Air Pollution and Cardiovascular Disease: AHA Scientific Statement

AHA Scientific Statement
Air Pollution and Cardiovascular Disease

A Statement for Healthcare Professionals From the Expert Panel on
Population and Prevention Science of the American Heart Association
Robert D. Brook, MD; Barry Franklin, PhD, Chair; Wayne Cascio, MD; Yuling Hong, MD, PhD;
George Howard, PhD; Michael Lipsett, MD; Russell Luepker, MD; Murray Mittleman, MD, ScD;
Jonathan Samet, MD; Sidney C. Smith, Jr, MD; Ira Tager, MD
Abstract—Air pollution is a heterogeneous, complex mixture of gases, liquids, and particulate matter. Epidemiological
studies have demonstrated a consistent increased risk for cardiovascular events in relation to both short- and long-term
exposure to present-day concentrations of ambient particulate matter. Several plausible mechanistic pathways have been
described, including enhanced coagulation/thrombosis, a propensity for arrhythmias, acute arterial vasoconstriction,
systemic inflammatory responses, and the chronic promotion of atherosclerosis. The purpose of this statement is to
provide healthcare professionals and regulatory agencies with a comprehensive review of the literature on air pollution
and cardiovascular disease. In addition, the implications of these findings in relation to public health and regulatory
Downloaded from http://circ.ahajournals.org/ by guest on April 3, 2018
policies are addressed. Practical recommendations for healthcare providers and their patients are outlined. In the final
section, suggestions for future research are made to address a number of remaining scientific questions. (Circulation.
2004;109:2655-2671.)
Key Words: AHA Scientific Statements 䡲 air pollution 䡲 cardiovascular diseases 䡲 respiration
cles” [PM2.5] ⬍2.5 ␮m, and “coarse particles” [PM10 to 2.5]).

R ecently, the American Heart Association (AHA) pub-
lished “Guidelines for Primary Prevention of Cardiovas-
cular Disease and Stroke” as an aid to healthcare profession-
These pollutants are associated with increased hospitaliza-
tion3 and mortality due to cardiovascular disease,4 – 6 espe-
als and their patients without established coronary artery cially in persons with congestive heart failure, frequent
disease or other atherosclerotic diseases.1 The statement was arrhythmias, or both.7 The well-established causal associa-
intended to complement the AHA/American College of tions between active and passive smoking with heart disease
Cardiology (ACC) “Guidelines for Preventing Heart Attack and stroke support the plausibility of an adverse effect of PM
and Death in Patients with Atherosclerotic Cardiovascular on the cardiovascular system.
Disease.”2 Both sets of recommendations emphasized multi- The most recent analysis of the National Mortality and
factorial interventions, especially more intensive measures/ Morbidity Air Pollution Study (NMMAPS), based on data
goals to modify individual cardiovascular risk factors with from 90 of the largest cities in the United States, estimated
diet, drugs, exercise, weight management, complete smoking that daily total and cardiopulmonary mortality increased in
cessation, and avoidance of secondhand smoke (SHS), or the short term by 0.21% (⫾0.06 standard error [SE]) and
combinations thereof. 0.31% (⫾0.09 SE), respectively, for each 10-␮g/m3 increase
Over the last decade, however, a growing body of epide- in PM10 (measured over a 24-hour period).8 To give some
miological and clinical evidence has led to a heightened context to a 24-hour PM10 increment of 10 ␮g/m3, the US
concern about the potential deleterious effects of ambient air Environmental Protection Agency (EPA) reported a range of
pollution on health and its relation to heart disease and stroke. maximum city-specific 24-hour PM10 concentrations from 26
Of special interest are several environmental air pollutants to 534 ␮g/m3.9 Data from the American Cancer Society
that include carbon monoxide, oxides of nitrogen, sulfur (ACS) cohort5 estimated that for each 10-␮g/m3 increase in
dioxide, ozone, lead, and particulate matter (“thoracic parti- annual average exposure to PM2.5, long-term all-cause, car-
cles” [PM10] ⬍10 ␮m in aerodynamic diameter, “fine parti- diopulmonary, and lung cancer mortality were increased by
The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside
relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required
to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on April 5, 2004. A single reprint
is available by calling 800-242-8721 (US only) or by writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX
75231-4596. Ask for reprint No. 71-0289. To purchase additional reprints: up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000
or more copies, call 410-528-4121, fax 410-528-4264, or e-mail [email protected]. To make photocopies for personal or educational use, call the
Copyright Clearance Center, 978-750-8400.
© 2004 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000128587.30041.C8
2655
2656 Circulation June 1, 2004
approximately 4%, 6%, and 8%, respectively. On the basis of between air pollution and cardiovascular disease. A brief
a job exposure matrix, Gustavsson et al10 reported increasing description of the different types of air pollutants is provided
risks of myocardial infarction among ⬇3000 Swedish work- first for background. In the remaining sections, the focus of
ers with increasing cumulative exposure to products from this statement is on PM, with occasional references to the
nonvehicular combustion processes. health effects of other pollutants, alone or in combination.
To evaluate whether high concentrations of ambient parti- The link between SHS and heart disease is outlined next,
cles can trigger the onset of acute myocardial infarction which provides a relevant model for the cardiovascular
(AMI), Peters and associates,11 using a case-crossover ap- effects of air pollution. In the following sections, many of the
proach, interviewed 772 patients with AMI as part of the pertinent epidemiological studies and the potential patho-
Determinants of Myocardial Infarction Onset Study. Elevated physiological mechanisms underlying the increased risk of
concentrations of PM2.5 were associated with a transient risk cardiovascular events due to PM are discussed. In the
of AMI onset during 2 separate time periods (within 2 hours summary and conclusion sections, the implications of these
and 1 day after exposure). On the other hand, investigators in data regarding public health policy and unanswered (future)
Seattle, Wash, did not find an association between high levels research questions are addressed.
of PM10 and the occurrence of primary cardiac arrest that
occurred outside of the hospital in presumably healthy Ambient Air Pollutants
adults12 or in subjects with known underlying heart disease.13 A brief description of several individual air pollutants is
A recent report by Suwa et al14 provides experimental provided first for background. A complete discussion is
evidence to support the hypothesis that these epidemiological beyond the scope of this statement, and interested readers
data truly reflect the deleterious effects of particulate pollu- may find a more comprehensive review on this subject
tion on the cardiovascular system. Compared with their elsewhere.26
control counterparts, hyperlipidemic rabbits exposed to PM10
showed more advanced coronary lesions, increased plaque Particulate Matter
size, more extensive atherosclerosis in the aorta, and an Airborne PM consists of a heterogeneous mixture of solid and
increase in the volume fraction of lesions composed of lipids liquid particles suspended in air, continually varying in size
(ie, plaques more likely to rupture).15 Other contemporary and chemical composition in space and time (Figure 1).
studies suggest that possible links between acute and/or Primary particles are emitted directly into the atmosphere,
chronic exposure to PM and cardiovascular events may be such as diesel soot, whereas secondary particles are created
related to increases in heart rate and blood pressure, fibrino- through physicochemical transformation of gases, such as
gen, and blood coagulation factors; arterial vasoconstriction; nitrate and sulfate formation from gaseous nitric acid and
inflammatory mediators (eg, C-reactive protein [CRP]); en- sulfur dioxide (SO2), respectively. The numerous natural and
dothelial injury/dysfunction; and decreases in heart rate anthropogenic sources of PM include motor vehicle emis-
variability (HRV).16 Consequences of these effects may sions, tire fragmentation and resuspension of road dust,
include myocardial ischemia (manifested as significant ST- power generation and other industrial combustion, smelting
segment depression during exercise testing,17 angina pectoris, and other metal processing, agriculture, construction and
or both), malignant ventricular arrhythmias,18 increased demolition activities, residential wood burning, windblown
plaque vulnerability, and enhanced potential for acute throm- soil, pollens and molds, forest fires and combustion of
bosis triggering acute coronary syndromes. Further support agricultural debris, volcanic emissions, and sea spray. Al-
that these changes can be attributed to air pollution comes though there are thousands of chemicals that have been
from studies of the effects of SHS, which is the single largest detected in PM in different locations, some of the more
contributor to indoor PM19 when a smoker is present. Expo- common constituents include nitrates, sulfates, elemental and
sure to SHS increases platelet activation,20 causes rapid organic carbon, organic compounds (eg, polycyclic aromatic
deterioration in endothelial function,21,22 promotes athero- hydrocarbons), biological compounds (eg, endotoxin, cell
sclerotic plaque development,23 and abets infarct expansion in fragments), and a variety of metals (eg, iron, copper, nickel,
experimental animals.24 Because exposure to the SHS of just zinc, and vanadium).
1 cigarette per day accelerates the progression of atheroscle- Largely because of the complex nature of PM, it has been
rosis,25 it is plausible that even low doses of air pollution measured and regulated based primarily on mass within
could have negative effects on coronary morphology and defined size ranges. In 1987, the regulatory focus shifted
circulation. from total suspended particles to particles that could readily
Collectively, these and other studies (described herein) penetrate and deposit in the tracheobronchial tree, or PM10
suggest that air pollution may accelerate the development of (PM with a median aerodynamic diameter of ⬍10 ␮m). In
coronary atherosclerosis and worsen its sequelae. Some of 1997, the US EPA promulgated 24-hour and annual average
these effects may occur over time, as with acceleration of the standards for PM2.5 (PM with median aerodynamic diameter
progression of atherosclerosis, or rather abruptly, as with the ⬍2.5 ␮m), comprising the size fraction that can reach the
triggering of an arrhythmia or myocardial infarction by acute small airways and alveoli. The existing federal PM10 stan-
inflammatory responses, altered platelet adhesiveness, or dards were retained, however, to address health effects that
perhaps vascular endothelial dysfunction. This AHA scien- could be related to the “coarse fraction” (PM10 to 2.5). Cur-
tific statement provides healthcare professionals and regula- rently, a separate PM10 to 2.5 standard is under consideration. In
tory agencies with a comprehensive review of the relationship general, PM2.5 originates mostly from combustion sources and
Brook et al Air Pollution and Cardiovascular Disease 2657
Figure 1. Particulate matter air pollution

size distribution.
includes primary and secondary particles, whereas the coarse nitrogen oxides include nitrous acid, nitrous oxide, peroxy-
fraction derives predominantly from natural sources, espe- acetyl nitrate (responsible for some of the irritant effects of
cially crustal material (including windblown soil) and grind- photochemical smog), nitrites, nitroso compounds, and other
ing processes. Important bioaerosols (eg, endotoxin, pollen nitrogen-containing acids. Most toxicological and epidemio-
grains, and fungal spores) are found mostly in the coarse logical research has focused on NO2, because of the fact that
fraction (and larger particles), although both endotoxin (an (1) NO2 is one of the regulated air pollutants for which
essential component of the cell wall of Gram-negative bac- standards are available worldwide; (2) NO from vehicular
teria) and the antigenic protein content of pollen grains can exhaust and power plants is largely converted to NO2; and (3)
also adsorb onto the surface of fine PM. Generally, larger NO2 plays a primary role in the formation of tropospheric
particles demonstrate a greater fractional deposition in the ozone (O3).
extrathoracic and upper tracheobronchial regions, whereas The main anthropogenic source of NOX in ambient air is
smaller particles (eg, PM2.5) show greater deposition in the fossil fuel combustion in motor vehicles and industrial
deep lung. Although PM2.5 generally behaves as a regional processes, particularly in power generation. High-
pollutant, there can be considerable small-scale spatial vari- temperature combustion results in the oxidation of atmo-
ability due to point source emissions (eg, a smelter) or spheric N2, first to NO and then to NO2. Motor vehicle
features such as street canyons in large cities. In addition, emissions near busy streets can result in high local NOX
prevailing wind patterns can affect human exposures. concentrations. The typical diurnal NOX pattern consists of a
More recently, considerable research attention has been low background concentration, with morning and late after-
devoted to ultrafine particles (UFPs) ⬍100 nm (0.1 ␮m) in noon peaks resulting from rush-hour traffic. Nitrogen in fossil
diameter, which result from combustion processes. UFPs tend fuels such as coal can be oxidized to NO2 under oxygen-rich
to be short-lived, because they agglomerate and coalesce into combustion conditions. NO2 and NO are both formed natu-
larger particles. However, they demonstrate very high depo- rally as a result of bacterial metabolism of nitrogenous
sition in human alveoli,27 account for a major portion of the compounds and, to a lesser extent, from fires, volcanoes, and
actual numbers of particles within PM, and have a high fixation by lightning. The generation of tropospheric ozone
surface area-to-mass ratio, potentially leading to enhanced and other photochemical oxidants is initiated with photolysis
biological toxicity. UFPs may even be able to pass directly of NO2, whereas NO acts as an ozone scavenger.32
into the circulatory system, which could allow them to be Significant human exposure can occur in nonoccupational
disseminated systemically.28 –30 indoor settings.33,34 Gas-burning appliances, such as unvented
furnaces and stoves, are the principal sources of indoor NOX,
Nitrogen Oxides although kerosene space heaters and tobacco smoke may also
Nitrogen oxides are reactive substances commonly under- play a role.35,36 In urban areas, infiltration of ambient NO2
stood to encompass nitric oxide (NO), nitrogen dioxide from vehicular emissions may also influence indoor expo-
(NO2), nitrogen trioxide, nitrogen tetroxide (N2O4), and di- sures.33 Several reports have also documented toxic concen-
nitrogen pentoxide (N2O5). These compounds are referred to trations of NO2 in ice-skating rinks.37,38
collectively as “NOX.” Gaseous nitric acid (HNO3), a major
source of particulate nitrate, is formed when NO2 reacts with Carbon Monoxide
hydroxyl radicals during the day and when N2O5 reacts with Carbon monoxide (CO) is a nearly ubiquitous product of
water vapor at night.31 Other members of the larger family of incomplete combustion of carbon-containing fuels. Outdoor
sources include motor vehicles; engines on motorboats, trial life forms would be unable to survive without this O3
lawnmowers, chain saws, and other devices that require fossil “shield.”
fuel combustion; residential wood burning; improperly ad- O3 has been recognized since the 1950s as the principal
justed gas-burning and oil appliances; coal combustion; and component of photochemical smog. In the troposphere, it is
tobacco smoking.39,40 In urban areas, the contributions of formed by the action of solar UV radiation on nitrogen oxides
diesel and stationary source combustion are relatively small and reactive hydrocarbons, both of which are emitted by
in relation to gasoline-powered engines.41 motor vehicles and many industrial sources. The reaction
CO is an odorless, colorless, and tasteless gas that binds to sequence involves photolysis of NO2 into NO and oxygen
hemoglobin with an affinity 250 times that of oxygen, thereby atoms. The latter react with molecular oxygen to form O3.
interfering with the systemic delivery of oxygen to tissues. In NO, however, rapidly scavenges O3, regenerating NO2 and
addition, binding of CO to hemoglobin causes an allosteric O2, as summarized below:
change in the conformation of the oxyhemoglobin complex
NO2⫹hv (295⬍v⬍430 nm)3NO⫹O
that increases the oxygen affinity of the remaining binding
sites and interferes with the release of O2 at the tissue level. O⫹O2⫹M3O3⫹M
In addition, CO binds to cytochrome oxidase, exacerbates
cellular hypoxia, and binds to other extravascular proteins NO⫹O33NO2⫹O2,
that include myoglobin, cytochrome P-450, catalase, and where M represents any nearby molecule that can absorb the
peroxidases.42 Given current ambient CO concentrations in energy of the reaction. Under steady-state conditions, there is
the United States, it is likely that in most circumstances, this
little accumulation of O3. However, many reactive organic

