CARDIOVASCULAR EFFECTS OF AIR POLLUTANTS
The effects of air pollution on cardiovascular disease is a relative new area of research. Historically, air pollution has not been regarded a significant risk factor for cardiovascular disease, but the World Health Organization estimates that >7 million premature deaths each year can be attributed to urban outdoor and indoor air pollution. Short-term exposure to high levels of particulate matter (PM), especially fine particles of <2.5 µm, has been found to trigger cardiovascular mortality due to myocardial infarction and heart failure. Long-term exposure increases the risk of cardiovascular mortality and reduces life expectancy. Reductions in PM exposure are associated with decreases in mortality. A growing body of evidence has linked PM to increased systemic inflammation, oxidative stress, thrombosis, cardiac ischemia, and heart rate variability. Further investigation of PM and other air pollutants is required to better understand their effects on cardiovascular disease. This will allow development of treatment and optimized prevention strategies in the future.
During the 20th century, three notable extreme air pollution episodes
focused the attention of the public and governments on the adverse public
health impact of air pollution. These events occurred in the Meuse Valley,
Belgium; Donora, Pennsylvania; and London, England, as a consequence of weather
conditions that trapped combustion products and other pollutants from coal
fires, vehicles, power plants, and industrial emissions in the air. The best
known of these events was the Great London smog. In 1952, a cold air inversion
trapped combustion products of the entire city of 8.3 million persons and its
industry, resulting in an extreme air pollution episode that claimed >10,000
lives. During this event, daily mortality increased nearly fourfold, and the
mortality rate remained significantly higher than usual for several weeks after
the air pollution event resolved. Surprisingly, the additional deaths that continued
to mount were not explained solely by pulmonary disease, but instead most
deaths were attributed to cardiovascular etiologies.
These important historical events had a profound impact on local and
governmental responses to air pollution and contributed significantly to the
passing of the Clean Air Act (CAA) in the United States in 1970, which has been
updated and modified several times since. Through the CAA, the U.S.
Environmental Protection Agency (EPA) has statutory responsibility to regulate
ambient air pollutants, including particulate matter (PM), sulfur dioxide (SO2),
nitrogen dioxide (NO2), carbon monoxide (CO), ozone (O3),
and lead. The levels of permissible air pollutants are established by the doses
at which a measurable health risk is anticipated, allowing for an adequate
margin of safety. This risk assessment is based on scientific data updated
every 5 years and published as the U.S. National Ambient Air Quality
Integrative Science Assessment. Although urban air pollution continues to be a
significant challenge, the overall quality of air in the United States has
improved continuously since the
implementation of the CAA. The improvement in
air quality has translated into decreased overall mortality and cardiopulmonary
mortality associated with exposure to air pollutants. Yet, despite the
remarkable progress made in air quality, health risks of air pollution remain.
Intermittent increases in air pollution pose challenges, particularly in
vulnerable and sensitive groups, such as older adults, those with low
socioeconomic positions, and in individuals with cardiovascular disease,
obesity, and diabetes mellitus.
PARTICULATE MATTER
Airborne PM is not a single compound but a mixture of materials that have
a carbonaceous core and associated constituents, such as organic compounds,
acids, metals, crustal components, and biological materials, including pollen,
spores, and endotoxins. Combustion processes, such as those in vehicles and
power plants, account for most human-generated PM. Importantly, particles
generated by mechanical processes, wind- blown dust, and wildfires also
contribute to the mass of PM.
Particles are classified based on their size. Ultrafine particles have an
equivalent aerodynamic diameter of <0.1 µm (approximately one one-thousandth
the diameter of a human hair). Fine particles (PM2.5) have a diameter
of ≤2.5 µm. Coarse particles (PM10) have a diameter between 2.5 and
10 µm. Only particles <10 µm in diameter are respirable (Fig. 18.1).
Ultrafine and fine particles are more likely to be produced by combustion,
whereas the coarse particles are more likely to contain crustal and biological
material. Outdoor PM readily penetrates into homes and buildings, depending on
building stock and the use of air conditioning and heating; thus, increases in
outdoor PM can result in increased indoor levels of PM. Cooking, smoking,
dusting, and vacuuming also contribute to indoor PM, although not much is known
about cardiovascular effects induced by exposure to indoor sources of air
pollution in the United States. The U.S. national air quality standard for the
allowable level of PM2.5 averaged over 24 hours is 35 µg/m3,
and the annual average is 12 µg/m3. The standard for PM10
averaged over 24 hours is 150 µg/m3.
