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Cardiovascular Effects of Air Pollution

PCCSU Volume 25, Lesson 29


The American College of Chest Physicians offers this lesson as a review of a previously offered self-study program. The program provides information on pulmonary, critical care, and sleep medicine issues. CME is no longer available for the PCCSU program.


  • Update your knowledge and understanding of pulmonary medicine topics.
  • Update your knowledge and understanding of critical care medicine topics.
  • Update your knowledge and understanding of sleep medicine topics.
  • Learn clinically useful practice procedures.

CME Availability

Effective July 1, 2013, PCCSU Volume 25 is available for review purposes only.

Effective December 31, 2012, PCCSU Volume 24 is available for review purposes only.

Effective December 31, 2011, PCCU Volume 23 is available for review purposes only. CME credit for this volume is no longer being offered

Effective December 31, 2010, PCCU Volume 22 is available for review purposes only. CME credit for this volume is no longer being offered.

Accreditation Statement

The American College of Chest Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

CME Statement

Credit no longer available as of July 1, 2013.

Disclosure Statement

The American College of Chest Physicians (CHEST) remains strongly committed to providing the best available evidence-based clinical information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our faculty members. It is not the intent of CHEST to eliminate all situations of potential conflict of interest, but rather to enable those who are working with CHEST to recognize situations that may be subject to question by others. All disclosed conflicts of interest are reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to ensure that such situations are properly evaluated and, if necessary, resolved. The CHEST educational standards pertaining to conflict of interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of science. Through our review process, all CHEST CME activities are ensured of independent, objective, scientifically balanced presentations of information. Disclosure of any or no relationships will be made available for all educational activities.

CME Availability

Volume 25 Through June 30, 2013
Volume 24 Through December 31, 2012
Volume 23 Through December 31, 2011
Volume 22 Through December 31, 2010

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PCCSU Volume 25 Editorial Board

Steven A. Sahn, MD, FCCP

Director, Division of Pulmonary and Critical Care Medicine, Allergy, and Clinical Immunology
Medical University of South Carolina
Charleston, SC

Dr. Sahn has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Deputy Editor
Richard A. Matthay, MD, FCCP

Professor of Medicine
Section of Pulmonary and Critical Care Medicine
Yale University School of Medicine
New Haven, CT

Dr. Matthay has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Alejandro C. Arroliga, MD, FCCP
Professor of Medicine
Texas A&M Health Science Center
College of Medicine
Temple, TX

Dr. Arroliga has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Paul D. Blanc, MD, FCCP
Professor of Medicine
University of California, San Francisco
San Francisco, CA

Dr. Blanc has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health, Flight Attendants Medical Research Institute – university grant monies
University of California San Francisco, US Environmental Protection Agency, California Environmental Protection Agency Air Resources Board – consultant fee
Habonim-Dror Foundation Board of Trustees – fiduciary position

Guillermo A. do Pico, MD, FCCP
Professor of Medicine
University of Wisconsin Medical School
Madison, WI

Dr. do Pico has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Ware G. Kuschner, MD, FCCP
Associate Professor of Medicine
Stanford University School of Medicine
Palo Alto, CA

Dr. Kuschner has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Teofilo Lee-Chiong, MD, FCCP
Associate Professor of Medicine
National Jewish Medical Center 
Denver, CO

Dr. Lee-Chiong has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health – grant monies (from sources other than industry)
Covidien, Respironics, Inc. – grant monies (from industry-related sources)
Elsevier – consultant fee

Margaret Pisani, MD, MPH, FCCP
Assistant Professor of Medicine
Yale University School of Medicine 
New Haven, CT

Dr. Pisani has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Stephen I. Rennard, MD, FCCP
Professor of Medicine
University of Nebraska Medical Center
Omaha, NE

Dr. Rennard has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

AstraZeneca, Biomark, Centocor, Novartis – grant monies (from industry-related sources)

Almirall, Aradigm, AstraZeneca, Boehringer Ingelheim, Defined Health, Dey Pharma, Eaton Associates, GlaxoSmithKline, Medacrop, Mpex, Novartis, Nycomed, Otsuka, Pfizer, Pulmatrix, Theravance, United Biosource, Uptake Medical, VantagePoint – consultant fee/advisory committee

AstraZeneca, Network for Continuing Medical Education, Novartis, Pfizer, SOMA – speaker bureau

Ex Officio
Gary R. Epler, MD, FCCP

Clinical Associate Professor of Medicine
Harvard Medical School
Brigham & Women's Hospital
Boston, MA

Dr. Epler has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Lilly Rodriguez
ACCP Staff Liaison

By Alessandra D’Alessandro, MD

Dr. D’Alessandro is from the University of Madgeburg School of Medicine, Germany.