pollutant serves more as an indicator of combustion-related compounds can facilitate the oxidation of NO to NO2 by
pollution than as a direct toxicant. However, in some situa- alternative mechanisms. These reactions reduce NO scaveng-
tions (eg, insufficiently ventilated parking structures), CO ing, which allows O3 concentrations to increase.45
could attain concentrations sufficient to lead to physiologi- Photochemical O3 formation tends to be greatest on warm,
cally meaningful increases in carboxyhemoglobin in persons sunny days. The typical profile of tropospheric O3 formation
with significant atherosclerotic disease or other cardiac in populated areas is characterized by a broad peak that lasts
conditions. from the late morning until the late afternoon or early
evening. However, large-scale transport may result in ele-
Sulfur Dioxide vated O3 concentrations that extend over thousands of square
Sulfur dioxide (SO2) is a highly irritating, colorless, soluble miles to include rural areas far removed from the precursor
gas with a pungent odor and taste. In contact with water, it sources. Thermal inversion height, wind speed and direction,
forms sulfurous acid, which accounts for its strong irritant addition of other O3 precursors along an air mass trajectory,
effects on eyes, mucous membranes, and skin.43 SO2 is and other factors affect the temporal O3 patterns downwind,
efficiently scrubbed from inhaled air in the upper airway. so that peak concentrations may occur anytime from noon
In the absence of human activities, background concentra- until late in the evening.46 Human activities are major sources
tions of ambient SO2 are very low, in the range of 1 ppb. In of O3 precursors, although the latter are also generated by
ambient air, the principal sources of SO2 include combustion nonanthropogenic processes that include the intrusion of
of sulfur-containing fuels, especially in power plants and stratospheric O3, the action of lightning on molecular oxygen,
diesel engines (prior to the reformulation of diesel fuels), and and chemical reactions involving naturally occurring nitrogen
roasting of metal sulfide ores. Sulfur dioxide is oxidized to oxides and organic compounds, such as biogenic methane and
sulfur trioxide, which, because of its strong affinity for water, other volatile organic compounds.45
can be rapidly hydrated to form sulfuric acid.44 Elevated
levels of SO2 have been associated with widespread illness in Secondhand Smoke
several 20th century air pollution catastrophes; however, The national awareness of SHS as a major risk factor for
much of the morbidity and mortality in these episodes may chronic disease was substantially heightened with the 1986
have been due to its role in the formation of particulate Report of the Surgeon General, “The Health Consequences of
sulfates. In nonoccupational settings, SO2 is generally found Involuntary Smoking,”47 and the 1992 EPA report on the
at substantially lower concentrations indoors than outside; respiratory health effects of SHS.48 The primary focus of the
however, the use of kerosene space heaters can generate Surgeon General’s report was on lung cancer and other
significant indoor concentrations.35 respiratory diseases,47 although evidence linking passive
smoking to heart disease was just beginning to emerge.49
Ozone Similarly, the EPA report focused primarily on the impact of
Ozone (O3) is a highly reactive, colorless-to-bluish gas with a SHS on lung cancer and asthma50 by reporting that an
characteristic odor associated with electrical discharges.43 estimated annual 3000 lung cancer deaths could be attributed
Low-level exposure is ubiquitous, because O3 is formed by to SHS.48
natural processes and by human activities. Ozone is formed in There is also clear evidence of an association of SHS and
the stratosphere by the action of solar radiation on molecular cardiovascular diseases. Several reports, including 2 recent
oxygen (O2). Because stratospheric O3 prevents high-energy separate meta-analyses of 17 and 18 individual studies,
UV radiation from penetrating the atmosphere, many terres- assessed the association of SHS with heart disease.20,51–53
Both estimated that nonsmoking spouses of smoking partners home with at least 1 smoker or being exposed to SHS at
experience an approximately 25% (95% confidence interval work.63 Forty-three percent of children lived in a home with
[CI] 17% to 32%) increased risk of heart disease.52,53 A at least 1 smoker, higher than the percentage observed among
review of 6 studies examining the association between SHS adults, which is due in part to children’s opportunity to be
in the workplace and cardiovascular disease noted that exposed to SHS by either a smoking mother or father.63 More
although none of the studies individually reached the level of recent reports available at the CDC website suggest that there
a significant association (P⬍0.05), there was a positive may be substantial decreased exposure to SHS over the
association in 5 of the 6 studies and a significant exposure- interval from 1991–1994 to 1999 –2000, with decreased
response relation between the intensity of SHS (measured by levels of cotinine in children (⫺58%), adolescents (⫺55%),
the number of cigarettes smoked by coworkers) and coronary and adults (⫺75%).63a
risk in 2 of 3 studies that examined the trend.54 Exposure to SHS in workplace settings is also surprisingly
It is likely that SHS acts to increase cardiac risk through high. Nineteen states participating in the Centers for Disease
both chronic (atherogenic) and acute pathways. A review of Control and Prevention’s Behavioral Risk Factor Surveil-
the association of SHS and subclinical measures of athero- lance System included questions related to working in a
sclerosis reported a consistent association of significantly smoke-free workplace during 1999. The survey reports a
increased intima-medial thickness of the carotid artery in 8 prevalence range of exposure to cigarette smoke at work from
reports.55 In addition, exposure to SHS has been shown 18% (District of Columbia) to 38% (Mississippi).64 Some
experimentally to have effects on endothelium-dependent other studies reported even higher rates.65,66
arterial dilatation21,22 and coronary flow reserve in humans.56 SHS exposure is associated with well-established increases
Initial reports on an association between SHS and stroke in relative risks for circulatory diseases. It directly affects, at
support the observed association with heart disease. Two some level, perhaps as much as two thirds of the population,
case-control studies have shown significantly increased odds with some suggestion that the proportion exposed may be
ratios of clinical stroke with exposure to SHS: 1.72 (95% CI decreasing. Although the increased risk for cardiovascular
1.07 to 2.77) and 2.59 (95% CI 1.51 to 4.47) for exposure to diseases associated with SHS exposure (relative risk [RR]
a spouse smoking 1 to 20 cigarettes a day and ⱖ21 cigarettes 1.25) has not drawn attention to it as a “major” cardiovascular
per day,57 respectively, and 1.82 (95% CI 1.34 to 2.49) for risk factor, the high prevalence of exposure does make it a
SHS exposure at home or work for at least 1 year during the major public health issue. Given past patterns of exposure, it
decade preceding the event.58 There was a 6% (95% CI 0.64 has been estimated that between 35 000 and 65 000 ischemic
to 1.75) increased odds of silent cerebral infarction in a heart disease deaths result from SHS annually.67,68 This is an
population-based cohort study of nonsmokers exposed to order of magnitude greater than the estimated 3000 annual
SHS in relation to those not exposed; however, this difference deaths from lung cancer. As such, SHS “pollution” represents
did not reach statistical significance.59 a substantial public health burden, ranking it as one of the
The impact of SHS on heart disease and stroke is also most important preventable causes of cardiovascular death.
supported by the remarkable “natural experiment” observed
when Helena, Mont, banned public smoking beginning June Epidemiology of Ambient Air Pollution and
5, 2002. During the 6-month period of the ban, admissions to Cardiovascular Disease
the local hospital for acute myocardial infarction dropped by An association between high levels of anthropogenic air
40%, a decline that was not observed in any of the other pollutants and human illnesses has been known for more than
hospitals from surrounding communities.60 The study inves- half a century. A few episodes of markedly increased mor-
tigators hypothesized that the reduction in hospital admis- tality rates during extreme elevations in urban pollution, such
sions was due to acute coagulation changes associated with as in the Meuse Valley, Belgium, in December 193069 and
reduced SHS exposure. during the London fog incident of 1952,70 sparked the initial
A recent review of the studies concluded that it is unlikely epidemiological research. As a result, a several-decades-long
that experimental biases can invalidate the general conclu- effort to reduce air pollution ensued and culminated in the
sions of the epidemiological studies.61 Moreover, the review Clean Air Act legislation of 1970. Despite improvements in
cites the strong experimental evidence that provides a bio- air quality over the past few decades, associations between
logical basis for the observed associations between SHS current ambient pollution levels and excess morbidity and
exposure and increased risk of cardiovascular disease.61 mortality have been consistently detected.71–76
The importance of SHS as a public health issue comes There are several hundred published epidemiological stud-
from the high prevalence of SHS exposure in the general ies linking air pollution with human illnesses. A number of
population. On the basis of the most recent data from the extensive reviews on this topic are available.77–79 Although
National Health Interview Survey, the prevalence of active many pollutants may cause disease individually or in combi-
cigarette smoking was 21.4% (95% CI 20.2% to 22.5%) in nation (eg, O3, SO2, and NO2),80 over the past decade, PM has
2003.62 NHANES III (1988 –1991) found that ⬇90% of become a major focus of research. During the past 15 years,
tobacco nonusers have detectable levels of serum cotinine,63 the magnitude of evidence and number of studies linking air
which suggests that as much as 65% of the entire population pollution to cardiovascular diseases has grown
are nonsmokers exposed to SHS. This arises primarily from substantially.77,78
exposures at home or at the workplace. Between 1988 and In broad terms, studies can be separated into those that
1991, among adult nonsmokers, 37% reported living in a have investigated the health effects of acute or chronic air
pollution exposure. Observations related to the adverse health mortality. The increased risks were limited to those with no
effects of short-term exposure are more numerous. In these more than a high school education. This suggests that 1 or
studies, population-wide changes in acute outcomes (mortal- more unaccounted-for factors, such as intraurban geographic
ity, symptomatology, hospitalizations, and healthcare visits) location or socioeconomic status, may be important determi-
are linked to short-term variations in ambient pollutant nants of health risk.
concentrations, most frequently through the use of Hoek et al83 confirmed the importance of within-city
population-based time-series analysis. More recently, case- residential variations as a risk factor for mortality due to air
crossover designs have been added to the analytical reper- pollution. In a cohort of 5000 adults followed up for 8 years,
toire. Publications on the health effects of long-term exposure exposure to traffic-related air pollutants was more highly
are few. These studies have involved analysis of data (eg, related to mortality than were citywide background levels. Of
total mortality and in some circumstances cardiovascular the various pollutant metrics, an indicator variable for living
events) from a few large cohorts from multiple geographic near a major road was most strongly associated with cardio-
locations that differ in the average chronic ambient concen- pulmonary mortality in this cohort (RR 1.95, 95% CI 1.09 to
trations and mixtures of air pollutants. 3.52). This study suggests that an individual’s exposure to the
“toxic” components of air pollution may vary as much within
Long-Term Health Effects Studies a single city as across different cities. Furthermore, it dem-
The first large, prospective cohort study that demonstrated an onstrates that emissions from motor vehicles, a common
adverse health impact of long-term air pollution exposure was source of urban air pollution, may be associated with an
the Harvard Six Cities study by Dockery et al.81 This study increased risk of mortality.
demonstrated that chronic exposure to air pollutants is inde-