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| FIG 18.1 Cardiovascular Effects of Air Pollutants. AV, Atrioventricular; CO, carbon monoxide; NO2, nitrogen dioxide; O3, ozone; SA, sinoatrial; SO2, sulfur dioxide. |
Particle size appears to have an impact on the health effects of PM, with PM2.5 having a stronger association with adverse cardiovascular outcomes than that of PM10, presumably due to deeper penetration of fine particles into the lung. PM air pollution, which has the most data for PM2.5, is associated with acute coronary syndrome (unstable angina and myocardial infarction), deep venous thrombosis, rhythm disturbances, stroke, and worsening of heart failure.
The cardiovascular effects associated with PM exposure can be categorized
as short-term and long-term. Short-term exposure over a few hours to weeks can
trigger cardiovascular disease that can be related to higher mortality and
nonfatal events. The strongest evidence is for ischemic heart disease events,
especially myocardial infarction and heart failure hospitalizations. Long-term
exposure over a few years increases cardiovascular
mortality even more than short-term exposure, and decreases life expectancy.
The causal link between inhaled particles depositing on respiratory
surfaces and cardiovascular health effects has been a topic of investigation
for the past two decades. Exposure to PM can increase heart rate and blood
pressure, and can decrease oxygen saturation within hours. PM also affects
pulmonary oxygen transport and neural modulation of the sinus node and the
vascular system, although the magnitude of these changes is small. An increase
in heart rate might be caused by an increase in sympathetic input to the heart
or a decrease in parasympathetic
input. Exposure to PM decreases cardiac vagal input, as suggested by a decrease
in heart rate variability (HRV). Yet, the association between changes in HRV
and ambient PM concentrations is inconsistent. Whether the differences relate
to the chemical composition of PM, other associated pollutants, age, sex,
genetic background, con- current cardiac disease, medications, or the HRV
methodology is not known. It is also not known whether change in HRV associated
with PM exposure represents an independent measure of risk.
Many epidemiological studies that investigated the associations between
air particle pollution and cardiovascular mortality and morbidity in single cities and multiple cities throughout the world showed concordance that ambient air
particle pollution is associated with increased cardiovascular mortality and
hospitalizations. Two of the most notable studies were the National Morbidity,
Mortality and Air Pollution Study and the Air Pollution and Health: A European
Approach Project. These studies addressed the effects of air pollution in many
U.S. and European cities, and showed that air particle pollution was associated
with an increased relative risk of cardiovascular mortality, ranging from 0.4%
to 1.5% for each 20 µg/m3 increase in PM10. Likewise,
other epidemiological studies linked exposure to PM, particularly
traffic-related particles, to the onset of myocardial infarction or
hospitalization for acute coronary syndrome, stroke, rhythm disturbances, and
heart failure, which were associations that were stronger among individuals
with underlying cardiac disease.
Long-term effects of air pollution were established in three important
cohort studies: the Harvard Six-Cities Study, the American Cancer Society
Study, and the Women’s Health Initiative Observational Study. In contrast to
previous studies, these studies investigated the long-term health effects of
fine PM for several years in multiple cities, characterized by a large gradient
in the concentration and types of air pollution. These studies showed a
positive association between PM2.5 and sulfate, and cardiopulmonary
mortality and cardiovascular events. Subjects who resided in the most heavily
polluted of the Harvard six cities lived on
average 2 years less than those who resided in the least polluted city, after
potential confounding and effect-modifying factors were taken into
consideration.
There are at least three possible mechanisms by which PM induces changes
in cardiac physiology: a neural reflex from afferents in the lung that interact
with PM directly or indirectly through associated pulmonary inflammation;
secondary effects of inflammatory cytokines and acute-phase reactants produced
systemically and in the lung, as well
as coagulation proteins; and direct effects of particles or adsorbed soluble
constituents of PM on cardiac membrane currents responsible for impulse
formation and repolarization. The observations that inhalation of
fine-particulate air pollution and O3 causes arterial
vasoconstriction, and that sympathetic activation reduces
endothelium-dependent, flow- mediated vasodilation, provide a mechanistic link
between the changes in HRV and the changes in vascular reactivity, which are
known risks for cardiac events. Because sudden shifts in neural input to the
heart may be arrhythmogenic, changes in HRV
imply changes in neural input to the heart as a mechanism of arrhythmia. Such
changes would be expected to increase the risk of cardiovascular events
secondary to thrombosis and arrhythmias.