Dr. D’Alessandro has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within this chapter.


  1. Describe the composition and main sources of air pollution.
  2. Review the main epidemiologic studies relating to air pollution and the development of cardiovascular disease.
  3. Quantify the risk of cardiovascular morbidity and mortality derived from air pollution.
  4. Understand the mechanism by which air pollution may cause cardiovascular disease.
  5. Evaluate the gap between epidemiologic and experimental evidence.

Key Words: air pollution; cardiovascular disease; environmental diseases; heart rate variability; hypertension; particulate matter

Abbreviations: ACS = American Cancer Society; APHEA, APHEA-2 = Air Pollution and Health: A European Approach; CAD = coronary artery disease; CAP = concentrated ambient particle; CI = confidence interval; CIMT = carotid intima-media thickness; CVD = cardiovascular disease; DBP = diastolic blood pressure; HRV = heart rate variability; LDL = low-density lipoprotein; LOX-1 = oxidized low-density lipoprotein receptor; MI = myocardial infarction; NADPH = nicotinamide adenine dinucleotide phosphate; OR = odds ratio; PM = particulate matter; PM2.5 = particulate matter with an aerodynamic diameter > 2.5 μm; PM10 = particulate matter with an aerodynamic diameter < 10 μm; RR = relative risk; SBP = systolic blood pressure; TLR = toll-like receptor; UFP = ultrafine particle with an aerodynamic diameter < 0.1 μm


Exposure to environmental air pollution has been established as a risk factor for triggering cardiovascular events after both long-term and short-term exposures. Based on available epidemiologic data, the World Health Organization estimates that air pollution causes 800,000 premature deaths worldwide each year. Although the relative risk (RR) for incident cardiovascular disease (CVD) posed by exposure to environmental air pollution is small compared with the risk posed by traditional risk factors, it still represents a relevant public health issue because of the number of people potentially affected.1 Throughout this article, a scientific statement from the American Heart Association1 has been referenced and is one of the main sources for structuring this article, which we strongly recommend reading.

Air Pollution

The composition of air pollution is highly variable and its anthropogenic component changes along with human activities in time and space. Air pollution consists of a mixture of compounds in gaseous (carbon monoxide, sulfur dioxide, nitrogen oxides, ozone, volatile organic compounds) and particle phases (particulate matter [PM]). The largest body of epidemiologic evidence links exposure to the PM component of air pollution with cardiovascular events in humans.1 PM fractions are commonly classified according to their aerodynamic diameter as thoracic particles (diameter < 10 μm [PM10]), fine particles (diameter < 2.5 μm [PM2.5]), and ultrafine particles (UFPs; diameter < 0.1 μm). PM fractions are different in composition, chemical properties, lifetimes in the atmosphere, and distances over which they can travel. The majority of PM mass consists of carbon, sulphate, nitrate, ammonium, and crustal components. Coarse particles are mainly generated by natural or human mechanical activity, such as by the action of the wind on the ground or sea surface, construction, agriculture, and resuspension from road surfaces. The coarse fraction has a relatively short atmospheric half-life of minutes to hours and travels usually from less than one to tens of kilometers from the source. Fine particles and UFPs are mostly generated by the combustion of fossil fuels. Particles generated through the combustion process have a core of elemental carbon that is coated with different chemicals, such as metals, sulfates, and nitrates. They have a longer atmospheric half-life from days to weeks and can travel longer distances, usually from tens to hundreds of kilometers. UFPs are either directly emitted to the atmosphere or are formed by the nucleation of gaseous constituents in the atmosphere.2 UFPs are the major component in vehicle emissions, which are the largest source of pollution in the urban environment.3

Most of the epidemiologic evidence accumulated in the past 15 years relates cardiovascular events to short-term or long-term exposure to either PM2.5 or UFPs; indeed, fine particles and UFPs have the largest surface area on which toxic hydrocarbons and metal can be coated. Toxicity also depends on the chemical composition of PM and on the chemicals absorbed on PM surface; further, they can penetrate deep into the respiratory tract and possibly translocate across epithelial cells.

Cardiovascular Risk Estimate (Short-term vs Long-term Studies)

Quantification of cardiovascular risk due to air pollution exposure has been convincingly obtained from epidemiologic studies conducted across the world. The studies involved are both short-term studies (time series and case-crossover) and long-term studies (cohort studies and case control). Short-term studies generally relate daily elevations in concentration of air pollutants with mortality or morbidity (hospital admission) caused by acute events, such as myocardial infarction (MI), cardiac arrhythmia, hypertensive episodes, and worsening heart failure. By contrast, long-term studies investigate the excess of overall mortality and cardiovascular mortality in relation to change in long-term air pollution exposure.