Until recently, the specific causes of the increased cardio-
pendently related to cardiovascular mortality. In a cohort of
vascular mortality due to long-term air pollution exposure
8111 adults with 14 to 16 years of follow-up, the adjusted
have remained unclear. In an analysis of the ACS study
overall mortality rate ratio for the most-polluted city versus
published this year, the investigators reported PM-mortality
the least-polluted city was 1.26 (95% CI 1.08 to 1.47).
associations with the specific cause of death.4 A statistically
Further adjustment for a variety of individual-level risk
robust association between PM2.5 and overall cardiovascular
factors that included tobacco smoking, gender, body mass
mortality was confirmed for a 10-␮g/m3 increase in long-term
index, educational attainment, occupational exposures, hyper-
exposure (RR 1.12, 95% CI 1.08 to 1.15). The single largest
tension, and diabetes did not significantly alter the relation-
increase in risk was for ischemic heart disease (RR 1.18, 95%
ship. Cardiovascular deaths accounted for the largest single
CI 1.14 to 1.23), which also accounted for the largest
category of the increased mortality. Of the 1401 validated
proportion of deaths. In addition, the risk for arrhythmia,
deaths, 646 were due to cardiovascular causes (International
Classification of Diseases, 9th Revision [ICD-9] codes 400 to heart failure, or cardiac arrest mortality was also increased
440). The risk ratios for lung cancer and overall cardiopul- (RR 1.13, 95% CI 1.05 to 1.21). There was no evidence for
monary mortality were increased by similar magnitudes. excess mortality in the entire cohort due to other reasons (eg,
Among air pollutants, elevations of PM2.5 and sulfates showed aortic aneurysms, stroke, diabetes, hypertensive disease, or
the strongest associations with disease. any respiratory illness). These findings suggest that air
These findings were complemented by similar observa- pollution promotes both ischemic and nonischemic cardio-
tions from the first analysis of air pollution in relation to vascular events.
mortality in the ACS Cancer Prevention II study population.82
Recently, a follow-up of the original ACS cohort by Pope et Short-Term Health Effects Studies
al,5 based on additional subject mortality and ambient pollut- The Six Cities81 and ACS4,5,82 studies provide strong evi-
ant data, has provided the largest study of the long-term dence for the occurrence of adverse cardiovascular effects
health effects of air pollution. In approximately 500 000 due to long-term air pollution exposure. However, many
adults who resided in all 50 states, chronic exposure to more studies have focused on short-term relationships be-
multiple air pollutants was linked to mortality statistics for a tween pollution exposure and adverse outcomes. The acute
16-year period. The ACS follow-up study increased the effects of air pollution are generally investigated by time-
degree of control for confounding variables, such as diet and series analyses of changes in health outcomes (eg, mortality)
gaseous copollutants. The primary results showed that each in relation to day-to-day variations in ambient air pollution
10-␮g/m3 increase in annual PM2.5 mean concentration, based concentrations. The 2 largest studies to date are the
on a number of different averaging periods, was associated NMMAPS in the United States6,8 and the Air Pollution and
with increases in all-cause, cardiopulmonary, and lung cancer Health: a European Approach (APHEA-2) project.84 These
mortality of 4%, 6%, and 8%, respectively. The relationship studies produced remarkably consistent results.
between PM2.5 and adverse health effects was linear and The NMMAPS observed outcomes in 50 million people in
without a discernible lower “safe” threshold. Mortality was the 20 largest cities in the United States. Average mortality
most strongly associated with PM2.5, sulfate particles, and rates were independently associated with particle concentra-
SO2. There also appeared to be an association between tions the day before death. Each 10-␮g/m3 elevation in PM10
cardiopulmonary mortality and summertime O3, when based was associated with an increase of 0.21% (⫾0.06 SE) and
on mean summer O3 levels from 1982 to 1998. Educational 0.31% (⫾0.09 SE) for daily all-cause and cardiopulmonary
level was a modifier of the risks estimated for PM-associated mortality, respectively.8
The APHEA-2 study demonstrated slightly more robust mias, and heart failure.98 A pooled analysis of hospital
associations between adverse health outcomes and air pollu- admissions studies showed significant increases in admission
tion.84 For 43 million people in 29 European cities, the rates of 0.8% and 0.7% for heart failure and ischemic heart
estimated increase in daily mortality was 0.6% (95% CI 0.4% disease, respectively, for each 10-␮g/m3 elevation in PM10.99
to 0.8%) for each 10-␮g/m3 increase in PM10. Cardiovascular More focused investigations have demonstrated elevated
deaths were increased by 0.69% (95% CI 0.31% to 1.08%).85 risks for AMI,11 implantable cardioverter defibrillator dis-
APHEA-2 based calculations on average particle concentra- charges,18 and myocardial ischemia during stress testing.17
tions the day of and 1 day before observed health outcomes (a Extreme elevations in air pollution have also been associated
2-day exposure time window). The NMMAPS investigators with increased blood pressure during a prolonged air stagna-
reported no differences among various lag time periods from tion episode in Europe.100 Finally, recent studies from Seoul,
0 to 2 days and therefore based their estimates solely on the South Korea101 and Taiwan102 have reported higher inci-
prior 24-hour period (1-day lag). The size of the observed dences of ischemic strokes in direct relation to changes in
health effect in a study is known to vary slightly depending on ambient particle concentrations. In summary, these findings
exposure metric and lag periods used in analyses. This may imply that short-term elevations in ambient particle levels are
have contributed to the stronger associations found in the capable of evoking cardiac arrhythmias, worsening heart
European study. Additional analyses of the APHEA-2 mor- failure, and triggering acute atherosclerotic/ischemic cardio-
tality data, based on lag periods up to 40 days, found that the vascular complications.
risk of adverse health effects associated with air pollution
more than doubled (eg, 1.97% increase in cardiovascular Populations at Elevated Risk
mortality [95% CI 1.38% to 2.55%] per 10-␮g/m3 elevation It is now reasonably well established that both short-term and
in PM10).85 This finding indicated that the increase in cardio- chronic air pollution exposures are related to cardiovascular
pulmonary mortality was not simply the result of “harvest- diseases. Whether there are specific individuals or subsets of
ing” (also called mortality displacement, which refers to the patients at increased relative risk is less well documented. A
advancement of death by no more than a few days for few observations have suggested that the elderly5,81,84,103 and
severely ill individuals). Analyses of data from other loca- those with less than a high school education (low socioeco-
tions also have indicated that the increased risks cannot be nomic status) may be particularly susceptible populations.5
explained solely by harvesting and that longer lags are Whether increased age per se or the high prevalence of
associated with higher relative risks of cardiopulmonary underlying cardiovascular disease and other risk factors
mortality.86 – 88 The higher relative risks demonstrated by explains the enhanced risk observed in elderly populations is
using this statistical modeling may reflect the accumulation unclear. The presence of preexisting chronic lung disease,
of both acute and subacute health effects over the longer lag coronary heart disease, and heart failure may also elevate
periods. short-term cardiovascular mortality risk.103 Most recently,
APHEA-2 found that cities with higher levels of the publications from 2 separate groups provide evidence that the
copollutant NO2 exhibited larger associations between acute risk for cardiovascular events in patients with diabetes
changes in PM concentrations and mortality. In the United mellitus may be 2-fold higher than for nondiabetics.104,105 It is
States, this modifying effect of NO2 was not demonstrated. plausible that both diabetes itself and the high incidence of
The APHEA-2 investigators speculated that this might reflect concomitant cardiovascular disease may explain this relation-
a higher proportion of NO2 that is derived from diesel exhaust ship. There is no convincing evidence that gender, race, and
in Europe. Outcome differences by geographical region were other preexisting coronary risk factors (eg, obesity, dyslipid-
also noted in both studies. In Europe, cities with warmer emia, and hypertension) increase the risk of cardiovascular
climates demonstrated stronger mortality associations with events due to air pollution.
air pollutants. The NMMAPS study in the United States The effect of tobacco smoking on the cardiovascular risk
reported stronger relationships in the Northeast than the due to long-term air pollution exposure was recently investi-
Southeast. It is plausible that differences in the underlying gated in the large ACS study.4 The risks for specific cardio-
susceptibility of the populations, time spent outdoors, com- vascular causes of death for each 10-␮g/m3 increase in the
mute times, and ambient meteorology, as well as differences long-term exposure to PM2.5 were stratified by smoking
in the overall ambient pollutant mixtures, underlie the ob- status. Ischemic heart disease mortality was consistently
served regional variability in risk estimates for both studies. elevated, with RRs of 1.22 (95% CI 1.14 to 1.29), 1.15 (95%
Hundreds of smaller, short-term studies have been pub- CI 1.07 to 1.23), and 1.16 (95% CI 1.07 to 1.27) for
lished over the last few decades on the effects of acute air never-smokers, former smokers, and current smokers, respec-
pollution exposure, as reviewed by Brunekreef and Holgate77 tively. Interestingly, smoking status clearly affected the risk
and Pope.78 Typically, short-term mortality rates73,88 hospital associated with several other causes of death. The risk due to
admissions,89 –91 emergency room visits,92,93 and symptom arrhythmias, heart failure, and cardiac arrest was not signif-
exacerbations94,95 have been shown to increase in relation to icantly elevated for those who never smoked (RR 1.04 [95%
variations in air pollution levels (time-series studies). Obser- CI 0.95 to 1.15]). However, among former and current
vations from across North America96,97 and Europe3,98 have smokers, the risk increased substantially, with RRs of 1.14
demonstrated higher rates of hospitalizations for all cardio- (95% CI 1.00 to 1.29) and 1.31 (95% CI 1.12 to 2.19),
vascular causes. Direct associations have also been identified respectively. Mortality risk due to hypertensive disease was
with respect to incidence of ischemic heart disease, arrhyth- also only increased in patients who actively smoked (RR
1.57, 95% CI 1.12 to 2.19). These findings show that erally, in the epidemiological studies, an individual subject’s
smoking, while not affecting the PM-associated risk from exposure level has been estimated from citywide pollution
ischemic heart disease, appeared to interact with air pollution measurement averages obtained from at most a few central
to increase the risk of death from other circulatory diseases. locations. Past studies have also been limited by the fact that the
numerous gaseous and particulate pollutants tend to covary in
Environmental Pollution and Congenital time and space. This has limited the ability to confidently link
Heart Disease health outcomes with any given pollutant, although this may be
Malformations of the cardiovascular system are among the an unrealistic goal given the complexity of the ambient pollutant
more frequently occurring congenital defects. The incidence mixture and the potential for combined toxic effects from many
of congenital heart disease is estimated at 8.1 per 1000 different combinations of constituents. Use of new tools such as
births.106 The actual rate may be underestimated, because geographic information systems and personal monitoring de-
some cases may be lethal in utero and result in spontaneous vices and better measures of the full toxic air pollution mix (eg,
abortion and stillbirths. Congenital heart disease is associated individual chemical and physical constituents or measurements
with genetic defects, infections (eg, rubella), radiation, med- of total oxidant capacity) may provide more refined estimates of
ications, and environmental exposures.106 –111 Recent data the adverse health effects that can be related to specific (mixtures
from Eastern Europe in areas with high levels of industrial of) components.
pollution suggest the possibility of increased heart defects.112– Despite many past limitations, there has been a strong
114 More recently, a study of birth records in Los Angeles, consistency in the findings among the array of assorted
Calif, found that odds ratios (ORs) for cardiac ventricular studies. A reasonable argument can now be made that the
septal defects increased in a dose-response fashion with “real” effects are likely to be even stronger than previously
increasing carbon monoxide exposure (OR for second quar- estimated. Indeed, a recent study suggests a more robust
tile 1.62 [95% CI 1.05 to 2.48], OR for third quartile 2.09 linkage. In a recent “natural experiment,” Clancy et al117 were
[95% CI 1.19 to 3.67], and OR for fourth quartile 2.95 [95% able to demonstrate a decrease in health effects after the
CI 1.44 to 6.05]).115 Also observed were valvular, aortic, and intentional lowering of air pollutant levels. These investiga-
truncal defects associated with O3 levels. PM and other tors compared 72 months of mortality data before and after a
measured air pollutants showed no association. Although ban on burning coal within the city of Dublin, Ireland, went
some animal data also suggest a relationship between air into effect. Nontraumatic deaths decreased by 5.7% (95% CI
pollutants and congenital cardiac defects, these epidemiolog- 4.0% to 7.0%) and cardiovascular mortality by 10.3% (95%
ical data can only be considered suggestive at this time. CI 8.0% to 13.0%). The authors estimated that the ban
resulted in 243 fewer cardiovascular deaths per year. The
Significance of Epidemiological Findings decrease in the mortality rate in this “natural experiment” is
Epidemiological research has served to drive major govern- more than twice what would be predicted by the short-term
mental regulations and thus has been the subject of intense time-series analyses.
scrutiny. Two of the largest studies of the health effects of
long-term air pollution exposure81,82 that have served as the Potential Biological Mechanisms
basis for the setting of annual average PM2.5 standards have The putative biological mechanisms linking air pollution to
undergone complete reanalyses by independent investigators heart disease involve direct effects of pollutants on the
to ensure reproducibility.116 The reanalyses validated the cardiovascular system, blood, and lung receptors, and/or
quality of the data and replicated the original results without indirect effects mediated through pulmonary oxidative stress
any substantial alteration in findings. Although exposure to and inflammatory responses. Direct effects may occur via
ambient air pollution poses smaller relative risks for incident agents that readily cross the pulmonary epithelium into the
cardiovascular disease than obesity or tobacco smoking, circulation, such as gases, and possibly UFPs28 –30 along with
because it is ubiquitous, the absolute number of people soluble constituents of PM2.5 (eg, transition metals). In addi-
affected is enormous, and exposure occurs over an entire tion, activation of pulmonary neural reflexes secondary to PM
lifetime. The adverse effects on the public health are clearly interactions with lung receptors may play a role. Ensuing
not limited to a harvesting effect as described earlier. Rather, alterations in autonomic tone, under appropriate circum-
Pope78 has estimated an average loss of life expectancy stances, might contribute to the instability of a vascular
directly related to chronic air pollution exposure from be- plaque or initiate cardiac arrhythmias. These direct effects of
tween 1.8 and 3.1 years for those living in the most polluted air pollution represent a plausible explanation for the occur-
cities in the United States. Cardiovascular causes account for rence of rapid (within a few hours) cardiovascular responses,
the majority (69%) of the overall excess in morbidity and such as increased myocardial infarctions.11 Less acute (sev-
mortality.78 eral hours to days) and chronic indirect effects may occur via
pulmonary oxidative stress/inflammation induced by inhaled
Present Controversies pollutants. This subsequently may contribute to a systemic
Given the continuous spatial and temporal variability of air inflammatory state, which may in turn be capable of activat-
pollution, combined with individuals’ movements through ing hemostatic pathways, impairing vascular function, and
numerous microenvironments every day, it is not surprising accelerating atherosclerosis. A general scheme illustrating
that exposure assessment in air pollution studies has always potential mechanisms of the effects of PM on the cardiovas-
been subject to varying degrees of measurement error. Gen- cular system is shown in Figure 2.
Figure 2. Possible biological mecha-