The effects of long-term exposure to fine particulate air pollution have
been inferred from linking cardiovascular risk factors and estimates of air pollution
exposure to the cause of death in epidemiological studies. These observational
studies showed that fine particulate air pollution increased the rate of
mortality from cardiopulmonary causes. The risk of cardiopulmonary mortality
was most strongly associated with fine particles compared with larger
particles. Although the mechanisms are unknown, possible explanations of the
risks include acceleration of atherosclerosis progression secondary to
increased oxidative stress or systemic inflammation, and modulation of factors
that enhance coronary plaque instability or electrical instability. Data are
emerging that show that PM accelerates atherosclerosis in humans and in animal
models of long-term PM exposure, although the effect is probably indirectly mediated
through increased inflammation and oxidant stress. For instance,
high-sensitivity C-reactive protein (hs-CRP) correlates with cardiac events.
The liver produces CRP in response to the cytokines interleukin (IL)-1, IL-6,
and tumor necrosis factor-α. Measurement of cytokines, and even hs-CRP, may
provide a mechanism to assess cardiovascular risk in response to PM exposure.
Because of the complexity of the
mechanisms that regulate initiation and progression of atherosclerosis, and the
complex constituents of PM, proof of a causal effect of PM on the development
of atherosclerosis will be a challenge. Yet, the Multi-Ethnic Atherosclerosis
Study substudy, MESA Air, did show an association between long-term exposure to
PM2.5 and NO2 and coronary artery calcium accumulation.
It is possible that PM has a direct effect on cardiac autonomic function,
on cardiac repolarization, or on both, and that PM increases an individual’s
susceptibility to myocardial ischemia and to ventricular fibrillation during
regional myocardial ischemia. Long-term exposure to air- borne PM might
initiate cellular signaling that affects the expression of the cellular
proteins that are important to electrical impulse formation and conduction in
the heart. Potential protein targets include structural proteins, as well as
voltage-gated and ligand-gated channels, and ion exchangers. Thus, cardiac
deaths associated with exposure to PM are likely to result from interaction of
the direct effects of PM on vascular function, cardiac electrophysiology,
autonomic regulation, and/or coronary thrombosis in individuals at high risk
for sudden cardiac death.
Exposure to secondhand tobacco smoke is a reasonable model for
understanding how exposure to PM mediates changes in the cardio- vascular
system and contributes to cardiac events. Acute exposure activates platelets
and decreases endothelial function in humans, whereas long-term exposure
accelerates the formation of atherosclerosis.
Sulfur Dioxide
SO2 is a gas produced by coal-burning power plants, smelters,
refineries, pulp mills, and food-processing plants. Typical ambient air
reactions include formation of sulfuric acid (acid rain) and sulfates. A
positive correlation exists between SO2 levels and hospital
admissions, the mortality rate in older adults, and the presence of
cardiovascular disease. It is often difficult to separate the contributions of
individual components of air pollution and to attribute them to health effects.
For example, in one study, the total mortality rate was estimated to increase
by 5% for each 0.038 parts per million (ppm) increase in SO2; yet,
the effects were no longer significant when respirable particles were included
in the statistical model. Thus, SO2 is likely to be a surrogate
marker of PM because of the common sources of SO2 and PM. The U.S.
national air quality standard for the allowable level of SO2
averaged over 1 hour is 75 ppb.
Nitrogen Dioxide
NO2 and nitric oxide (NO) are reactive gases produced by
gasoline and diesel fuel combustion, electric power generation, chemical
manufacturing, soil emission (including fertilizers), and solid waste disposal.
NO2 is also a major indoor air pollutant produced by gas stoves and
gas heaters. Both gases are critical components of the photo-oxidation cycle
and O3 formation. NO is also produced endogenously at levels that
can exceed 1 ppm. It is a mediator and a strong vasodilator and bronchodilator.
The ultimate fate of NO2 and NO in ambient air and biological fluids
is the formation of nitrite and nitrate.
NO2 is primarily associated with long-term respiratory
effects. Children and adults with existing respiratory diseases are at
increased respiratory risk from NO2 inhalation. Healthy individuals
have shown slightly reduced cardiac output when inhaling NO2 during
exercise. Increased levels of NO2 and black carbon are positively
associated with arrhythmias. A positive significant association also exists
between NO2 and an increased risk of myocardial infarction. Numerous
epidemiological studies have linked elevated levels of NO2 to
coronary heart disease. Prolonged exposure of coronary heart disease patients
to NO2 has been shown to correlate with reduced HRV. Daily exposure
to NO2, particularly in older adults, was significantly associated
with daily emergency department
visits for ischemic heart disease. The U.S. national air quality standard for the allowable level of NO2
averaged over 1 hour is 100 ppb, and
averaged over a year is 53 ppb.
CO is produced by combustion. When inhaled, CO binds avidly to
hemoglobin, thereby reducing the capacity of blood to deliver oxygen to the tissues. Within
tissue, CO may bind to cytochrome P-450, cytochrome oxidase, and myoglobin,
which affects intracellular function. Individuals most susceptible to these
effects have flow-limiting coronary disease.