CVD Mortality

The effect of short-term changes in air pollution and daily changes in cardiovascular death counts have been reviewed in recent works.1 The findings of most studies indicate that the daily short-term increase of air pollution is linked with a parallel rise of all-cause mortality and, particularly, that elevation in daily PM levels may increase CVD-related mortality. Among the hundreds of studies conducted worldwide, there are several large, multicity, daily time-series studies that have analyzed data in relation to millions of people. The most striking finding of those studies has been the reproducibility of the results across continents. For instance, the National Morbidity, Mortality, and Air Pollution Study included 50 million people in the 90 largest cities in the United States, and the results indicated that there is, on average, an approximate increase of 0.5% in total nonaccidental mortality per 10 μg/m3 increase in PM10 concentration at 1 day following exposure (ie, there is a 1-day lag). The PM10 effect was slightly greater for cardiorespiratory mortality than for total mortality at 1 day after exposure.4 Similar results were reported in Europe from the Air Pollution and Health: A European Approach (APHEA and APHEA-2) studies, which included 43 million people in 29 European cities. The estimated increase in cardiovascular deaths was 0.76% for each 10-μg/m3 increase in PM10.5 Further, the combined European and North American approach study analyzed data from APHEA and the National Morbidity, Mortality, and Air Pollution Study, as well as from Canadian studies.6 In this analysis, a daily increase of 10 μg/m3 of PM10 was associated with a rise of all-cause mortality ranging from 0.2% to 0.6%, the largest effect being observed in Canada.6 The detrimental effect of air pollution on mortality was greater for those who were unemployed and for individuals older than 75 years of age.6 In addition, no lower limit was found below in which exposure to PM10 was not associated with excess mortality across all of the regions.6

An even larger effect of air pollution on CVD-related mortality has been suggested in the results from long-term studies. Two large cohort-based mortality studies, the Harvard Six Cities and the American Cancer Society (ACS) studies, were reported in the 1990s.7,8 In both studies, particulate and sulfate pollution was associated with increases in all-cause and cardiopulmonary mortality. Those studies, which were later extended and reanalyzed, prompted a scientific and political debate that ultimately led the US Environmental Protection Agency, after withstanding legal challenge from industry groups, to revise the air quality standard for PM. This allowed the United States to obtain more restrictive PM2.5 regulation than Europe or Canada. Briefly, the Harvard Six Cities study investigated a cohort of 8,111 adults across six cities with 14 to 16 years of follow-up and showed that each increase in 10 μg/m3 of PM2.5 was associated with a 13% increase in all-cause mortality and an 18% increase in CVD-related mortality. In the extended follow-up of this study, the previous results were confirmed for 8 additional years, with findings suggestive of a significant increase in risk of death for every 10 μg/m3 rise in PM2.5; in addition, the researchers also noted that a reduction of overall mortality was associated with decreased mean PM2.5 (10 μg/m3) between periods.9

The extended 16-year follow-up of the ACS study analyzed mortality data in approximately 500,000 residents of all 50 US states. After the researchers controlled for typical confounders, they found that each rise of 10 μg/m3 in fine particulate air pollution was associated with an approximately 4% and 6% increased risk of all-cause and cardiopulmonary mortality, respectively.10 However, one of the criticisms posed with regard to the large epidemiologic studies was that the surrogates of exposure assessed as community average concentrations do not accurately reflect individual exposure. To assess this issue, Jerret and colleagues11 analyzed data of nearly 21,000 Los Angeles residents (a subset of the ACS cohort); and due to the smaller sample size, they could employ a more accurate exposure matrix that linked zip codes and residential areas of the participants with a local monitoring station. The authors observed an effect of pollution on mortality that was nearly three times larger than that seen in multicity models with a stronger association between air pollution and ischemic heart disease.

As one would expect, the association between PM inhalation and CVD mortality has also been observed in the occupational setting. A cohort study conducted in Sweden followed 176,309 male construction workers for more than 30 years and compared them with 71,778 unexposed workers.12 In this cohort, occupational exposure to PM, particularly to diesel exhaust, was associated with an increased relative risk for coronary artery disease (CAD).12

