytes and T cells
along with increased levels of TNF- α, MCP- 1, IL- 6,
I L- 1β, and chemoattractants including soluble inter-
cellular adhesion molecule-1 (sICAM-1) and circulat-
ing vascular cell adhesion molecule-1 (sVCAM-1).114
This response appears to be dose- dependent, and
several components of air pollution including PAHs—
NO2, PM2.5, and PM10—have been associated with
increases in inflammatory biomarker signatures. The
inflammatory cytokines are likely derived mainly from
the cells in the lung epithelium and the circulating im-
mune cells. Additionally, PM10 was found to stimulate
alveolar macrophages to release the prothrombotic
cytokine IL- 6, which activates pathways that can ac-
celerate arterial thrombosis and increase the risk of
cardiovascular events.11 6 Both chronic and acute ex-
posures to PM2.5 activate the release of proinflam-
matory and vasoactive factors that contribute to
cardiopulmonary pathology and accordingly, reduc-
ing exposure to PM2.5 would benefit cardiopulmonary
health by decreasing both immediate and long- term
cardiopulmonary disease risk.4,12,79,81–83
A sensor of cell injury called the “inflammasome,”
which includes an IL- 1β- processing platform, plays
a crucial role in IL- 1β maturation and secretion from
cells. Nucleotide-binding domain (NOD)-like receptor
protein 3 (NLRP3) inflammasomes monitor mem-
brane integrity and pore- forming toxins, crystals,
and many other noxious stimuli and are involved in
I L- 1β processing and maturation.117–11 9 Produced by
epithelial and inflammatory cells, IL- 1β plays a cen-
tral role in the inflammatory processes in blood, lung,
cardiac, and vascular tissues. IL- 1β is initially synthe-
sized as pro- IL- 1β, an inactive precursor. Pro- IL- 1β
is then cleaved inside the cell by the inflammasome
complex.120 O n c e p r o - I L- 1β is processed, the mature
I L- 1β product is secreted and binds to the IL- 1 re-
ceptor (Figure2121). In non- lymphoid organs, IL- 1β is
expressed in tissue macrophages in the lung.122,123
There are 2 cell- surface IL- 1 receptors, IL- 1 type re-
ceptor (IL- 1R1) and IL- 1R2, a decoy receptor. IL- 1R1
initiates inflammatory responses when binding to
I L- 1β and has been reported to be expressed by T-
lymphocytes, cardiac- derived and lung- derived fi-
broblasts, alveolar epithelial type II cells and vascular
endothelial cells. IL- 1R2, which does not initiate signal
transduction, is expressed in a variety of hematopoi-
etic cells, especially in B lymphocytes, mononuclear
phagocytes, polymorphonuclear leukocytes, and
bone marrow cells. Notably, expression levels of IL-
1R1 and IL- 1R2 are different among the cell types;
for example, alveolar epithelial type II cells express
IL- 1R1, but not IL- 1R2. The IL- 1β pathway has been
targeted effectively by different products available as
inhibitors for human use as recombinant human or
soluble inhibitors (Figure2).120
I L- 1β is linked to exposure to air pollution. PM2.5
exposure has been shown to increase rates of reac-
tive airway disease and MI associated with the re-
lease of IL- 1β from monocytes and macrophages.7, 8
Components of PM from air pollution, including PAHs,
activate human monocytes by stimulating cells such
as pulmonary endothelial cells, showing that inhaled
PM from pollution induces pulmonary and systemic
inflammation.124 Different mechanisms have been
proposed for the activation of the inflammasome by
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Kim etal Air Pollution and Cardiovascular Disease
air pollution.125 ,126 Among them, the NLRP3 inflam-
masome is a prototype inflammasome, which has
been reported to be activated by diesel exhaust, to-
bacco smoke, e- cigarette liquid, ozone, and reactive
oxygen species in pollution.12 7 Provoost et al128 re-
cently published a study in a murine model demon-
strating that air pollution particle- induced pulmonary
inflammation was mediated by IL- 1β, but was NLRP3/
caspase- 1- independent. Our research using blood
samples from 100 adolescents exposed to known
quantities of ambient air pollution show that, even
after 1week of ambient air pollution exposure, there
was a significant (P=0.017) association between IL-
1β increases in plasma and increases in ambient air
pollution exposure, specifically PM2.5.129
Epithelial Activation Barrier and
Inflammation From Pollution
In considering the pathways that pollutants gain entry
to the bloodstream, epithelial cells should be consid-
ered the first line of defense, as they are essential
components of the innate immune response and are
barriers to pollutants. Upper and lower respiratory
epithelial cells are exposed to air pollution, whereas
gastrointestinal epithelial cells are exposed to food
and water pollution. Mucosal epithelium produces