A study of the long-term health effects of CO exposure in a comparison
of bridge and tunnel workers showed that the relative risk of coronary artery
disease was greater in tunnel workers. Prolonged exposure to CO and attendant
carboxyhemoglobin (COHb) concentration in excess of 10% increased heart rate,
systolic blood pressure, red blood cell mass, and blood volume. CO has been
implicated in atherogenesis and in increased risk of myocardial infarction. In
general, controlled exposure to CO reduces the time to onset of
electrocardiographic evidence of exercise-induced ischemia and angina in
individuals with ischemic heart disease, and increases the frequency of
ventricular arrhythmias during exercise. These effects occur at COHb levels as
low as 2.9%. The baseline COHb in healthy nonsmokers is 0.5% to 1.0%. Prolonged
exposure to 9 ppm CO would produce a blood COHb level of approximately 2%.
Thus, the U.S. national air quality standards for CO (35 ppm averaged over 1 hour
and 9 ppm averaged over 8 hours) should provide protection even for a sensitive
population with ischemic heart disease.
O3 is a secondary air pollutant formed in the atmosphere by
photo- chemical reactions involving primary pollutants, volatile organic com-
pounds, and NOs. The U.S. national ambient air quality standard for
ground-level O3 is 0.07 ppm averaged over 8 hours. Exposure to O3
irritates mucous membranes, decreases lung function, increases the reactivity
of airways, and causes airway inflammation. Consequently, O3
exposure can cause symptoms of chest pain and decreased exercise capacity.
Initial epidemiology studies that showed associations between PM and mortality
were not able to reproducibly show similar relationships between O3
and mortality, primarily because there is a close correlation of these two
pollutants in many cities. However,
several epidemiology studies showed associations between exposure to O3
and increased mortality and morbidity. In one
study, an increase in O3 of 21.3
ppb increased the cardiovascular disease mortality rate by 2.5% and the
respiratory disease mortality rate by 6.6%; the effect of O3 was
independent of that of other pollutants. Whether O3 and PM affect
the cardiovascular system by similar or different mechanisms remains unknown.
AIR POLLUTION
EFFECTS ON CONGENITAL HEART
DISEASE
There are several case-control and retrospective studies that have
inves-tigated the association of maternal exposure to air pollution and the
risk of congenital heart disease. Each study focused on a different air
pollutant. Higher levels of PM2.5 exposure were associated with an
increased risk of nonisolated truncus arteriosus, total anomalous pulmonary
venous return, coarctation of the aorta, and interrupted aortic arch, as well
as any critical isolated and nonisolated congenital heart defect in Florida.
The exposure to the 90th percentile of SO2 in Italy was associated
with an increased prevalence of congenital heart disease and ventricular septal
defects. CO, NO, and black smoke exposure in Northeast England were associated with congenital heart disease.
Mechanisms linking air pollution to congenital heart disease remain extremely
challenging to study, mainly due to the difficulty in estimating the net effect
of environmental pollution in comparison to underlying comorbidities and
individual lifestyle factors in pregnant mothers.
WHAT PATIENTS CAN DO TO PROTECT AGAINST CARDIOVASCULAR EFFECTS OF AIR
POLLUTION
Patients with heart disease should be made aware of the increased risk
associated with exposure to air pollution and educated about strategies to
decrease exposure. Patients can reduce their exposure and risk by decreasing
their time outdoors when air pollutants are at concentrations believed to
impart a health risk and/or by decreasing the intensity of outdoor physical
activity. For example, if a patient usually jogs, exercising indoors in an
air-conditioned environment can be recommended. If an alternative and
acceptable indoor location is not available, one should walk instead of jog.
Outdoor PM contributes to indoor PM. When conditions are severe (e.g., wood
smoke secondary to a wildfire), activities should be restricted indoors as
well, and consideration should be given to using high-efficiency particulate
air filter air cleaners to reduce indoor PM levels. PM and NO2 are
typically elevated in the morning and afternoon when automotive and truck
traffic increases during rush hour commutes. O3 concentration increases
in the heat of the day, and therefore, is highest in the midday and in the
summer months. In general, patients can reduce exposure by the following:
limiting exercise outdoors in the afternoons when air pollutant concentrations
are high; exercising indoors or away from roadways; closing doors and windows,
and using air conditioning; seeking out air quality reports and forecasts; and
using the Air Quality Index (AQI) to guide outdoor activities. The AQI provides
a national standard for reporting daily air quality and providing anticipated
health effects for the quality reported. The AQI can be reviewed daily in the
local media or on the EPA website.