Finally, because of the pathophysiologic implication, two of the most recent epidemiologic cohort studies restricted to women should be mentioned. Miller and colleagues13 investigated a cohort of approximately 66,000 healthy postmenopausal women and reported that every 10 μg/m3 PM2.5 increase in exposure over a 6-year period increased the risk of cardiovascular events by 24% and cardiovascular-related death by 76%. In another cohort of women, which was a subset of the Nurses’ Health Study from the northeastern United States,14 an increase of 10 μg/m3 modeled estimates of PM10 exposures was associated with an approximately 16% increased risk of all-cause mortality and a 40% increase in fatal coronary heart disease. Interestingly, these two studies, which were based on cohorts of only women but investigated two different sizes of PM exposures, had some similar key findings. For example, cardiovascular mortality risk estimates were larger than those of previous cohort studies, obese women (body mass index > 30 kg/m2) were at greater RR, and the increases in mortality (all-cause and cardiovascular) were larger than the increase in nonfatal cardiovascular events. Since coronary disease in women is characterized by more diffuse atherosclerosis than in men, it is possible that a diffuse coronary vascular alteration predisposes them to a higher air pollution-related risk.

Altogether, the epidemiologic studies indicate that the excess of mortality derived from long-term exposure is larger than the excess of mortality after short-term exposure. Thus, it is unlikely that the excess of mortality observed after short-term exposure only reflects a mortality displacement or “harvesting” of the frails.15

Epidemiologic Evidence for a Single CVD Outcome

Ischemic Heart Diseases/MI
Several studies have investigated the association between exposure to air pollution and incidence of ischemic heart disease/MI after short-term and long-term exposures. A case-crossover study by Peters and colleagues16that investigated the onset of MI in 691 patients found a strong association (odds ratio [OR] 2.92, 95% confidence interval [CI] 2.22-3.83) between exposure to traffic and onset of MI in the following hour. Although the contribution of other factors linked to traffic, such as noise and stress, could not be ruled out, the study results highly suggest that traffic-related exposure to fine particles may be responsible for the observed effect. In addition, exposure to traffic appeared to be associated with larger risks among women, patients 60 years or older, people with diabetes, and those who were unemployed.16

Indeed, in a recent review of the literature, Bhaskaran and coauthors17 summarized the results of short-term studies linking air pollution exposure to incidence of MI. They found that the findings of short-term studies support an association between daily exposure to PM2.5 and incidence of MI and, in particular, that every increment of 10 μg/m3 of PM2.5 is associated with an increased risk of MI between 5% and 17%.17 A very interesting finding comes from a case-crossover study18 investigating acute MI in patients for whom previous coronary angiogram data were available. In this study, exposure to PM2.5 was found to be associated with incidence of MI but only in participants with previously documented, at least, one-vessel disease, thus conferring plausibility to the somewhat surprising notion that exposure to relative low levels of PM2.5 may trigger MI. In this study, only vulnerable participants (ie, those with previously documented CAD) were susceptible to the effects of air pollution.

Among the long-term studies, the ACS study, an ongoing, prospective mortality study in which about 1.2 million Americans were followed over time, PM2.5 exposures were most strongly associated with mortality attributable to ischemic heart disease. A 10-μg/m3 elevation in fine PM was associated with an 18% increase in mortality from ischemic heart disease.19 Furthermore, in an analysis of 196,000 patients who survived a first MI, Zanobetti and Schwartz20 showed that long-term exposure to PM10 was associated with a higher risk of adverse post-MI outcomes, namely death, subsequent MI, and heart failure. In this study, the highest risk was observed for subsequent MI.20 In addition, the results from a case-control study of 5,049 confirmed cases of acute MI suggested that living near a major roadway and a higher level of cumulative traffic near the participants’ residences were significantly associated with occurrence of acute MI21; traffic was used as a proxy for PM exposure. Living near a major road and long-term exposure to nitrogen dioxide but not PM2.5, have been associated with increased risk for ischemic heart disease. This association was shown in a trial of 2,360 patients who were referred during 1992 to 1999 to a pulmonary clinic in Canada.22 Finally, the Nurses Health Study found that long-term PM exposure was associated with fatal ischemic cardiac events,14 whereas the association with nonfatal MI was not statistically significant. Similarly, the Women’s Health Initiative study found that exposure to increased concentrations of fine particulate air pollution was associated with an increased risk of first cardiovascular events; and although the increased risk applied to nonfatal and fatal cardiovascular events, the risk of death associated with higher levels of PM2.5 was larger than the risk of all first events.13