antimicrobial peptides, cytokines, and chemokines,
activates intraepithelial and subepithelial cells, which
supports the physical, chemical, and immunological
barrier.130–13 6 Epithelial cells respond to pollution by
releasing cytokines such as IL- 25, IL- 33, and TSLP,
which initiate inflammation by activating dendritic
cells, T helper cells, innate lymphoid cells, and mast
cells.137 Once exposed to pollution, the epithelial
tight- junctions barrier in the nasal and oral mucosa
open, allowing pollutants to enter directly into the
bloodstream and deeper tissues,132,138–14 8 which initi-
ate distant tissue inflammation like in the cardiovas-
cular systems. For example, exposure to PM2.5 has
shown to break down the nasal epithelial barrier by
breaking down cellular tight junctions and release
proinflammatory cytokines,149 which play key roles in
the progression of cardiovascular and cardiopulmo-
nary diseases.150 –153
Currently there are substantial data showing
that pollutants such as cigarette smoke, particulate
matter, diesel exhaust, ozone, nanoparticles, deter-
gents, as well as cleaning agents and chemicals in
household substances all can damage and open the
epithelial barrier.14 9 ,15 4 –1 6 3 Opening this barrier initi-
ates the inflammatory cascade in tissues, especially
cardiac and pulmonary tissues, which become vul-
nerable to systemic inflammation and the damaging
Figure2. Potential therapeutic targets on the interleukin- 1 pathway.
IL indicates interleukin; IL1RAP, Interleukin-1 receptor accessory protein; IL-1R1, Interleukin 1 receptor,
type I; IL-1R2, Interleukin 1 receptor, type II; IRAK 1/2/4, interleukin-1 receptor-associated kinase 1, 2, 4;
MyD88, Myeloid differentiation primary response 88; NF-kB, Nuclear Factor kappa-light-chain-enhancer
of activated B cells; rh, recombinant human; rhIL-1RA, recombinant human interleukin-1 receptor
antagonist; sIL-1R, soluble type 1 interleukin-1 receptor; and TRAF6, TNF receptor associated factor 6.
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Kim etal Air Pollution and Cardiovascular Disease
effects of air pollution, particularly in children and
young adults.164
Vascular Remodeling
Research has shown that fine and ultrafine particles
can cross the alveoli, and enter the bloodstream, di-
rectly affecting tissues involved in CVD.16 5 Specifically,
one study found in patients undergoing carotid
endarterectomy that inhaled gold nanoparticles
entered the blood stream and became deposited in
the carotid artery.166 In fetuses of pregnant mice, pol-
lutants alter vascular development manifested at birth
as atrial septal defects and coronary malformation.167
Brook etal168 found that after only 2hours of inhala-
tion of fine PM and ozone at concentrations found in
urban environments, healthy young adults showed sig-
nificant brachial artery vasoconstriction. Also, healthy
college students with a history of prenatal exposure to
air pollution, compared with those not exposed, had
significant carotid artery stiffness.16 9 These studies
suggest that the increased inflammatory signal is de-
rived not only from the pulmonary exposure, but also
a direct exposure of the vascular wall to systemic oxi-
dative stress and inflammation, leading to activation
of the pathways causing vascular injury and vascular
remodeling via atherosclerosis and plaque buildup. In
children whose vasculature is still developing, expo-
sure to pollution can alter the structure and function
of the vascular wall and potentially predispose them
for future cardiovascular complications as shown by a
recent study of 733 Dutch children aged 5years dem-
onstrating that exposure to PM2.5 and nitrogen oxides
caused decreased arterial distensibility.17 0
Endothelial Injury
Individuals exposed to fine PM from pollution have
signs of endothelial injury and dysfunction along
with increased markers of systemic inflammation.171
Specifically, episodic PM2.5 exposure in young adults
was associated with increased antiangiogenic plasma
profiles and elevated levels of circulating monocytes
and T (but not B) lymphocytes, indicating increased
endothelial cell apoptosis.114 Similarly, healthy young
non- smoking males exposed to ultrafine PM and gases
demonstrated 50% reduction in endothelial function,
as measured by flow- mediated dilation of the brachial
ar te r y.172 These authors concluded that gaseous pol-
lutants affect large artery endothelial function, whereas
PM inhibit the post- ischemic dilating response of small
arteries. Further, patients with diabetes mellitus ex-
posed to PM2.5, black carbon, and sulfates showed
decreased endothelium- dependent and endothelium-
independent vascular reactivity, particularly to PM2.5
and black carbon, and the effect was more pro-