nisms linking PM with cardiovascular
disease.
Pulmonary and Systemic Oxidative Stress cluding nuclear factor-␬B and activator protein-1, which
and Inflammation upregulate the expression of genes for cytokines, chemo-
Inhalation of air pollutants induces pulmonary oxidative kines, and other proinflammatory mediators.132 DEPs or
stress and inflammation.118 Exposure of human lungs to organic extracts of DEPs can, through oxidant effects on
concentrated PM119 and O3120 produces an inflammatory mitochondria, induce apoptosis or necrosis of macrophages
response consistent with in vivo animal models121 and in vitro and respiratory epithelial cells, possibly decreasing the host
cellular models.122–125 The presence of soluble transition defenses to respiratory infection or increasing airway
metals in PM enhances the inflammatory responses126 via reactivity.136
increased oxidative stress.127,128 However, lung inflammation Endotoxin, usually associated with coarse particles, has
may also occur via direct UFP effects independent of transi- also been shown to induce proinflammatory cytokine produc-
tion metals or soluble components.129 Similarly, O3 mediates tion137,138; increase lung inflammation, airway responsive-
a pulmonary inflammatory response via oxidative stress118,130 ness, and systemic immune cell populations; and decrease
and an impairment in lung function that can be attenuated by lung function.139,140 Endotoxin has been found to account for
antioxidants.131 in vitro cytotoxicity and cytokine production related to PM2.5
Oxidative stress occurs after exposure to ultrafine carbon and coarse PM exposures141,142; however, its role in the
black and diesel exhaust particles (DEPs),129,132 ambient overall toxicity of ambient PM remains to be clarified.
PM2.5,133 and cigarette smoke. A recent in vivo experiment The intrapulmonary responses elicited by PM may also be
using in situ chemiluminescence demonstrated the rapid due in part to neurogenic inflammation. Sensory neurons in
occurrence of oxidative stress even in tissues beyond the contact with irritant particles (eg, within the conducting
lung. After exposure to concentrated ambient PM2.5 for 2 airways) can be stimulated to release neuropeptides (eg,
hours, there was a doubling in reactive oxygen species substance P, calcitonin gene related peptide, and neurokinin
generation in the hearts and lungs of rats.134 This may occur A), which can initiate airway inflammatory events, including
in response to a variety of transition metals134 or free radical release of cytokines, vasodilation, and mucus secretion.
components known to exist within PM2.5 as a result of Neuropeptides act on a variety of cell types within the lung,
atmospheric chemical reactions.135 Personal exposure to am- including epithelial and smooth muscle cells (resulting in
bient concentrations of PM2.5 is also associated with increased modulation of inflammation and increased airway respon-
levels of markers of lipid and protein oxidation in human siveness), as well as immune cells (polymorphonuclear leu-
blood.133 Pulmonary inflammation results at least in part kocytes [PMNs], lymphocytes, eosinophils, and others), thus
because of the increased production of free radicals.118 amplifying the inflammatory response. Recent in vitro exper-
Oxidative stress activates specific transcription factors, in- iments indicate that specific irritant (capsaicin or vanilloid)
receptors on neurons mediate PM-related neurogenic inflam- cular events. Subsequently, evidence supporting this hypoth-
mation, as evidenced by responses to particles originating esis has slowly been accumulating. As described above,
from diverse sources.143 several studies of controlled exposures to particles demon-
Several controlled-exposure studies demonstrate that inha- strate increases in both cellular and biochemical markers of
lation of particles119,144,145 and O3120 evokes both a pulmonary pulmonary and systemic inflammation.
and a systemic inflammatory response in humans. One hour Exposure to PM increases fibrinogen,119,147 a key compo-
of exposure to very high concentrations of diesel exhaust has nent in blood coagulation and platelet thrombosis and a major
been shown to induce an inflammatory reaction in the lungs determinant of blood viscosity. Blood viscosity has been
of healthy adults. This response included increased numbers associated with severity of cardiovascular disease151 and has
of PMNs, T- and B-lymphocytes, mast cells, and inflamma- been found to increase in association with increased levels of
tory mediators.144 One of these studies showed an increase in ambient total suspended particles and SO2.152 Fibrinogen is
adhesion molecules that facilitate the passage of inflamma- also well established as an important independent risk factor
tory cells from the circulation into the airways. In the blood, for myocardial infarction and stroke. Epidemiological data
platelets and PMNs increased, which suggests that exposure suggest potential effects of particulate air pollution on blood
to DEPs stimulated the bone marrow to release these cells coagulation.152–154 Of note is that the strength of plasma level
into the circulation. of fibrinogen to predict cardiac events and death in middle-
Exposure to DEP has been shown to increase intra-airway aged men is modified by the presence of other inflammation-
transcription of mRNA for interleukin (IL)-8 (a protein that sensitive proteins,155 which suggests that inflammation has a
attracts PMNs to sites of injury)146 and increased production significant role in the determination of cardiovascular risk. In
of IL-8 and growth-regulating oncogene-␣ (GRO)-promoting addition, enhanced platelet aggregation may further promote
airway inflammation. Exposure of healthy adults to concen- acute thrombosis formation after exposure to diesel ex-
trated ambient particles (CAP) for 2 hours can increase haust156 and UFPs.157 The mechanisms responsible for plate-
airway inflammation without concomitant lung injury.119 let activation and fibrinogen elevation remain to be fully
Nevertheless, plasma fibrinogen was elevated by the CAP elucidated. Nevertheless, these findings support the notion
exposure relative to filtered air. This controlled exposure that air pollution can acutely increase the risk of thrombosis,
study suggests that exposure to ambient particles in healthy thus promoting ischemic events.
humans can result in a mild pulmonary inflammatory re- Increased concentrations of IL-6 are associated with an
sponse and increased blood factors that effect coagulation, increased risk of cardiovascular events158,159 and mortality.160
even without lung damage. A similar human study also Serum Il-6, IL-1␤, and granulocyte macrophage colony-
demonstrated an increase in blood fibrinogen after short-term stimulating factor are increased in healthy male subjects after
exposure to CAP.147 However, no other changes in inflam- exposures to increased air pollution due to forest fires and are
matory mediators or other coagulation factors were found. increased in vitro with exposure of human lung macrophages
Additional studies support the existence of a systemic to urban PM10.161 Il-6 is directly involved in regulation of the
inflammatory response beyond the lungs after air pollution synthesis of C-reactive protein in the liver. CRP is a sensitive
exposure. In humans, exposure to forest fire smoke (mea- indicator of infection, injury, and inflammation and is linked
sured as PM10 and SO2) at levels that did not result in changes to increased risk of cardiovascular disease.162,163 CRP con-
in lung function nevertheless resulted in stimulation of bone centration has been shown to be positively associated with
marrow to release immature PMNs into the circulation.148 exposure to total suspended particles164 and PM10.153
In an animal experiment, rabbits that received 5 mg of The mechanisms by which CRP increases the risk of
PM10 intrapharyngeally twice per week for 3 weeks exhibited cardiovascular events is the subject of intense research. One
increased production of PMNs in the bone marrow and possibility is that CRP impairs endothelial vasoreactivity in
accelerated release into the circulation.149 The PM10 exposure individuals with preexisting coronary artery disease.165 In
resulted in diffuse inflammation of the lungs, with particles addition, CRP may contribute directly to the development and
present in alveolar macrophages, lung epithelial cells, and progression of atherosclerosis via a number of mechanisms
airway walls. The effects on PMN production in bone marrow that involve enhanced formation of foam cells, recruitment of
and release of immature cells into the blood were associated monocytes into the arterial wall, stimulation of prothrombotic
with the numbers of particles ingested by alveolar tissue factors, decreased NO synthase activity, and expression
macrophages. of adhesion molecules.166 Inflammation (proinflammatory
cytokines, CRP, and components of innate immunity) plays a
Effects of Inflammation, Oxidative Stress, and significant role in the genesis of atherosclerosis and in plaque
Alterations in Blood-Borne Factors on the instability.167 It is possible, therefore, that air pollution–
Cardiovascular System mediated systemic inflammation both promotes atherosclero-
Changes in the composition of the blood may result from air sis formation over the long term14 and instigates acute plaque
pollution exposure, with potentially serious effects on indi- instability and sudden cardiovascular events in the short term.
viduals with cardiovascular disease. Nearly a decade ago, Indeed, in hyperlipidemic rabbits exposed to PM, the pro-
Seaton et al150 proposed a general hypothesis that exposure to gression of coronary atherosclerosis and extracellular lipid
inhaled particles induces alveolar inflammation, leading to pools increased after 4 weeks.14 The degree of plaque
exacerbation of preexisting lung disease, increased blood formation correlated with the number of alveolar macro-
coagulability, and an associated increased risk of cardiovas- phages that phagocytosed PM. These effects are likely to be
superimposed on the effects of age, hypertension, hyperlip- mechanistic link between air pollution and cardiovascular
idemia, diabetes, and other conditions associated with under- mortality by promoting fatal tachyarrhythmias. A recent
lying inflammation. study of controlled exposure to CAP provides further support
Alterations in vascular tone due to air pollution exposure to the notion that PM is capable of reducing HRV.182 In
have also been demonstrated. The inhalation of high urban general, the decrease of HRV occurs rapidly and is inversely
levels of CAP and ozone for 2 hours caused conduit arterial proportional to the increase in the concentration of PM.
vasoconstriction in healthy adults.168 Similarly, small pulmo- However, in one study,177 short-term measures of parasym-
nary arteries were shown to constrict after short-term expo- pathetic tone (r-MSSD) were increased in a group of individ-
sure to CAP in rats.169 It is possible that the acute systemic uals with preexisting heart disease. It is conceivable that in
inflammation and oxidative stress133,134 are responsible for certain populations, air pollution–mediated bradyarrhythmias
triggering endothelial dysfunction leading to vasoconstric- may also contribute to sudden death.
tion.170 In support of this hypothesis, impaired arterial endo- The relevance that these observed short-term changes in
thelial relaxation and decreased NO formation have been HRV have in relation to the worsening of cardiovascular
shown to occur in vessels exposed to DEPs owing to excess outcomes and the triggering of significant arrhythmias over
reactive oxygen species generation.171 Alternatively, in- the long term remains unclear. However, some evidence
creased production of endothelins may play a role in the acute suggests that PM exposure does promote clinically meaning-
vasoconstriction.172 ful changes in cardiac electrophysiology. The incidence of
At present, the precise mechanisms underlying the rapid cardiac arrhythmias has been associated with exposure to
alterations in vascular tone remain to be resolved. However, a PM2.5 in high-risk individuals (eg, individuals having an
few published reports support the relevance of these findings by implanted cardioverter defibrillator). In 100 patients moni-
demonstrating an effect of air pollution on cardiovascular he- tored for ⬇3 years, NO2 and CO concentrations were most
modynamics.100,172 Ambient air pollution increases blood pres- strongly related to implanted cardioverter defibrillator dis-
sure in cardiac rehabilitation patients173 and in adults with lung charges, whereas particulate black carbon showed a slightly
disease.174 Indeed, arterial vasoconstriction is a likely explana- lesser degree of association with such events.18 Although this
tion for the findings of the ULTRA study (The Exposure and study is limited by the small number of high-risk patients and
Risk Assessment for Fine and Ultrafine Particles in Ambient by the lack of individual clinical data beyond implanted
Air). Ambient levels of PM 2 days before submaximal exercise cardioverter defibrillator discharges, it does suggest a poten-
testing were significantly associated with increased ST-segment tial for adverse effects of PM and gaseous pollutants on
depression during the test.17 This finding suggests that air cardiac autonomic balance. A recent mortality time-series
pollution exposure conveys a greater susceptibility to myocar- study98 further supports this observation. The risks of mor-
dial ischemia, as demonstrated in an experimental study of dogs tality from threatening arrhythmias were shown to increase in
exposed to CAP.175 These results also offer insight regarding the relation to 7-day mean levels of black smoke and PM10.
relationship between exposure to PM and the timing of AMI.11 These clinical observations are consistent with several
Significant associations were identified between symptom onset studies reporting the induction of cardiac arrhythmias in
and both acute (levels within 2 hours before symptoms) and compromised animals (ie, with pulmonary and systemic
subacute (previous-day average concentration) exposures to hypertension) exposed to PM.183 Dogs exposed to CAP for 6
PM2.5. Sudden arterial vasoconstriction (and/or possibly en- hours on 3 consecutive days showed increases in low- and
dothelial dysfunction) could conceivably instigate acute cor- high-frequency HRV, as well as an elevated low frequency/
onary syndromes by triggering plaque instability or by high frequency ratio.184 In addition, exposure to residual oil
decreasing myocardial perfusion in patients with existing fly ash, a component of PM, decreased HRV and increased
atherosclerosis. arrhythmia frequency in a myocardial infarction model of
rats.185 These animal exposure findings support the notion
Disturbances of the Cardiac Autonomic that air pollution is capable of altering autonomic balance in
Nervous System a manner that favors significant tachyarrhythmias. The un-
Mortality associated with air pollution might be further derlying mechanisms responsible remain unclear but may
explained, at least in part, by alterations in the autonomic involve activation of pulmonary neural reflex arcs, direct
input to the heart. HRV, resting heart rate, and blood pressure effects of pollutants on cardiac ion channels, or consequences
are modulated by a balance between the 2 determinants of of the heightened systemic inflammatory state.
autonomic tone (the sympathetic and parasympathetic ner-
vous systems). Decreased HRV predicts an increased risk of Summary
cardiovascular morbidity and mortality in the elderly and Air pollution consists of a complex mixture of compounds in
those with significant heart disease.176 This is generally gaseous (eg, NO2, SO2, CO, O3), liquid, and solid phases. PM
determined by analyses of time (eg, standard deviation of itself is a heterogeneous mixture of suspended particles that
normal RR intervals [SDNN]) and frequency domains (eg, vary in chemical composition and size, ranging from clusters
low frequency/high frequency ratio by power spectral analy- of molecules (with diameters of several nanometers) to coarse
sis, reflecting autonomic balance) measured during 24 hours PM (up to 10 ␮m and beyond). Among the many natural and
of electrocardiography. Because overall HRV (SDNN) de- anthropogenic sources of air pollution, the combustion of
creases in response to ambient PM exposure,177–181 decreased fossil fuels is a major contributor in urban and industrialized
parasympathetic input to the heart may provide an important societies.
Numerous epidemiological studies conducted worldwide Current US EPA National Ambient Air Quality Standards for PM
have demonstrated consistent associations between short- (1997 NAAQS)
term elevations in PM and increases in daily cardiovascular Time Period PM10, ␮g/m3 PM2.5, ␮g/m3
morbidity and mortality. Several studies have also reported
Annual 50 15
adverse cardiovascular outcomes in relation to long-term PM
Daily 150 65
exposure. Elderly patients, those with underlying coronary or
pulmonary disease, lower socioeconomic populations, and The annual standard is satisfied when the 3-year average of the mean PM
diabetics may be at particularly increased risk. At present, the levels measured in a community is less than or equal to the indicated number.
The daily standard is met when the 3-year average of the 98th or 99th
constituent PM responsible for mediating these effects, along
percentile of 24-hour PM levels in each community is less than or equal to the
with the roles of the various gaseous copollutants, remain to indicated number.
be clarified.
Experimental evidence has revealed plausible biological greater in regions such as the industrial Midwest (41%) and
mechanisms whereby PM has the potential to cause and southern California (60%). In light of these data, there is a
exacerbate cardiovascular disease. One pathway involves the clear potential to improve the national public health and to
initiation of pulmonary and systemic oxidative stress and substantially reduce cardiovascular morbidity and mortality
inflammation by components within PM. Subsequently, a by reducing PM levels to current EPA standards. The poten-
cascade of physiological responses may follow that are tial cardiovascular health effect of reducing the gaseous
capable of instigating cardiovascular events. These include
copollutants remains less certain.
alterations in blood rheology that favor thrombosis, cardiac
dysrhythmias, acute vascular dysfunction, plaque instability,