Cerebrovascular Disease
In the last 10 years many, but not all, short-term studies have reported an association between short exposure to air pollution, mortality, and hospitalization for ischemic cerebrovascular disease.1 Again, it is interesting to observe that studies conducted in different countries, such as Korea, Finland, Taiwan, Canada, France, and the United States, all with different degrees of air pollution, indicate that there is an increased risk for mortality and hospitalization deriving from short-term exposure to air pollutants. In a recent case-crossover study, Wellenius and colleagues23 reviewed the medical records of approximately 1,700 patients hospitalized for ischemic stroke in the Boston area over 10 years. In this study, which included high-quality pollution data and diagnostic criteria confirmed by hospital chart review, the authors showed that 24-h exposure to moderate air pollution (PM2.5 15-40 μg/m3) increased the risk of ischemic stroke (ischemic stroke onset [OR], 1.34; 95% CI, 1.13-1.58) compared with a 24-h period of exposure to lower levels of air pollution (PM2.5 = 15 μg m3).23 Although most studies do show a positive association between ischemic stroke and short-term exposure to air pollution (24 h), contrasting findings (even from the same group) have been reported.23,24

Among the long-term studies, the Women’s Initiative Health study found that long-term exposure to air pollution was associated with an increased risk for stroke (cerebrovascular disease event [OR], 1.35, for every increment of 10 μg/m3 of PM2.5),13 whereas the ACS Study did not find any such association.19 Finally, comparing cognitive testing obtained every 2 years from the Nurses’ Health Study Cognitive Cohort, which included 19,409 US women aged 70 to 81 years, Weuve and colleagues25 observed that higher levels of estimated long-term exposure to PM10 and PM2.5 are associated with a faster cognitive decline in older women.

Cardiac Arrhythmia
Epidemiologic studies on cardiac arrhythmia due to air pollution show mixed results.

Several short-term studies, mostly investigating data obtained from implanted cardioverter-defibrillators, have observed associations between fine PM, related pollutants, and cardiac arrhythmias,26,27 whereas others did not show any association.28 A recent study investigating hospitalization for atrial fibrillation could not find a significant association with short-term exposure to air pollution.29 Finally, some studies have reported an association between cardiac arrest and exposure to air pollution, while others did not.1

Heart Failure
Several short-term studies have shown an increase in daily hospitalization for heart failure associated with short-term changes in PM exposure,1 and a recent Spanish study found that higher UFP concentrations were related to hospitalization for heart failure.30 Among the cohort studies, the ACS study found a statistically significant association between long-term exposure to PM2.5 and mortality due to heart failure (RR, 1.13; 95% CI, 1.05-1.21 per 10 μg/m3).19

Peripheral Arterial and Venous Diseases
The relationship between air pollution and peripheral vascular diseases also has offered mixed results. A recent cohort study following 27,347 postmenopausal women 50 to 79 years of age did not find any consistent evidence of a direct association between venous thromboembolic risk and short-term or long-term PM2.5 or PM10 exposure.31 However, results from a previous case-control study conducted in Italy have shown a robust association between PM10 exposure and the risk of deep venous thrombosis.32 Moreover, other studies have suggested links between traffic or PM10 exposure, deep venous thrombosis, pulmonary embolism, and venous thromboembolism.1

Summary of Epidemiologic Evidence
To date, epidemiologic evidence suggests that both short-term and long-term exposure to air pollution increases mortality and morbidity in exposed individuals; specifically, the evidence is strong for ischemic heart disease. Particularly, time-series studies estimate that a 10-μg/m3 increase in mean 24-h PM2.5 concentration increases RR for daily cardiovascular mortality by approximately 0.4% to 1.0%. By contrast, cohort studies estimate that a 10-μg/m3 increase in long-term average exposure to PM2.5 is associated with an increased mortality risk for CVD, ranging in different cohort studies between 3% and 76%.1,15

Short-term exposure to air pollution may trigger acute MI, particularly in susceptible individuals, such as the elderly, those with pre-existing CAD, and people with diabetes. Women and those who are obese may also be at a higher risk. Long-term exposures to PM2.5 increase the risk for cardiovascular mortality to an even greater extent than short-term exposures, and these exposures reduce life expectancies within a population by several months to a few years.1 Importantly, reduction in PM2.5 levels decreases cardiovascular mortality at the population level within a few years.15 The existing level of overall evidence is moderate for heart failure and ischemic stroke, and it is modest or mixed for peripheral vascular and cardiac arrhythmia/arrest.1

Presently, three complementary mechanistic pathways have been postulated and are being experimentally explored. The first so-called “indirect pathway” relies on the original hypothesis that inhaled particles cause an inflammatory reaction in the lung with a subsequent spill of inflammatory mediators into the systemic circulation. The second pathway implies a direct translocation of pollutant components, possibly in the UFP range, into the systemic circulation, either naked or after incorporating into the macrophage; however, to date there is only limited evidence of inhaled nanoparticles being translocated across the alveolar-blood barrier. The third pathway involves the generation of an autonomic imbalance caused by inhaled PM, which stimulates lung nerve reflexes through irritant receptors and alters systemic autonomic balance (eg, parasympathetic nervous system withdrawal, sympathetic nervous system activation, or both). It is possible that a combination of all three pathways is responsible for promoting atherogenesis, promoting atherothrombosis, and altering the conduction capacity of the heart, thus leading to the observed cardiovascular morbidity and mortality.33