nounced in those with type- 2 diabetes mellitus.173
Plaque Instability
In mice exposed to diesel emissions, formed plaques
were advanced to a fragile, vulnerable state.174 Chronic
pollution exposure of children, adolescents, and adults
can potentially lead to a shift in the plaque morphology
and content towards a more vulnerable state. In adults,
even short- term pollution exposure was associated with
higher levels of biomarkers consistent with reduced
plaque stability.17 5 Furthermore, Yang etal72 found that
PM2.5 exposure was correlated with the development
of plaque with higher- risk characteristics based on CT
analysis suggesting that pollution exposure can modify
plaque stability, which increases the risk of MI.
Platelet Aggregation and Thrombosis
Another potential CVD outcome is increased MI and
stroke from acute exposure to pollution. Specifically, PM
exposure has been linked to CVD and stroke, possibly
mediated through proinflammatory or pro- thrombotic
mechanisms.176,177 As noted above, exposure to PM2.5
has been linked to an increase in systemic oxidative
stress and inflammation as well as a modulatory effect
on tissue factors that have all been implicated as poten-
tial mechanisms of increased platelet activation.178 The
aryl hydrocarbon receptor pathway has also been impli-
cated in increasing tissue factor production from vascu-
lar smooth muscle cells in response to ligand activation,
leading to increased thrombosis.179 This has been con-
firmed by research in adults exposed to air pollution.180
In healthy adults exposed to traffic- related pollution, Xu
etal175 reported increased thrombogenicity as measured
by prothrombin time and fibrin degradation products.
Additionally, in a 10- year study of 870 patients with deep
vein thrombosis and 1210 controls, Baccarelli et al181
found that higher mean PM10 exposure during the year
before examination was associated with shortened pro-
thrombin time and increased deep vein thrombosis risk.
Epigenetics and Gene- Environment
Interactions
Exposure to pollution has also been linked to an altered
epigenetic state. Specifically, exposure to PAH and to-
bacco smoke contribute to gene expression modifica-
tions through epigenetic remodeling by 3 primary targets:
CpG methylation, amino acid tail modification on his-
tones, and aberrant microRNAs expression.18 2 Histone
modification via methylation occurs post- translationally
while miRNAs can control expression of other genes
post- transcriptionally.183 Changes to these targets can
influence DNA folding, DNA- transcription factor inter-
action, transcript stability, and other methods of gene
silencing (heterochromatin) or activation (euchromatin).
Several studies indicate a role of pollution- produced
epigenetic remodeling on the immune system. DNA
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Kim etal Air Pollution and Cardiovascular Disease
methylation has been associated with changes in IL- 4
and IFN- γ transcription.183 Studies with mouse models
demonstrate that increases in immunoglobulin E levels
are associated with hypomethylation at IL- 4 promoter
CpG sites and hypermethylation of IL- 4 and IFN- γ pro-
moter CpG sites.18 4 Histone acetylation is associated
with IL- 4, IL- 13, IL- 5, IFN- γ, CXCL10, and FOXP3+ tran-
scription patterns.18 3 Finally, miRNA- mediated silencing
has been found to repress transcripts associated with
human leukocyte antigen G, or HLA- G, IL- 13, IL- 12p35,
transforming growth factor beta, or TGFβ, and the
pituitary-specific, Octamer, Neural, or POU domain, a
bipartite DNA binding domain.183 Importantly, we be-
lieve these epigenetic modifications from exposure to
air pollution may have the greatest consequences to
prenatal and infant populations.18 2
We and others have found an increase in the global
methylation signal in the peripheral blood of children
and adults exposed to pollution.129 ,185–188 Furthermore,
pollution exposure- related effects may be inherited to
the fetus through epigenetic mechanisms.18 9 The inher-
itance of epigenetic modification in the mother could
potentially result in babies and children more prone to
increased obesity and hypertension. Gruzieva etal36 ex-
amined associations between NO2 exposure and cord
blood DNA methylation in pregnant women and also
NO2 exposure in children aged 4 and 8years. Exposure
to NO2 during pregnancy was associated with differen-
tial offspring DNA methylation in mitochondria- related
genes and was also linked to differential methylation
as well as expression of genes involved in antioxidant
defense pathways. In this study, Gruzieva etal36 also
found NO2 exposure of young children was linked to
differential methylation as well as increased expression
of genes involved in antioxidant defense pathways.