Conclusions and Recommendations
and the long-term development of atherosclerosis. Additional Most3– 8,81 but not all12,13 studies have found positive associ-
pathways may also be involved, such as changes in auto-
ations between several different air pollutants and adverse
nomic balance via lung neural reflex arcs and/or by PM (or
health outcomes. The results of observational studies are
certain components) reaching the circulation and beyond.
influenced by numerous factors, including characteristics of
the air pollution, the population studied, and methodological
Potential for Prevention/Public Policy issues, such as control of relevant confounders. The lack of
The increase in relative risk for cardiovascular disease due to
complete uniformity is not surprising given that numerous
air pollution for an individual is small compared with the
variables (atmospheric conditions, geographic locations, co-
impact of the established cardiovascular risk factors. How-
hort characteristics, sample sizes, exposure estimates, and
ever, because of the enormous number of people affected,
statistical modeling) can affect the results. Our understanding
even conservative risk estimates translate into a substantial
increase in total mortality within the population. The impact of the relevant biological mechanisms involved also remains
on cardiovascular disease therefore represents a serious pub- incomplete. Nevertheless, the existing body of evidence is
lic health problem. The latest draft of the US EPA Air Quality adequately consistent, coherent, and plausible enough to draw
Criteria for Particulate Matter has confirmed the presence of several conclusions.193 At the very least, short-term exposure
an apparent linear dose-response relationship between PM to elevated PM significantly contributes to increased acute
and adverse events.186 Data from all North American studies cardiovascular mortality, particularly in certain at-risk subsets
demonstrate that this curve is without a discernible threshold of the population. Hospital admissions for several cardiovas-
below which PM concentrations pose no health risk to the cular and pulmonary diseases acutely increase in response to
general population.186 At present-day levels, ⬇40 000 deaths higher ambient PM concentrations. The evidence further
per year in Austria, France, and Switzerland combined have implicates prolonged exposure to elevated levels of PM in
been attributed to PM.187 Estimates based on time-series reducing overall life expectancy on the order of a few years.
studies suggest that ⬇5000 excess deaths per year in Cana- On the basis of these conclusions and the potential to
da188 and 6000 cardiovascular events in the United King- improve the public health, the AHA writing group supports
dom189 can be attributed to poor air quality. Approximately 1 the promulgation and implementation of regulations to expe-
in 50 myocardial infarctions were thought to be triggered by dite the attainment of the existing National Ambient Air
outdoor air pollution in a London, England, study.3 On a Quality Standards. Moreover, because a number of studies
global scale, the World Health Organization has estimated have demonstrated associations between particulate air pol-
that 800 000 deaths occur per year and 7.9 million disability- lution and adverse cardiovascular effects even when levels of
adjusted life-years are lost annually due to PM exposure.189a ambient PM2.5 were within current standards,5,11 even more
Given the burden of epidemiological evidence, the US stringent standards for PM2.5 should be strongly considered by
EPA updated the National Ambient Air Quality Standards in the EPA. Additional approaches to reduce the burden of
1997 to specifically include PM2.5 (Table).190 The most disease related to air pollution should be highlighted. The
current estimates by the EPA suggest that attainment of these levels of O3 and PM in many US cities are published daily by
standards would reduce total mortality by 23 000 deaths the EPA, along with a health alert system that reflects
annually and cardiovascular hospital admissions by 42 000 recommended changes in activity. This information is also
per year in the United States.191 Nevertheless, 19% of all US available and updated daily on the EPA AIRNow web site
counties with air-quality monitoring systems are presently not (http://www.epa.gov/airnow). The AHA supports these rec-
meeting these standards.192 This percentage is substantially ommendations as guidelines for activity restriction for per-
sons with known heart disease (or with an “at-risk” profile by • Demonstrate the occurrence of such cardiovascular
Framingham or another scoring system), and pulmonary end points at environmentally relevant concentrations
disease, the elderly, and those with diabetes mellitus. A of ambient pollutants.
concerted effort should be made to educate healthcare pro- • Determine causal pathways, which may become tar-
viders and at-risk patients alike about this source of informa- gets for future means of preventive strategies
tion and about the potential health hazards of elevated air • Determine whether long-term exposure to PM at
pollution levels. The AHA should also actively work to environmentally relevant concentrations promotes the
educate the public and public policy makers about the effects genesis/progression of atherosclerosis in humans.
of air pollution on cardiovascular disease by featured presen- 2. Identification of the differential toxicity of various
tations at the annual Scientific Sessions, AHA-sponsored constituents and sources of air pollution, including:
public education activities, and advocacy. • Specific chemical and biological constituents of PM
In October 2003, the EPA expanded its Air Quality Index (eg, metals, carbon, polycyclic aromatic hydrocar-
program to include information on particle pollution, or fine bons, endotoxin).
particles. Next-day forecasts and real-time air quality informa- • The role of different PM size fractions, including
tion about particle pollution are available on the AIRNow Web UFPs (⬍0.1 ␮m) and the coarse fraction (PM10 to 2.5).
site for more than 150 cities across the country. Air quality • The effects of gaseous copollutants alone or in com-
bination with PM.
forecasts and reports for particle pollution are available in the
3. Epidemiological investigations designed to address
local media (newspapers, television, and radio) in these cities
some of the limitations of prior reports, including
and in the national media. The EPA is working to increase the