Evidence of an association between long-term exposure to air pollution and atherogenesis in humans has been shown in a cross-sectional study of about 800 residents in the Los Angeles area. In this population, Künzli and colleagues34 assessed carotid intima-media thickness (CIMT), a measure of subclinical atherosclerosis, and correlated it with individual exposure to PM2.5. Individual annual mean PM2.5 exposure was derived from a geostatistical model and assigned to study participants based on their residential area. For every 10-μg/m3 increase in PM2.5, CIMT increased by approximately 4%. Interestingly, among older participants (≥ 60 years of age), women, never-smokers, and those reporting lipid-lowering treatment at baseline, the associations of PM2.5 and CIMT were larger, with the strongest associations in women ≥ 60 years of age.34 In a later study, the same group examined data from five double-blind randomized trials that assessed effects of various treatments on the change in CIMT.35 The trials investigated nearly 1,500 residents of the Los Angeles area and related CIMT progression to traffic proximity and PM2.5 exposure. Living within 100 m of a highway was positively associated with CIMT progression. However, for PM2.5 exposure, coefficients were only of borderline statistical significance.35

Further, in a prospective cohort study of approximately 4,500 adults living in the Ruhr area of Germany, which is a highly urbanized and industrialized environment, Hoffmann and colleagues36 showed that living near a major road increases the coronary artery calcium score (a marker of coronary atherosclerosis) by approximately 60%. In a subsequent study of the same cohort, Bauer and coauthors37 showed that the increase in CIMT was highly correlated with yearly PM2.5 exposure. However, not all of the studies show the same strength of association. For instance, in the Multi-Ethnic Study of Atherosclerosis, investigators evaluated the association of 20-year exposure to PM with CIMT, carotid artery calcium, and ankle-brachial artery indices, which were measured later in adulthood at the end of the 20-year period. The authors found that there was a small measurable effect on CIMT but not on carotid artery calcium or the ankle-brachial artery index.38

In addition, experimental studies using animal models demonstrate that air pollution may initiate or accelerate atherosclerosis. Intrapharyngeal instillation of PM10 in an hyperlipidemic model of rabbits resulted in the progression of atherosclerotic lesions, increased plaque-cell turnover and extracellular lipid pools in coronary and aortic lesions, and increased lipids in aortic lesions.39 Sun and colleagues40 reported that inhalation of concentrated air particles in a murine model of atherosclerosis resulted in increased plaque lipid content, macrophage infiltration, and the induction of vascular reactive oxygen species. The size of inhaled particles may also play a role because UFP exposure in the mouse model causes a higher degree of atherosclerotic lesions.41

However, the mechanism by which inhaled air pollutants may promote atherosclerosis is not clear; particularly puzzling is the transfer of toxicity from inhalation at the pulmonary level to systemic cardiovascular outcome. Recent experimental studies highlight the role of pattern-recognition receptors, including toll-like receptors (TLRs) and the lectin-like oxidized low-density lipoprotein (LDL) receptor, which can be activated from inhaled PM at the pulmonary site and drive the systemic inflammatory manifestation.42 In an important experimental work, Lund and colleagues43 demonstrated that exposure to environmental-traffic-derived air pollutants results in up-regulation of the oxidized LDL receptor (LOX-1).43 That LOX-1 mediates the extrapulmonary expression and activity of several proatherosclerotic pathways, including vascular matrix metallopeptidase-9, macrophage/monocyte infiltration, and endothelin-1 production, resulting from inhaled combustion emissions. Interestingly, similar elevations in plasma soluble LOX were also observed in humans exposed to vehicular emissions.43

More recently, Kampfrath and colleagues44 have shown that inhaled PM stimulates the formation of oxidized phospholipids, which are derived from the oxidation of lung surfactants, in the bronchoalveolar lavage fluid of exposed mice. Oxidized phospholipids activate a positive feedback response in the lungs that also involves TLR4 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, leading to enhanced superoxide production and mobilization of mononuclear cells from bone marrow into the circulation and vascular wall, specifically into the perivascular adipose where they generate reactive oxygen species via NADPH oxidase. This ultimately causes vascular inflammation and dysfunction in the aortic wall and in several other systemic vascular beds.44

Epidemiologic studies associate short-term exposure to air pollution with acute cardiovascular events, such as acute coronary syndrome. The major cause of acute coronary syndrome is atherosclerotic plaque rupture and thrombus formation. Thus, alteration at the vessel wall (vascular dysfunction) or formation of a thrombus may be involved in the generation of acute vascular events.45