Genetic alterations also likely contribute to suscep-
tibility of a child to the development of cardiovascular
alterations in response to air pollution exposure. Eze
etal190 found that a common functional variant in the
IL6 gene interacted with PM10 exposure- dependent
IL- 6 levels in the circulation. We have shown that an
environment sensing transcription factor for the aryl
hydrocarbon receptor, which has been shown to be
activated by several components of pollution and to-
bacco smoke, is regulated both transcriptionally and
epigenetically by TCF21, a gene associated with in-
creased risk for atherosclerosis and MI.191
LIFETIME DISEASE RISK—
STRATEGIES FOR PREVENTION AND
INTERVENTION
As we have discussed, the evidence of air pollution
exposure affecting cardiovascular health begins in
the neonatal period and continues throughout child-
hood and adolescence. The lifetime risk of CVD is
the accumulated risks from the developmental pe-
riod into childhood, adolescence, and adulthood
(Figure3). Because children are most vulnerable to
environmental influences, improving their environ-
ment and reducing pollutant exposure during this
critical phase can have significant long- term health
benefits by altering the overall disease trajectory.
Accordingly, this window of time offers an important
opportunity for intervention.
For maximum impact, interventions could be im-
plemented at both the individual and population levels
(Figure4). At the individual level, children and parents
can be taught several simple but effective measures
to reduce exposures. First, increasing awareness of
air quality indices has shown to significantly change
pollution- avoiding behaviors.19 2 Second, staying in-
doors and using personal protective devices such
as N95 masks during acute periods of intense expo-
sure, as well as use of home air filtration devices can
significantly reduce pollution exposure. For example,
N95 facemasks reduced acute particle- associated
airway inflammation in young healthy adults living in
China.19 3
Currently, there is little evidence that dietary in-
tervention or chemoprevention (ie, antioxidant or an-
tithrombotic agents) can have an overall long- term
survival benefit from pollution exposure. Carnosine
supplementation has been shown to mitigate PM2.5-
induced effects on bone marrow stem- cell pop-
ulations in mice and may be one approach for
preventing immune dysfunction in humans exposed
to pollution.194 In addition, cobalamin (vitamin B12)
supplementation has been shown to protect against
superoxide- induced cell injury in human aortic en-
dothelial cells,19 5 one known outcome from oxidative
stress after air pollution exposure.196 Recently, in a
large prospective cohort of >500 000 individuals in
the United States followed for an average of 17years,
Lim etal197 reported that, based on questionnaire of
exposure history, there was a correlation between
long- term exposure to fine PM and CVD mortality risk,
and a Mediterranean diet reduced this risk. Also, in 1
study of young students exposed to high levels of air
pollution in China, use of omega- 3 fatty acids stabi-
lized the levels of multiple biomarkers of inflammation
and oxidative stress.198
Current Evidence- Based Interventions
Although we know that interventions to reduce air pol-
lution exposure can reduce the incidence of CVD, no
randomized clinical trial has yet been proposed to dem-
onstrate that long- term reduction in pollution exposure
results in reducing CVD mortality. We need to design
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Kim etal Air Pollution and Cardiovascular Disease
randomized clinical trials that will establish the effective-
ness of interventions; however, traditional randomized
trials would not be practical for this purpose given the
large number of participants required and the difficulty of
implementing individual monitoring. Several ways to im-
prove participant selection for a more targeted interven-
tion trial would be to develop an individual risk- calculator,
and use biomarkers to identify higher- risk patients.19 9,200
Healthcare providers play a critical role to help re-
duce the harmful effect of air pollution on children. Not
only can they treat children’s illnesses, they can also
help educate the community about factors that con-
tribute to air pollution and work with community lead-
ers to reduce exposures and mitigate risks. Research
should be aimed at developing established consen-
sus guidelines that can help providers effectively
counsel patients and families who are dealing with