studies that involve the following:
number of state and local air quality agencies that forecast and
• Better characterization of the populations of individ-
report real-time particle pollution levels. It is expected that
uals at high risk related to short-term elevations in
within a few years, this program will mirror the O3 program in
PM (eg, comorbidities).
terms of geographic coverage and availability to the public. The
• Improvement of exposure estimates and metrics (eg,
AIRNow Web site also contains information about the health use of personal monitoring systems).
effects of particle pollution, and the EPA is developing a section • Examination of the relationships between traffic
with information and tools for healthcare professionals. emissions and adverse cardiac effects.
Although there is a strong case that air pollution increases • Investigation of the roles of copollutants and
the risk of cardiovascular disease, we recognize the need to confounders.
address a number of remaining scientific questions. Both the • Assessment of the effect of medications on the acute
US EPA and the National Institutes of Health have increased cardiovascular effect of air pollution (eg, HMG-CoA
the priority of research funding in an effort to overcome these reductase inhibitors).
shortcomings, and a committee of the National Research • Evaluation of the shape of the dose-response curve
Council set out a long-range research agenda in 1998.194 A (identification of any threshold concentrations of
workshop sponsored by these and other agencies was con- various pollutants).
vened in August 2002 to foster multidisciplinary research on • Improved estimations of the population-wide health
the cardiovascular effects of PM. The AHA writing group benefits of reducing PM and other pollutants.
supports these measures and recognizes several important • More thorough examination of the relationships be-
areas for future research80,192: tween ambient air pollution concentrations and ad-
1. Improve our understanding of the underlying biological verse reproductive outcomes, including those involv-
mechanisms. ing congenital cardiac anomalies
• Better describe the basic mechanisms (mediators, cell
signaling, pathways) involved in altering HRV (auto- Acknowledgment
nomic tone), vascular function, and atherogenesis. The writing group recognizes Susan Lyon Stone of the US
Environmental Protection Agency for providing information on the
• Increased use of relevant animal models of exposure
Air Quality Index program.
when investigating cardiovascular outcomes (eg, in-
halation chambers at meaningful CAP concentra- References
tions). Experiments using intrapulmonary installation 1. Pearson TA, Blair SN, Daniels SR, et al, for the American Heart
provide insight into basic mechanisms; however, the Association Science Advisory and Coordinating Committee. AHA
guidelines for primary prevention of cardiovascular disease and stroke:
ability to extrapolate findings to humans is limited 2002 update: consensus panel guide to comprehensive risk reduction for
owing to the route of administration of extraordinarily adult patients without coronary or other atherosclerotic vascular
high quantities of PM. diseases. Circulation. 2002;106:388 –391.
2. Smith SC, Blair SN, Bonow RO, et al. AHA/ACC Scientific Statement:
• Determine the pathophysiological relevance of the
AHA/ACC guidelines for preventing heart attack and death in patients
many pathways that may contribute to the develop- with atherosclerotic cardiovascular disease: 2001 update: a statement for
ment of both acute and chronic disease. healthcare professionals from the American Heart Association and the
• Demonstrate reproducibility of the relevant potential American College of Cardiology. Circulation. 2001;104:1577–1579.
3. Poloniecki JD, Atkinson RW, de Leon AP, et al. Daily time series for
mechanisms under a variety of pollutant regimens and cardiovascular hospital admissions and previous day’s air pollution in
subject risk profiles. London, UK. Occup Environ Med. 1997;54:535–540.
4. Pope CA, Burnett RT, Thurston GD, et al. Cardiovascular mortality and 28. Nemmar A, Vanbilloen H, Hoylaerts MF, et al. Passage of intratra-
long-term exposure to particulate air pollution: epidemiological cheally instilled ultrafine particles from the lung into the systemic
evidence of general pathophysiological pathways of disease. Circu- circulation in hamster. Am J Respir Crit Care Med. 2001;164:
lation. 2004;109:71–77. 1665–1668.
5. Pope CA, Burnett RT, Thun MJ, et al. Lung cancer, cardiopulmonary 29. Nemmar A, Hoet PH, Vanquickenborne B, et al. Passage of inhaled
mortality, and long-term exposure to fine particulate air pollution. particles into the blood circulation in humans. Circulation. 2002;105:
JAMA. 2002;287:1132–1141. 411– 414.
6. Samet JM, Dominici F, Curriero FC, et al. Fine particulate air pollution 30. Oberdorster G, Sharp Z, Atudorei V, et al. Extrapulmonary translocation
and mortality in 20 U.S. cities, 1987–1994. N Engl J Med. 2000;343: of ultrafine carbon particles following whole-body inhalation exposure
1742–1749. of rats. J Toxicol Environ Health A. 2002;65:1531–1543.
7. Mann JK, Tager IB, Lurmann F, et al. Air pollution and hospital 31. US Environmental Protection Agency. Air Quality Criteria for Oxides of
admissions for ischemic heart disease in persons with congestive heart Nitrogen. Vol I. Research Triangle Park, NC: US Environmental Pro-
failure or arrhythmia. Environ Health Perspect. 2002;110:1247–1252. tection Agency; 1993:3–14. Publication No. EPA/600/8-91/049aF.
8. Dominici F, McDermott A, Daniels D, et al. Mortality among residents 32. Lipsett MJ. Oxides of nitrogen and sulfur. In: Sullivan JB, Krieger GR,
of 90 cities. In: Special Report: Revised Analyses of Time-Series Studies eds. Clinical Environmental Health and Toxic Exposures. 2nd ed. Phil-
of Air Pollution and Health. Boston, Mass: Health Effects Institute; adelphia, Pa: Lippincott Williams & Wilkins; 2001:818 – 832.
2003:9 –24. 33. Spengler J, Schwab M, Ryan PB, et al. Personal exposure to nitrogen
9. US Environmental Protection Agency. Peak air quality statistics for the dioxide in the Los Angeles Basin. J Air Waste Manage Assoc. 1994;44:
six principal pollutants by metropolitan statistical area, 2002 (Table). 39 – 47.
Available at: http://www.epa.gov/airtrends/msafactbook-db.pdf. 34. Marbury MC, Harlos DP, Samet JM, et al. Indoor residential NO2
Accessed April 12, 2004. concentrations in Albuquerque, New Mexico. JAPCA. 1988;38:
10. Gustavsson P, Plato N, Hallqvist J, et al, for the Stockholm Heart 392–398.
Epidemiology Program (SHEEP) study group. A population-based case- 35. Leaderer BP. Air pollutant emissions from kerosene space heaters.
referent study of myocardial infarction and occupational exposure to Science. 1982;218:1113–1115.
motor exhaust, other combustion products, organic solvents, lead, and 36. Borland C, Higenbottam T. Nitric oxide yields of contemporary UK, US
dynamite. Epidemiology. 2001;12:222–228. and French cigarettes. Int J Epidemiol. 1987;16:31–34.
11. Peters A, Dockery DW, Muller JE, et al. Increased particulate air 37. Smith W, Anderson T, Anderson HA, et al. Nitrogen dioxide and carbon
pollution and the triggering of myocardial infarction. Circulation. 2001; monoxide intoxication in an indoor ice arena: Wisconsin, 1992. MMWR
103:2810 –2815. Morb Mortal Wkly Rep. 1992;41:383–385.
12. Sullivan J, Ishikawa N, Sheppard L, et al. Exposure to ambient fine 38. Karlson-Stiber C, Höjer J, Sjöholm Ö, et al. Nitrogen dioxide pneu-
particulate matter and primary cardiac arrest in persons with and without monitis in ice hockey players. J Intern Med. 1996;239:451– 456.
clinically recognized heart disease. Am J Epidemiol. 2003;157:501–509. 39. Hampson NB, Norkool DM. Carbon monoxide poisoning in children
13. Levy D, Sheppard L, Checkoway H, et al. A case-crossover analysis of riding in the back of pickup trucks. JAMA. 1992;267:538 –540.
particulate matter air pollution and out-of-hospital primary cardiac 40. Hagberg M, Kolmodin-Hedman B, Lindahl R, et al. Irritative com-
arrest. Epidemiology. 2001;12:193–199. plaints, carboxyhemoglobin increase and minor ventilatory function
14. Suwa T, Hogg JC, Quinlan KB, et al. Particulate air pollution induces changes due to exposure to chain-saw exhaust. Eur J Respir Dis. 1985;
progression of atherosclerosis. J Am Coll Cardiol. 2002;39:935–942. 66:240 –247.
15. Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable 41. Harrison RM. Measurements of concentrations of air pollutants. In:
patient: a call for new definitions and risk assessment strategies: part I. Holgate ST, Samet JM, Koren HS, et al, eds. Air Pollution and Health.
Circulation. 2003;108:1664 –1672. San Diego, Calif: Academic Press; 1999:63– 81.
16. Donaldson K, Stone V, Seaton A, et al. Ambient particle inhalation and 42. Seger DL, Welch LW. Carbon monoxide. In: Sullivan JB, Krieger GR,
the cardiovascular system: potential mechanisms. Environ Health eds. Clinical Environmental Health and Toxic Exposures. 2nd ed. Phil-
Perspect. 2001;109(suppl 4):523–527. adelphia, Pa: Lippincott Williams & Wilkins; 2001:722–727.
17. Pekkanen J, Peters A, Hoek G, et al. Particulate air pollution and risk of 43. Lipsett MJ. Ozone. In: Sullivan JB, Krieger GR, eds. Clinical Environ-
ST-segment depression during repeated submaximal exercise tests mental Health and Toxic Exposures. 2nd ed. Philadelphia, Pa: Lippincott
among subjects with coronary heart disease: the Exposure and Risk Williams & Wilkins; 2001:806 – 818.
Assessment for Fine and Ultrafine Particles in Ambient Air (ULTRA) 44. World Health Organization. Air Quality Guidelines for Europe. WHO
study. Circulation. 2002;106:933–938. Regional Publications, European Series No. 23. Copenhagen, Denmark:
18. Peters A, Liu E, Verrier RL, et al. Air pollution and incidence of cardiac World Health Organization; 1987.
arrhythmia. Epidemiology. 2000;11:11–17. 45. US Environmental Protection Agency, Office of Research and Devel-
19. Spengler JD. Long-term measurements of respirable sulfates and par- opment, National Center for Environmental Assessment. Air Quality
ticles inside and outside homes. Atmos Environ. 1981;15:23–30. Criteria for Ozone and Related Photochemical Oxidants. Washington,
20. Glantz SA, Parmley WW. Passive smoking and heart disease: mech- DC: US Environmental Protection Agency; 1996. Publication No. EPA/
anisms and risk. JAMA. 1995;273:1047–1053. 600/P-93/004a-cF. Available at: http://cfpub.epa.gov/ncea/cfm/rec-
21. Celermajer DS, Adams MR, Clarkson P, et al. Passive smoking and ordisplay.cfm?deid⫽2831. Accessed April 15, 2004.
impaired endothelium-dependent arterial dilatation in healthy young 46. Lioy PJ, Dyba RV. Tropospheric ozone: the dynamics of human
adults. N Engl J Med. 1996;334:150 –154. exposure. Toxicol Ind Health. 1989;5:493–504.
22. Woo KS, Chook P, Leong HC, et al. The impact of heavy passive 47. US Department of Health and Human Services. The Health Conse-
smoking on arterial endothelial function in modernized Chinese. J Am quences of Involuntary Smoking: A Report of the Surgeon General.
Coll Cardiol. 2000;36:1228 –1232. Washington, DC: US Department of Health and Human Services; 1986.
23. Penn A, Snyder CA. Inhalation of sidestream cigarette smoke accel- 48. US Environmental Protection Agency, Office of Research and Devel-
erates development of arteriosclerotic plaques. Circulation. 1993;88(pt opment, Office of Health and Environmental Assessment. Respiratory
1):1820 –1825. Health Effects of Passive Smoking (Also Known as Exposure to Sec-
24. Zhu BQ, Sun YP, Sievers RE, et al. Exposure to environmental tobacco ondhand Smoke or Environmental Tobacco Smoke—ETS). Washington,
smoke increases myocardial infarct size in rats. Circulation. 1994;89: DC: US Environmental Protection Agency; 1992. Publication No. EPA/
1282–1290. 600/6-90/006F. Available at: http://cfpub.epa.gov/ncea/cfm/rec-
25. Penn A, Chen LC, Snyder CA. Inhalation of steady-state sidestream ordisplay.cfm?deid⫽2835. Accessed April 15, 2004.
smoke from one cigarette promotes atherosclerotic plaque development. 49. California Environmental Protection Agency (Cal/EPA). Health Effects
Circulation. 1994;90:1363–1367. of Exposure to Environmental Tobacco Smoke. National Cancer Institute
26. Seinfeld JH, Pandis SN. Atmospheric Chemistry and Physics: From Air Smoking and Tobacco Control Monographs, No. 10. Available at: http://
Pollution to Climate Change. New York, NY: John Wiley & Sons; cancercontrol.cancer.gov/tcrb/monographs/10/. Accessed April 13,
1998:1–1326. 2004.
27. Daigle CC, Chalupa DC, Gibb FR, et al. Ultrafine particle deposition in 50. Schwartz J. Secondhand smoke finding struck down. Washington Post.
humans during rest and exercise. Inhal Toxicol. 2003;15:539 –552. Sunday, July 19, 1998: A1.
51. Wells AJ. Heart disease from passive smoking in the workplace. J Am 75. Bates DV, Sizto R. Air pollution and hospital admissions in Southern
Coll Cardiol. 1998;31:1–9. Ontario: the acid summer haze effect. Environ Res. 1987;43:317–331.
52. Thun M, Henley J, Apicella L. Epidemiologic studies of fatal and 76. Bates DV, Sizto R. Relationship between air pollutant levels and
nonfatal cardiovascular disease and ETS from spousal smoking. Environ hospital admissions in Southern Ontario. Can J Public Health. 1983;74:
Health Perspect. 1999;107(suppl 6):841– 846. 117–122.
53. He J, Vupputuri S, Allen K, et al. Passive smoking and the risk of 77. Brunekreef B, Holgate ST. Air pollution and health. Lancet. 2002;360:
coronary heart disease: a meta-analysis of epidemiologic studies. N Engl 1233–1242.
J Med. 1999;340:920 –926. 78. Pope CA. Epidemiology of fine particulate air pollution and human
54. Kawachi I, Colditz GA. Workplace exposure to passive smoking and health: biologic mechanisms and who’s at risk? Environ Health
risk of cardiovascular disease: summary of epidemiologic studies. Perspect. 2000;108:713–723.
Environ Health Perspect. 1999;107(suppl 6):847– 851. 79. Brook RD, Brook JR, Rajagopalan S. Air pollution: the “heart” of the
55. Howard G, Wagenknecht LE. Environmental tobacco smoke and problem. Curr Hypertens Rep. 2003;5:32–39.
measures of subclinical vascular disease. Environ Health Perspect. 80. HEI Health Review Committee and Scientific Staff. Understanding the
1999;107(suppl 6):837– 840. health effects of components of the particulate matter mix: progress and
56. Otsuka R, Watanabe H, Hirata K, et al. Acute effects of passive smoking next steps. HEI Perspectives. Cambridge, Mass: Health Effects Institute;
on the coronary circulation in healthy young adults. JAMA. 2001;286: April 2002. Available at: http://www.healtheffects.org/Pubs/
436 – 441. Perspectives-2.pdf. Accessed April 15, 2004.
57. You RX, Thrift AG, McNeil JJ, et al, for the Melbourne Stroke Risk 81. Dockery DW, Pope CA, Xu X, et al. An association between air
Factor Study (MERFS) Group. Ischemic stroke risk and passive pollution and mortality in six US cities. N Engl J Med. 1993;329:
exposure to spouses’ cigarette smoking. Am J Public Health. 1999;89: 1753–1759.
572–575. 82. Pope CA, Thun MJ, Namboodiri MM, et al. Particulate air pollution as
58. Bonita R, Duncan J, Truelsen T, et al. Passive smoking as well as active a predictor of mortality in a prospective study of U.S. adults. Am J
smoking increases the risk of acute stroke. Tob Control. 1999;8: Respir Crit Care Med. 1995;151(pt 1):669 – 674.
156 –160. 83. Hoek G, Brunekreef B, Goldbohm S, et al. Association between mor-
59. Howard G, Wagenknecht LE, Cai J, et al. Cigarette smoking and other tality and indicators of traffic-related air pollution in the Netherlands: a
risk factors for silent cerebral infarction in the general population. cohort study. Lancet. 2002;360:1203–1209.
Stroke. 1998;29:913–917. 84. Katsouyanni K, Touloumi G, Samoli E, et al. Confounding and effect
60. Sargent R, Shepard RM, Glantz SA. Reduced incidence of admissions modification in the short-term effects of ambient particles on total
for myocardial infarction associated with smoking ban: before and after mortality: results from 29 European cities within the APHEA2 Project.
study. BMJ. 2004;328:977–980. Epidemiology. 2001;12:521–531.
61. Howard G, Thun MJ. Why is environmental tobacco smoke more 85. Zanobetti A, Schwartz J, Samoli E, et al. The temporal pattern of
strongly associated with coronary heart disease than expected? A review
respiratory and heart disease mortality in response to air pollution.
of potential biases and experimental data. Environ Health Perspect.
Environ Health Perspect. 2003;111:1188 –1193.
1999;107(suppl 6):853– 858.
86. Schwartz J. Harvesting and long term exposure effects in the relation
62. Centers for Disease Control and Prevention, National Center for Health
between air pollution and mortality. Am J Epidemiol. 2000;151:
Statistics. Early Release of Selected Estimates Based on Data From the
440 – 448.
January–March 2003 National Health Interview Survey. Available at:
87. Dominici F, McDermott A, Zeger SL, et al. Airborne particulate matter
http://www.cdc.gov/nchs/data/nhis/earlyrelease/200309_08.pdf.
and mortality: timescale effects in four US cities. Am J Epidemiol.
Accessed April 13, 2004.
2003;157:1055–1065.
63. Pirkle JL, Flegal KM, Bernert JT, et al. Exposure of the US population
88. Schwartz J. The distributed lag between air pollution and daily deaths.
to environmental tobacco smoke: the Third National Health and
Epidemiology. 2000;11:320 –326.
Nutrition Examination Survey, 1988 to 1991. JAMA. 1996;275:
89. Linn WS, Szlachcic Y, Gong H, et al. Air pollution and daily hospital
1233–1240.
admissions in metropolitan Los Angeles. Environ Health Perspect.
63a.Centers for Disease Control and Prevention. Second National Report on
Human Exposure to Environmental Chemicals. Revised March 2003. 2000;108:427– 434.
NCEH Pub. No. 02-0716. Available at: http://www.cdc.gov/exposurere- 90. Wong TW, Lau TS, Yu TS, et al. Air pollutions and hospital admissions
port/. Accessed May 12, 2004. for respiratory and cardiovascular diseases in Hong Kong. Occup
64. State-specific prevalence of current cigarette smoking among adults and Environ Med. 1999;56:679 – 683.
the proportion of adults who work in a smoke-free environment: United 91. Zanobetti A, Schwartz J, Dockery DW. Airborne particles are a risk
States, 1999. MMWR Morb Mortal Wkly Rep. 2000;49:978 –982. factor for hospital admissions for heart and lung disease. Environ Health
65. Gerlach KK, Shopland DR, Hartman AM, et al. Workplace smoking Perspect. 2000;108:1071–1077.
policies in the United States: results from a national survey of more than 92. Delfino RJ, Murphy-Moulton AM, Burnett RT, et al. Effects of air
100,000 workers. Tob Control. 1997;6:199 –206. pollution on emergency room visits for respiratory illnesses in Montreal,
66. Shopland DR, Gerlach KK, Burns DM, et al. State-specific trends in Quebec. Am J Respir Crit Care Med. 1997;155:568 –576.
smoke-free workplace policy coverage: the current population survey 93. Schwartz J, Slater D, Larson TV, et al. Particulate air pollution and
tobacco use supplement, 1993 to 1999. J Occup Environ Med. 2001;43: hospital emergency room visits for asthma in Seattle. Am Rev Respir
680 – 686. Dis. 1993;147:826 – 831.
67. Wells AJ. Passive smoking as a cause of heart disease. J Am Coll 94. Schwartz J, Dockery DW, Neas LM, et al. Acute effects of summer air
Cardiol. 1994;24:546 –554. pollution on respiratory symptom reporting in children. Am J Respir Crit
68. Smoking-attributable mortality and years of potential life lost: United Care Med. 1994;150(pt 1):1234 –1242.
States, 1984. MMWR Morb Mortal Wkly Rep. 1997;46:444 – 451. 95. Timonen KL, Pekkanen J. Air pollution and respiratory health among
69. Nemery B, Hoet PH, Nemmar A. The Meuse Valley Fog of 1930: an air children with asthmatic or cough symptoms. Am J Respir Crit Care
pollution disaster. Lancet. 2001;357:704 –708. Med. 1997;156(pt 1):546 –552.
70. Logan WP. Mortality in the London fog incident, 1952. Lancet. 1953; 96. Burnett RT, Smith-Doiron M, Steib D, et al. Effects of particulate and
1:336 –338. gaseous air pollution on cardiorespiratory hospitalizations. Arch Environ
71. Schwartz J, Dockery DW. Particulate air pollution and daily mortality in Health. 1999;54:130 –139.
Steubenville, Ohio [published erratum appears in Am J Epidemiol. 97. Schwartz J. Air pollution and hospital admissions for heart disease in
1995;141:87]. Am J Epidemiol. 1992;135:12–19, discussion 20 –25. eight US counties. Epidemiology. 1999;10:17–22.
72. Ozkaynak H, Thurston GD. Associations between 1980 U.S. mortality 98. Hoek G, Brunekreef B, Fischer P, et al. The association between air
rates and alternative measures of airborne particle concentration. Risk pollution and heart failure, arrhythmia, embolism, thrombosis, and other
Anal. 1987;7:449 – 461. cardiovascular causes of death in a time series study. Epidemiology.
73. Pope CA, Schwartz J, Ransom MR. Daily mortality and PM10 pollution 2001;12:355–357.
in Utah Valley. Arch Environ Health. 1992;47:211–217. 99. Morris RD. Airborne particulates and hospital admissions for cardio-
74. Schwartz J. Particulate air pollution and daily mortality in Detroit. vascular disease: a quantitative review of the evidence. Environ Health
Environ Res. 1991;56:204 –213. Perspect. 2001;109(suppl 4):495–500.
100. Ibald-Mulli A, Stieber J, Wichmann HE, et al. Effects of air pollution on 125. Li XY, Gilmour PS, Donaldson K, et al. Free radical activity and
blood pressure: a population-based approach. Am J Pub Health. 2001; pro-inflammatory effects of particulate air pollution (PM10) in vivo and
91:571–577. in vitro. Thorax. 1996;51:1216 –1222.
101. Hong YC, Lee JT, Kim H, et al. Air pollution: a new risk factor in 126. Ghio A, Devlin R. Inflammatory lung injury after bronchial instillation
ischemic stroke mortality. Stroke. 2002;33:2165–2169. of air pollution particles. Am J Respir Crit Care Med. 2001;164:
102. Tsai SS, Goggins WB, Chiu HF, et al. Evidence for an association 704 –708.
between air pollution and daily stroke admissions in Kaohsiung, Taiwan. 127. Donaldson K, Brown DM, Mitchell C, et al. Free radical activity of
Stroke. 2003;34:2612–2616. PM10: iron-mediated generation of hydroxyl radicals. Environ Health
103. Goldberg MS, Burnett RT, Bailar JC, et al. Identification of persons with Perspect. 1997;105(suppl 5):1285–1289.
cardiorespiratory conditions who are at risk of dying from the acute 128. Jiang N, Dreher KL, Dye JA, et al. Residual oil fly ash induces cyto-
effects of ambient air particles. Environ Health Perspect. 2001; toxicity and mucin secretion by guinea pig tracheal epithelial cells via an
109(suppl 4):487– 494. oxidant-mediated mechanism. Toxicol Appl Pharmacol. 2000;163:
104. Zanobetti A, Schawart J. Are diabetics more susceptible to the health 221–230.
effects of airborne particles? Am J Respir Crit Care Med. 2001;164: 129. Brown DM, Stone V, Findlay P, et al. Increased inflammation and
831– 833. intracellular calcium caused by ultrafine carbon black is independent of
transition metals or other soluble components. Occup Environ Med.
105. Goldberg MS, Burnett R, Bailar JC, et al. The association between daily
2000;57:685– 691.
mortality and ambient air particle pollution in Montreal, Quebec: 2:
130. Frampton MW, Pryor WA, Cueto R, et al. Ozone exposure increases
cause-specific mortality. Environ Res. 2001;86:26 –36.
aldehydes in epithelial lining fluid in human lung. Am J Respir Crit Care
106. Elliot RS, Edwards JE. Pathology of congenital heart disease. In: Hurst
Med. 1999;159(pt 1):1134 –1137.
JW, ed. The Heart. 4th ed. New York, NY: McGraw-Hill; 1978.
131. Samet JM, Hatch GE, Horstman D, et al. Effect of antioxidant supple-
107. Congenital Heart Disease Study Group. Primary prevention of con-
mentation on ozone-induced lung injury in human subjects. Am J Respir
genital heart disease. In: Wright IS, Fredrickson DT, eds. Cardiovascu-
Crit Care Med. 2001;164:819 – 825.
lar Diseases: Guidelines for Prevention and Care. Inter-Society Com- 132. Shukla A, Timblin C, BeruBe K, et al. Inhaled particulate matter causes
mission for Heart Disease Resources. Washington, DC: Government expression of nuclear factor (NF)-kappaB–related genes and oxidant-
Printing Office; 1972:116. dependent NF-kappaB activation in vitro. Am J Respir Cell Mol Biol.
108. Higgins IT. The epidemiology of congenital heart disease. J Chronic 2000;23:182–187.
Dis. 1965;18:699 –721. 133. Sorensen M, Daneshvar B, Hansen M, et al. Personal PM2.5 exposure
109. Nora JJ. Etiologic factors in congenital heart diseases. Pediatr Clin and markers of oxidative stress in blood. Environ Health Perspect.
North Am. 1971;18:1059 –1074. 2003;111:161–166.
110. Alberman ED, Goldstein H. Possible teratogenic effect of cigarette 134. Gurgueira SA, Lawrence J, Coull B, et al. Rapid increases in the
smoking. Nature. 1971;231:529 –530. steady-state concentration of reactive oxygen species in the lungs and
111. Rose V, Gold RJ, Lindsay G, et al. A possible increase in the incidence heart after particulate air pollution inhalation. Environ Health Perspect.
of congenital heart defects among the offspring of affected parents. J Am 2002;110:749 –755.
Coll Cardiol. 1985;6:376 –382. 135. Dellinger B, Pryor WA, Cueto R, et al. Role of free radicals in the
112. Smrcka V, Leznarova D. Environmental pollution and the occurrence of toxicity of airborne fine particulate matter. Chem Res Toxicol. 2001;14:
congenital defects in a 15-year period in a south Moravian district. Acta 1371–1377.
Chir Plast. 1998;40:112–114. 136. Li N, Sioutas C, Cho A, et al. Ultrafine particulate pollutants induce
113. Norska-Borowka I, Bursa J. Infant morbidity and mortality in a region oxidative stress and mitochondrial damage. Environ Health Perspect.
of ecological disaster. Folia Med Cracov. 1993;34:73– 83. 2003;111:455– 460.
114. Antipenko EN, Kogut NN. The results of an epidemiological study of 137. Monn C, Becker S. Cytotoxicity and induction of proinflammatory
congenital developmental defects in children in cities with different cytokines from human monocytes exposed to fine (PM2.5) and coarse
levels of atmospheric pollution. Russian. Vestn Ross Akad Med Nauk. particles (PM10-2.5) in outdoor and indoor air. Toxicol Appl Pharmacol.
1993;3:32–36. 1999;155:245–252.
115. Ritz B, Yu F, Fruin S, et al. Ambient air pollution and risk of birth 138. Becker S, Soukup JM. Exposure to urban air particulates alters the
defects in Southern California. Am J Epidemiol. 2002;155:17–25. macrophage-mediated inflammatory response to respiratory viral
116. Krewski D, Burnett RT, Goldberg MS, et al. Reanalysis of the Harvard infection. J Toxicol Environ Health A. 1999;57:445– 457.