Thrombus Formation: Some experimental studies in humans have reported associations between exposure to air pollution and alteration of coagulation factors, such as von Willebrand factor, fibrinogen, and platelet activity.1 However, other studies reported no associations between exposures and platelets, fibrinogen, von Willebrand factor, and factor VII.1 In a recent, observational exposure study, 34 healthy adult volunteers commuted for 2 h by bus, car, or bicycle during the morning rush in a European city. Shortly before exposure and 6 h after exposure, blood samples were taken and analyzed for club cell (Clara) protein 16, blood cell count, coagulation markers, and inflammation markers. In this real-life exposure study, Zuurbier and colleagues46 failed to find an association between air pollution exposure and markers of coagulation or inflammation.

By contrast, Rich and coworkers47 investigated changes in heart rate, blood pressure, and some biomarkers of inflammation and thrombosis in 125 healthy young volunteers before, during, and after the Beijing Olympics. In fact, during the Olympics, thanks to effective pollution control measures (eg, restriction of the operations of industrial combustion facilities, banning of certain vehicles and trucks, vehicles only allowed through the city on alternating days), concentrations of PM and gaseous pollutants were substantially reduced. After the end of the Olympics, the level of ambient pollutant returned to baseline values. In this study, changes in concentration of air pollutants were accompanied by statistically significant improvements in some, but not all, of the biomarkers related to platelet adhesion and activation, namely a 34.0% decrease of the platelet activation factor P-selectin and a 13.1% decrease of the von Willebrand factor during the period of the Olympics. The P-selectin value returned toward baseline after the Olympics. Although they are of uncertain clinical significance, the findings of this study support the concept that short-term changes in air pollution can elicit a prothrombotic response, even in healthy young adults.47 Interestingly, enhanced platelet activity and thrombus formation in an ex vivo perfusion chamber (Badimon chamber) was demonstrated 2 to 6 h after healthy volunteers were exposed to diluted diesel exhaust.48 To explain the lack of consistency among findings from different studies, it has been hypothesized that the blood level measurements of coagulation factors or biomarkers of thrombosis could potentially miss a relevant biologic effect at the vascular wall.1

One other important aspect that is emerging in the recent literature is the possibility that the effects of air pollution on CVD are mediated by genetic polymorphism or epigenetic interaction. A recent investigation of a cohort of 704 elderly men participating in the Veteran Administration Normative Aging study found an association between current concentrations of traffic-related air pollutants and increased levels of intermediary CVD-related blood markers (fibrinogen, C-reactive protein, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1) after short-term and intermediate-term exposures to air pollution (up to 1 month).49 In addition, the results suggest that those responses vary with a person’s baseline DNA methylation pattern.49

Vascular Function: Some inhalational exposure studies indicate that short-term exposure to particulate air pollution may induce a short-lived vasoconstriction of the conduit artery. The mechanism by which PM exposure can cause this effect is not clear; either an increase of endothelin activity or an augmented sympathetic autonomic nervous system has been postulated.1 Moreover, an impairment of the endothelium-dependent vasodilation has also been reported. This latter effect is more likely due to reduced nitric oxide bioavailability as a consequence of systemic proinflammatory and oxidative response.1 In a series of experiments, Brook and colleagues50reported that, in healthy volunteers, experimental inhalation of PM2.5 causes an immediate conduit arterial vasoconstriction and a delayed (after 24 h) reduction of endothelium-dependent vasodilation. The degree of endothelial dysfunction is associated with postexposure tumor necrosis factor (TNF)-α level, thus suggesting an inflammatory-mediated mechanism. Further, Peretz and colleagues51 exposed healthy adults and people with metabolic syndrome to diesel exhaust for 2 h. They found a dose-dependent constriction of the brachial artery and an elevation of plasma endothelin without a reduction of the endothelium-dependent vasodilation. The magnitude of the effect was surprisingly higher in healthy volunteers compared with the volunteers with metabolic syndrome. In addition, Mills and colleagues52 showed that 1 h exposure to DE (300 μg/m3) impairs the vasodilation response of the resistance vessels to acetylcholine, bradykinin, and nitroprusside.