acute or chronic exposures. Recently, Hadley etal11
outlined the role of healthcare providers and clinical
approaches that factor in air pollution to preventive
cardiac care. This includes a patient- screening tool
that indicates known risk factors for air pollution expo-
sure and cardiovascular risks. Developing an individ-
ual risk calculator that incorporates pollution exposure
with traditional risk metrics—such as the American
College of Cardiology/American Heart Association
(ACC/AHA) and Atherosclerotic Cardiovasular Disease
(ASCVD) 10- year risk calculator—may help to further
stratify patient risks so that interventions can be tar-
geted to the higher- risk groups.11
The 2004 American Academy of Pediatrics rec-
ommendations on the health hazards of air pollution
in children201 underscore the importance of pediatri-
cians who play an important role in educating families
and children about the harmful effects of pollution and
helping to reduce exposures. Pediatricians who serve
as physicians for schools or for team sports should
be aware of the health implications of pollution alerts
to provide appropriate guidance to school and sports
officials, particularly in communities with high levels of
pollution.201 Physicians can do much to protect chil-
dren by educating their local policymakers about the
need for cleaner air and the need to replace older die-
sel buses, and limit school bus idling wherever children
congregate.202
Population- Based Approaches
At the population level, we need policy measures to
decrease the overall emission of harmful pollutants.
The American Heart Association has published sev-
eral position papers on the role of pollution on car-
diovascular health, and concluded that there is an
urgent need to advocate for strong regulations and
policy to curtail pollution.79 Regulations and fiscal
Figure3. Early intervention can improve cumulative lifetime risk of cardiovascular disease.
CVD indicates cardiovascular disease.
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Kim etal Air Pollution and Cardiovascular Disease
strategies such as increased taxation of gasoline and
diesel fuels or a carbon tax on emissions would ef-
fectively reduce air pollution levels. Other population-
level approaches include using monitoring stations to
build exposure maps and community alert networks
(Figure4).
We also should consider optimizing air quality
standards further. Current research suggests that
current United States and European standards are
still too high, especially considering the pediatric
population that is more susceptible to cardiovas-
cular morbidity and mortality.203,204 Furthermore,
as discussed by Hadley et al,11 the most effective
intervention occurs at lower pollution exposure lev-
els, as most of the increase in conferred risk oc-
curs at PM2.5 concentrations of 40 to 100 μg/m3,
after which there is a plateau of accrued risk from
pollution exposure.205,206 Anecdotal and historical
observations strongly suggest that interventions to
reduce exposures to PM would reduce risk of CVD,
just as implementing policies to reduce tobacco
exposure can lower hospitalizations for cardiopul-
monary diseases. For example, it has been esti-
mated that full implementation of the New York City
fuel oil regulations would prevent >300 premature
deaths and >500 emergency department visits and
hospitalizations for respiratory or cardiovascular
causes each year.207,208
GAPS IN KNOWLEDGE AND
RESEARCH NEEDS
While most epidemiologic studies address the ef-
fects of short- term pollution exposure on acute CVD
outcomes, we believe more research is needed to
understand the long- term cumulative effects of air
pollution on cardiovascular end points. The differ-
ences in the mechanisms leading to cardiovascu-
lar events from short- term exposure and long- term
exposure are not well understood, and we need to
better characterize the mechanisms from short- term
exposure (eg, from wildfires) and long- term exposure
(eg, from diesel exhaust). Many subclinical physio-
logical changes occur in response to exposure to air
pollution, and identifying these subclinical changes is
one way to gain insight to the mechanisms leading to
cardiovascular events.
Improved measurements of individual exposure
are an important prerequisite for personalized care,
and currently, pollution exposure to an individual is
estimated mostly based on the person’s location of
Figure4. Combined population- level and individual- level approaches for reducing exposures to air pollution and reducing
cardiovascular disease burden.