Six Cities Study and the American Cancer Society Study of Particulate 139. Michel O, Nagy AM, Schroeven M, et al. Dose-response relationship to
Air Pollution and Mortality. Cambridge, Mass: Health Effects Institute; inhaled endotoxin in normal subjects. Am J Respir Crit Care Med.
2000. 1997;156(pt 1):1157–1164.
117. Clancy L, Goodman P, Sinclair H, et al. Effects of air-pollution control 140. Vogelzang PF, van der Gulden JW, Folgering H, et al. Endotoxin
on death rates in Dublin, Ireland: an intervention study. Lancet. 2002; exposure as a major determinant of lung function decline in pig farmers.
Am J Respir Crit Care Med. 1998;157:15–18.
360:1210 –1214.
141. Soukup JM, Becker S. Human alveolar macrophage responses to air
118. Kelly FJ. Oxidative stress: its role in air pollution and adverse health
pollution particulates are associated with insoluble components of
effects. Occup Environ Med. 2003;60:612– 616.
coarse material, including particulate endotoxin. Toxicol Appl
119. Ghio AJ, Kim C, Devlin RB. Concentrated ambient air particles induce
Pharmacol. 2001;171:20 –26.
mild pulmonary inflammation in healthy human volunteers. Am J Respir
142. Monn C, Naef R, Koller T. Reactions of macrophages exposed to
Crit Care Med. 2000;162(pt 1):981–988.
particles ⬍10 microm. Environ Res. 2003;91:35– 44.
120. Aris RM, Christian D, Hearne PQ, et al. Ozone-induced airway inflam-
143. Veronesi B, Oortgiesen M, Roy J, et al. Vanilloid (capsaicin) receptors
mation in human subjects as determined by airway lavage and biopsy. influence inflammatory sensitivity in response to particulate matter.
Am Rev Respir Dis. 1993;148:1363–1372. Toxicol Appl Pharmacol. 2000;169:66 –76.
121. Godleski JJ, Clarke RW, Coull BA, et al. Composition of inhaled urban 144. Salvi S, Blomberg A, Rudell B, et al. Acute inflammatory responses in
air particles determines acute pulmonary responses. Ann Occup Hyg. the airways and peripheral blood after short-term exposure to diesel
2002;46(suppl 1):419 – 424. exhaust in healthy human volunteers. Am J Respir Crit Care Med.
122. Costa DL, Dreher KL. Bioavailable transition metals in particulate 1999;159:702–709.
matter mediate cardiopulmonary injury in healthy and compromised 145. Nightingale JA, Maggs R, Cullinan P, et al. Airway inflammation after
animal models. Environ Health Perspect. 1997;105(suppl controlled exposure to diesel exhaust particulates. Am J Respir Crit Care
5):1053–1060. Med. 2000;162:161–166.
123. Kennedy T, Ghio AJ, Reed W, et al. Copper-dependent inflammation 146. Salvi SS, Nordenhall C, Blomberg A, et al. Acute exposure to diesel
and nuclear factor-kappaB activation by particulate air pollution. Am J exhaust increases IL-8 and GRO-alpha production in healthy human
Respir Cell Mol Biol. 1998;19:366 –378. airways. Am J Respir Crit Care Med. 2000;161(pt 1):550 –557.
124. Brain JD, Long NC, Wolfthal SF, et al. Pulmonary toxicity in hamsters 147. Ghio AJ, Hall A, Bassett MA, et al. Exposure to concentrated ambient
of smoke particles from Kuwaiti oil fires. Environ Health Perspect. particles alters hematologic indices in humans. Inhal Toxicol. 2003;15:
1998;106:141–146. 1465–1478.
148. Tan WC, Qiu D, Liam BL, et al. The human bone marrow response to 173. Zanobetti A, Schwartz J, Sher D, et al. Blood pressure and heart rate
acute air pollution caused by forest fires. Am J Respir Crit Care Med. associated with PM2.5 in a cardiac rehabilitation study. Presented at:
2000;161(pt 1):1213–1217. American Thoracic Society 98th Annual Conference; May 17–23, 2002,
149. Mukae H, Vincent R, Quinlan K, et al. The effect of repeated exposure Atlanta, Ga.
to particulate air pollution (PM10) on the bone marrow. Am J Respir Crit 174. Linn WS, Gong H, Clark KW, et al. Day-to-day particulate exposures
Care Med. 2001;163:201–209. and health changes in Los Angeles area residents with severe lung
150. Seaton A, MacNee W, Donaldson K, et al. Particulate air pollution and disease. J Air Waste Manag Assoc. 1999;49(9 Spec No):108 –115.
acute health effects. Lancet. 1995;345:176 –178. 175. Wellenius GA, Coull BA, Godleski JJ, et al. Inhalation of concentrated
151. Junker R, Heinrich J, Ulbrich H, et al. Relationship between plasma ambient air particles exacerbates myocardial ischemia in conscious
viscosity and the severity of coronary heart disease. Arterioscler Thromb dogs. Environ Health Perspect. 2003;111:402– 408.
Vasc Biol. 1998;18:870 – 875. 176. Task Force of the European Society of Cardiology and the North
152. Peters A, Döring A, Wichmann HE, et al. Increased plasma viscosity American Society of Pacing and Electrophysiology. Heart rate vari-
during an air pollution episode: a link to mortality? Lancet. 1997;349: ability: standards of measurement, physiological interpretation, and
1582–1587. clinical use. Circulation. 1996;93:1043–1065.
153. Seaton A, Soutar A, Crawford V, et al. Particulate air pollution and the 177. Pope CA, Verrier RL, Lovett EG, et al. Heart rate variability associated
blood. Thorax. 1999;54:1027–1032. with particulate air pollution. Am Heart J. 1999;138(pt 1):890 – 899.
154. Peters A, Perz S, Döring A, et al. Activation of the autonomic nervous 178. Liao D, Creason J, Shy C, et al. Daily variation of particulate air
system and blood coagulation in association with an air pollution pollution and poor cardiac autonomic control in the elderly. Environ
episode. Inhal Toxicol. 2000;12:51– 61. Health Perspect. 1999;107:521–525.
155. Lind P, Hedblad B, Stavenow L, et al. Influence of plasma fibrinogen 179. Magari SR, Hauser R, Schwartz J, et al. Association of heart rate
levels on the incidence of myocardial infarction and death is modified by variability with occupational and environmental exposure to particulate
other inflammation-sensitive proteins: a long-term cohort study. Arte- air pollution. Circulation. 2001;104:986 –991.
rioscler Thromb Vasc Biol. 2001;21:452– 458. 180. Creason J, Neas L, Walsh D, et al. Particulate matter and heart rate
156. Nemmar A, Hoet PH, Dinsdale D, et al. Diesel exhaust particles in lung variability among elderly retirees: the Baltimore 1998 PM study. J Expo
acutely enhance experimental peripheral thrombosis. Circulation. 2003; Anal Environ Epidemiol. 2001;11:116 –122.
107:1202–1208. 181. Gold DR, Litonjua A, Schwartz J, et al. Ambient pollution and heart rate
157. Nemmar A, Hoylaerts MF, Hoet PH, et al. Ultrafine particles affect variability. Circulation. 2000;101:1267–1273.
experimental thrombosis in an in vivo hamster model. Am J Respir Crit 182. Devlin RB, Ghio AJ, Kehrl H, et al. Elderly humans exposed to con-
Care Med. 2002;166:998 –1004. centrated air pollution particles have decreased heart rate variability. Eur
158. Ridker PM, Rifai N, Stampfer MJ, et al. Plasma concentration of Respir J. 2003;21(suppl 40):76 – 80.
interleukin-6 and the risk of future myocardial infarction among 183. Campen MJ, Costa DL, Watkinson WP. Cardiac and thermoregulatory
apparently healthy men. Circulation. 2000;101:1767–1772. toxicity of residual oil fly ash in cardiopulmonary-compromised rats.
159. Lindmark E, Diderholm E, Wallentin L, et al. Relationship between Inhal Toxicol. 2000;12(suppl 2):7–22.
interleukin 6 and mortality in patients with unstable coronary artery 184. Godleski JJ, Verrier RL, Koutrakis P, et al. Mechanisms of morbidity
disease: effects of an early invasive or noninvasive strategy. JAMA. and mortality from exposure to ambient air particles. Res Rep Health Eff
2001;286:2107–2113. Inst. 2000;91:5– 88; discussion 89 –103.
160. Volpato S, Guralnik JM, Ferrucci L, et al. Cardiovascular disease, 185. Wellenius GA, Saldiva PH, Batalha JR, et al. Electrocardiographic
interleukin-6, and risk of mortality in older women: the Women’s Health changes during exposure to residual oil fly ash (ROFA) particles in a rat
and Aging Study. Circulation. 2001;103:947–953. model of myocardial infarction. Toxicol Sci. 2002;66:327–335.
161. van Eeden SF, Tan WC, Suwa T, et al. Cytokines involved in the 186. US Environmental Protection Agency, Office of Research and Devel-
systemic inflammatory response induced by exposure to particulate opment, National Center for Environmental Assessment, Research
matter air pollutants (PM10). Am J Respir Crit Care Med. 2001;164: Triangle Park Office. Air Quality Criteria for Particulate Matter
826 – 830. (Fourth External Review Draft). Research Triangle Park, NC: US Envi-
162. Toss H, Lindahl B, Siegbahn A, et al, for the FRISC study group: ronmental Protection Agency; 2003. Publication No. EPA/600/P-
Fragmin during Instability in Coronary Artery Disease. Prognostic 99/002aD and bD. Available at: http://cfpub.epa.gov/ncea/cfm/rec-
influence of increased fibrinogen and C-reactive protein levels in ordisplay.cfm?deid⫽58003. Accessed April 15, 2004.
unstable coronary artery disease. Circulation. 1997;96:4204 – 4210. 187. Kunzli N, Kaiser R, Medina S, et al. Public-health impact of outdoor and
163. Ridker PM. High-sensitivity C-reactive protein: potential adjunct for traffic-related air pollution: a European assessment. Lancet. 2000;356:
global risk assessment in the primary prevention of cardiovascular 795– 801.
disease. Circulation. 2001;103:1813–1818. 188. Burnett RT, Cakmak S, Brook JR. The effect of the urban ambient air
164. Peters A, Fröhlich M, Döring A, et al. Particulate air pollution is pollution mix on daily mortality rates in 11 Canadian cities. Can J
associated with an acute phase response in men: results from the Public Health. 1998;89:152–156.
MONICA-Augsburg study. Eur Heart J. 2001;22:1198 –1204. 189. Routledge HC, Ayres JG, Townend JN. Why cardiologists should be
165. Fichtlscherer S, Rosenberger G, Walter DH, et al. Elevated C-reactive interested in air pollution. Heart. 2003;89:1383–1388.
protein levels and impaired endothelial vasoreactivity in patients with 189a.World Health Organization. World Health Report 2002. Geneva: World
coronary artery disease. Circulation. 2000;102:1000 –1006. Health Organization; 2002. Available at: http:www.who.int/whr/
166. Bhatt DL, Topol EJ. Need to test the arterial inflammation hypothesis. 2002/en/. Accessed May 12, 2004.
Circulation. 2002;106:136 –140. 190. Available at: http://www.epa.gov/oarpg/t1/.
167. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Cir- 191. US Environmental Protection Agency. Final Report to Congress on
culation. 2002;105:1135–1143. Benefits and Costs of the Clean Air Act, 1990 to 2010. Washington, DC:
168. Brook RD, Brook JR, Urch B, et al. Inhalation of fine particulate air US Environmental Protection Agency; 1999. Publication No. EPA410-
pollution and ozone causes acute arterial vasoconstriction in healthy R-99-001. Available at: http://www.epa.gov/oar/sect812/. Accessed
adults. Circulation. 2002;105:1534 –1536. April 13, 2004.
169. Batalha JR, Saldiva PH, Clarke RW, et al. Concentrated ambient air 192. US Environmental Protection Agency, Office of Air Quality Planning
particles induce vasoconstriction of small pulmonary arteries in rats. and Standards. Review of the National Ambient Air Quality Standards
Environ Health Perspect. 2002;110:1191–1197. for Particulate Matter: Policy Assessment of Scientific and Technical
170. Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker Information. OAQPS Staff Paper—First Draft. Research Triangle Park,
of atherosclerotic risk. Arterioscler Thromb Vasc Biol. 2003;23: NC: US Environmental Protection Agency; 2003. Publication No. EPA-
168 –175. 452/D-03-001.
171. Ikeda M, Watarai K, Suzuki M, et al. Mechanism of pathophysiological 193. Kriebel D, Tickner J, Epstein P, et al. The precautionary principle in
effects of diesel exhaust particles on endothelial cells. Environ Toxicol environmental science. Environ Health Perspect. 2001;109:871– 876.
Pharm. 1998;6:117–123. 194. National Research Council (NRC), Committee on Research Priorities for
172. Bouthillier L, Vincent R, Goegan P, et al. Acute effects of inhaled urban Airborne Particulate Matter. Research Priorities for Airborne Par-
particles and ozone: lung morphology, macrophage activity, and plasma ticulate Matter, Vol. 1: Immediate Priorities and a Long-Range
endothelin-1. Am J Pathol. 1998;153:1873–1884. Research Portfolio. Washington, DC: National Academy Press; 1998.
Air Pollution and Cardiovascular Disease: A Statement for Healthcare Professionals From
the Expert Panel on Population and Prevention Science of the American Heart Association
Robert D. Brook, Barry Franklin, Wayne Cascio, Yuling Hong, George Howard, Michael
Lipsett, Russell Luepker, Murray Mittleman, Jonathan Samet, Sidney C. Smith, Jr and Ira Tager
Circulation. 2004;109:2655-2671
doi: 10.1161/01.CIR.0000128587.30041.C8
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AHA Scientific Statement

Air Pollution and Cardiovascular Disease

cles” [PM2.5] ⬍2.5 ␮m, and “coarse particles” [PM10 to 2.5]).

Figure 1. Particulate matter air pollution

little accumulation of O3. However, many reactive organic

demonstrated that chronic exposure to air pollutants is inde-

Figure 2. Possible biological mecha-

dysrhythmias, acute vascular dysfunction, plaque instability,

and in the national media. The EPA is working to increase the

Reprints: Information about reprints can be found online at:

Subscriptions: Information about subscribing to Circulation is online at:

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