In a subsequent study of patients with CAD, Mills and colleagues53 demonstrated that exercise-induced ST-segment depression is greater when inhaling diesel exhaust compared with inhaling filtered air, although a contemporary impairment of the vascular function could not be demonstrated in this study. The authors suggest that this might have been due to the characteristic of the study population (ie, pre-existing endothelial dysfunction in patients with CAD) and selected time of measures or medications taken by the patient, and they hypothesize that a vascular dysfunction at the coronary site may be responsible for the enhanced ischemic effect of exercise that was observed. Finally, Lund and colleagues54 showed that exposing healthy young adults to 100 μg/m3 of diesel exhaust for 2 h raises the plasma endothelin-1 level and matrix metallopeptidase-9 expression and activity within 30 min. Thus, even short-term exposures can rapidly alter factors, such as MMP activity, which are mechanistically linked to causing atherosclerotic plaque disruption. However, not all the studies have been consistent in showing a vasomotor effect after human experimental exposure to air pollution.1

Blood Pressure: Human experimental studies of the effect of inhaling air pollutants on blood pressure have produced different results in various experimental settings. For instance, exposures to concentrated ambient particles and ozone have been associated with acute arterial vasoconstriction and increased diastolic blood pressure (DBP) (3 to 6 mm Hg) but small or no increases in systolic blood pressure (SBP).50 In a study of healthy adults completing a 2-h walk along a Beijing roadway, Langrish, and colleagues55 found that exposure to ambient PM2.5 (86 to140 g/m3) amplified exercise-induced increases in SBP. Further, they observed a 7-mm Hg reduction of SBP when the participants wore PM-reducing masks. Finally, in a recent experimental study, 45 people who had never smoked were exposed to diesel exhaust (200 μg/m3 of fine PM) and filtered air for 120 min on days separated by ≥ 2 weeks. Blood pressure was measured pre-exposure, at 30-min intervals during exposure, and 3, 5, 7, and 24 h after the initial exposure. In this study, inhaling diesel exhaust was associated with a rapid increase (4.4 mm Hg combining readings 30 to 90 min after exposure) in SBP but not DBP in young people who did not smoke, and it was independent of the perception of exposure.56

A recent, observational cohort trial studied 848 elderly men and followed up with them for approximately 12 years in the Boston area in an attempt to determine the relationship between long-term exposure to traffic-related air pollution and blood pressure. The results indicated that long-term exposure to traffic particles was associated with increased blood pressure; in particular, an increase in 1-year average black carbon exposure (0.32 μg/m3) was associated with a 2.64-mm Hg increase in SBP (95% CI, 1.47-3.80) and a 2.41-mm Hg increase in DBP (95% CI, 1.77-3.05).57

Heart Rate Variability
Several panel and experimental human studies have investigated the relationship between exposure to air pollution and reduction of heart rate variability (HRV). In fact, since HRV is regulated by the autonomic nervous system, its variations may provide useful information on autonomic control of the heart after exposure to air pollution.

In one study, elderly individuals who were otherwise healthy experienced significant decreases in HRV immediately after exposure to concentrated ambient particles (CAPs).58 Gong and colleagues59 studied healthy men and men with asthma who were exposed to coarse CAPs while performing intermittent exercise. HRV was not immediately affected after the exposure, but it did decrease in both groups at 4 and 22 h after the end of the exposure; greater responses were seen in the healthy group.59 In another study, the same group of researchers exposed healthy elderly individuals and those with COPD to CAP for 2 h with intermittent mild exercise.60Surprisingly, HRV, over many hourly intervals, was lower after CAP exposure in the healthy elderly participants but not in those with COPD.60 In another study, Samet and colleagues61 compared the effects of 2-h exposures with intermittent exercise to ultrafine (average concentration 47 μg/m3), fine (average concentration 120 μg/m3), and coarse (average concentration 89 μg/m3) CAP among healthy participants. In this study, only the coarse fraction CAP produced a statistically significant decrease in the standard deviation of normal-to-normal heart rate 20 h after exposure compared with filtered air. Exposure to UFP and fine CAP did not affect HRV.61

It should be mentioned that panel studies and some controlled-exposure studies have reported no acute changes or, on occasion, increases in HRV metrics in subsets of individuals.1


In summary, there is strong coherent and reproducible epidemiologic evidence that exposure to air pollution poses a modest but significant risk for cardiovascular health.

However, epidemiologic studies are often limited because they do not assess individual exposure but rather use data from monitor stations to estimate individual exposure. Thus, individual estimates may not be accurate even after adjusting for typical confounders. In contrast, panel studies and human experimental exposure studies do not show the same magnitude of effects that one would expect based on the epidemiologic data. Nevertheless, results of epidemiologic analysis are consistent across continents and show a dose-response relationship between exposure and adverse cardiovascular outcomes; but, more importantly, efforts to reduce air pollution have been associated with improvements in cardiovascular outcome. In view of the great public health burden of CVD and the important contribution of air pollution to cardiovascular morbidity and mortality, additional research addressing mechanistic pathways, population susceptibility, and risk reduction strategies is necessary.


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