CV indicates cardiovascular; and RCT indicates randomized clinical trial.
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Kim etal Air Pollution and Cardiovascular Disease
residence. However, such an estimate does not in-
clude the amount of time the person might spend
indoors versus outdoors, the amount of time spent
at work or school, the extent of exposure to house-
hold pollution, as well as the vital capacity and re-
spiratory rate of the person. Even when exposed to
similar levels of pollution, children absorb more pol-
lutants because they breathe more often than adults,
are often outdoors more than adults, and are lower
to the ground where some pollutants may concen-
trate.15 Several surrogate markers can be considered
as a measure of exposure. A panel of blood biomark-
ers may allow us to estimate the systemic effect of
both short- term and long- term exposures114 and, as
we have seen, increased inflammatory markers such
a s I L- 6 , I L- 1β, IL- 10, DNA methylation, and TNF have
been found in young children and adults exposed to
pollution.36 ,115 , 209 Also, measures of exhaled breath
condensate, fluid formed by cooling down exhaled
air, can be used to measure the amount of oxida-
tive stress biomarkers—reactive aldehydes—and in-
flammatory markers related to pollution exposure.210
These biomarkers should be incorporated and tested
for their efficacy in prospective trials of intervention,
perhaps including anti- IL- 1β therapies. Future re-
search should also be directed toward better under-
standing the mechanism of epithelial barrier damage
from particulate matter, ozone, nanoparticles, deter-
gents, as well as cleaning agents and chemicals in
household substances.
In this contemporary review, we have focused pri-
marily on the effects of ambient air pollution, especially
components of PM and PAHs. Although sufficient data
are available to support preventive action, it is yet un-
clear how the different components of pollution—car-
bon monoxide, nitrogen oxides, sulfur dioxide, ozone,
ambient PM, and lead—each affect the cardiovascular
system.
Of the different pollution components, fine PM is
known to be highly toxic to the cardiopulmonary sys-
tem. However, we still do not fully understand whether
all types of PM (eg, wildfire smoke versus diesel ex-
haust) are equally toxic or which specific components
determine toxicity. The most studied particle matter
is PM2.5, which is especially harmful because they
can penetrate into the pulmonary alveoli where they
can induce a local inflammatory response. Ultrafine
particles, a component of PM2.5, can penetrate the
alveolar- capillary barrier and enter the bloodstream.
Several studies have established that PM induces
inflammatory effects211–213 and oxidative stress,212,214
yet it is not yet clear to what extent such effects are
different for PM collected at different locations or
from different sources.215 The proinflammatory and
oxidative potential of PM may be influenced by varia-
tions in PM chemical and physical composition.216,217
PM composition is determined by whether the emis-
sions originate from cars, trucks, industry, or agricul-
tural activities, and emissions are further affected by
variations in temperature and meteorological con-
ditions through atmospheric changes.218 As such,
although much research has concentrated on the
effects of PM in animals and humans, we still have
limited information on PM chemical components from
different sources and locations.219 PM, especially
PM10, includes biological components such as fun-
gal spores and endotoxins, elemental carbon, sulfur,
nitrogen, metal compounds, and complex hydrocar-
bons such as PAH.10 Some of these PM components
have been shown to induce systemic inflammation.
For example, endotoxin and PAH initiate monocyte
inflammatory responses mediated by reactive ox-
ygen species,124,220,221 and transition metals (iron,
manganese, chromium, copper) induce cytotoxicity
and oxidative stress.222 While some studies indicate a
degree of differential toxicity from such components
as endotoxin, specific metals, PAH, and elemental
carbon,218 current knowledge does not allow us to
precisely quantify the health effects of individual PM
components or PM from different sources. To bet-
ter inform regulatory strategies in the future, we must
more fully understand the health effects of various PM
components from different sources, which will allow
us to identify the causal agents. This will help for-
mulate more targeted strategies for harm reduction.
It will also help us to appropriately lower the current
annual ambient air quality standards, considering the
more susceptible populations, especially our chil-
dren. Collaborating with rapidly developing countries,
where extremely unhealthy air quality level is a daily
concern, will help us to develop impactful research
that will be applicable in both the United States and
throughout the world.
CONCLUSIONS
With the rapid rise in industrial development came in-
creased emission of air pollutants harmful to human
health. Regardless of the pollution source, polluted
air is shared by us all, especially our children, who
are most vulnerable. The lifetime cumulative expo-
sure to pollution is increasing in children, and cur-
rent evidence shows that long- term exposure, even
in utero, leads to increased prevalence of hyperten-
sion, obesity, and metabolic disorders, resulting in a
greater CVD burden in our future generations. The
concept of life time and acute exposure should be
well integrated to public health and devices to moni-
tor individual and regional exposure should be im-
proved and focused on new dangers of exposure.
Development of biomarkers that identify the levels
of exposure, tissue and systemic inflammation, and
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J Am Heart Assoc. 2020;9:e014944. DOI: 10.1161/JAHA.119.014944 15
Kim etal Air Pollution and Cardiovascular Disease
tissue damage is essential to overcome diseases
linked to pollution. We must develop clinical guide-
lines to effectively mitigate the risk of increased ex-
posure to pollution. Continued research into the
mechanisms of pollution- induced CVD and policies
to limit emissions and promote preventive efforts to
limit exposure, especially during childhood and ado-
lescent years, all will have significant long- term ben-
efits for the future.
ARTICLE INFORMATION
Affiliations
From the Division of Cardiovascular Medicine, Department of Medicine
(J.B.K., F.H.), Sean N. Parker Center for Allergy and Asthma Research (M.P.,
C.D., V.S., R.P., E.S., K.C.N.), Stanford Cardiovascular Institu te (J.B.K.,
F.H., J.C.W.), and Depar tment of G enetics and Center for Genomics and
Personalized Medicine (M.P.S.), Stanford University, Stanford, CA; Swiss
Institute for Allergy and Asthma Research (SIAF ), University of Zurich, Davos,
Switzerland (C.A .); Department of Medicine, Universit y of California San
Francisco and Division of Environmental Health Sciences, School of Public
Health, University of California Berkeley, CA (J.B.).
Acknowledgments
All authors listed on this review contributed to the sci entific content and edit-
ing in their areas of expertise. The authors thank Dr Aaron Bernstein of the
Center for Climate, Hea lth, and the Global Environment at Harvard Medical
School for his suggestions.
Sources of Funding
We received funding suppor t from National Institutes of Health
K08HL133375 (Kim), Tobacco- Related Disease Research Program
T30IP0999 (Kim), Tobacco- Related Disease Research Program 27IR-
0012 (Wu), Sean N Parker Center for Allergy and Asthma Research at
Stanford University (Nadeau, Dant, Smith, Prunicki, Patel), National
Institute of Environmental Health Sciences P01ES022849- 05 (Nadeau),
NHBLI R01HL118612 (Nadeau), National Institute of Environmental Health
Sciences R01ES020926 (Nadeau).
Disclosures
Dr Nadeau reports grants from National Institute of Allergy and Infectious
Diseases, Food Allergy Re search & Education, End Allergies Together,
Allergenis, and Ukko Pharma; grant awardee at National Institute of Allergy
and Infec tious Diseases, National Institute of Environmental Health Scie nces,
National Heart, Lung, and Blood Institute, and the Environmental Protection
Agency; involved in Clinical trials with Regeneron, Genentech, AImmune
Therapeutics, DBV Technologies, AnaptysBio, Adare Pharmaceuticals, and
Stallergenes- Greer; Research Sponsorship by Novartis, Sanofi, Astellas,
Nestle; Data and Safet y Monitoring Board member at Novartis and National
Heart, Lung, and Blood Institute; co- founded BeforeBrands, Allada pt,
ForTra, and Iggenix; director of Food Allergy Research & Education and
World Health Organization ( WHO) Center of Exce llence; persona l fees from
Regeneron, Astra zeneca, ImmuneWorks, and Cour Pharmaceutic als. Dr.
Akdis reports grants from Allergopharma, grants from Idorsia, grants from
Swiss National Science Foundation, grants from Christine Kühne- Center
for Allergy Research and Education, grants from European Commission’s
Horison’s 2020 Framework Programme, Cure, grants from Novar tis
Research Institutes, grants from Astra Zeneca, grants from Scibase, advi-
sory board membership in Sanofi/Regeneron. The remaining authors have
no disclosures to report.
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