Cardiovascular effects of ambient particulate air pollution exposure

Introduction

An association between high levels of air pollutants and human disease has been known for more than half a century. Air pollution is composed of a heterogeneous mixture of compounds including ozone (O₃), carbon monoxide (CO), sulfur dioxide (SO₂), nitrogen oxides (NO_x), liquids and particulate matter (PM). Substantial epidemiological evidence implicates air pollution, in particular PM, as a major risk factor with serious consequences on human health.^1-3 Of particular interest in PM are the particles that are ≤ 10 μm in diameter (PM₁₀), since these are the PM that ultimately enter the lungs.⁴ PM is further divided into coarse (10 to 2.5 μm, PM_10-2.5), fine (<2.5 μm, PM_2.5) and ultrafine particles (<0.1 μm, PM_0.1).¹ These particles are composed of solid and liquid components that originate from vehicle exhaust, road dust, smokestacks, forest fires, windblown soil, volcanic emissions, and sea spray. Particle size, surface area, and chemical composition determine the health risk posed by PM. Particulate and gaseous pollutants co-exist in the air and may both induce adverse health effects, whereas compelling data implicate PM as a major perpetrator of various types of human disease. PM rarely exists by itself within the ambient environment since gaseous and semi-volatile/volatile compounds (i.e. aldehydes and polycyclic aromatic hydrocarbons) are constantly changing and interacting. Many of these vapor-phase compounds attach to the surface of PM and/or themselves form secondary aerosol particles.

Due to their small size, PM_2.5 and PM_0.1 are inhaled deeply into the lungs, with a portion depositing in the alveoli and entering the pulmonary circulation, and presumably the systemic circulation. The adverse effects of PM on the cardiovascular system have been established in a series of major epidemiologic and observational studies.^5-9 Although life expectancy has been improved significantly since air pollution levels have been reduced,^10-13 the mechanisms of the effects of air pollution on cardiovascular disease remain unclear. In this review, primary effects of PM on the cardiovascular system will be summarized, along with potential mechanisms involved in disease progression. In addition, PM-exaggerated cardiovascular-associated disorders, such as obesity and metabolic syndrome, are also described in relation to progression following PM exposure.

Cardiac Events and Hospital Admission

Cardiac function requires an appropriate interplay among three key components: balanced tone of the autonomic nervous system, adequate myocardial function as the motor unit, and rhythmic initiation and conduction of electrical impulses to maintain the sequence and latency of atrial and ventricular activation and repolarization.¹⁴ PM exposure can result in significant changes in many cardiovascular indices, such as heart rate, heart rate variability, blood pressure, and blood coagulability.

Epidemiological studies have shown an association between air pollution and adverse health effects since the 1930s.¹⁵ In the 1970s, broad investigations were conducted on human health, in particular pulmonary and cardiovascular diseases.^16-18 Since the 1990s, studies concerning air pollution and cardiovascular diseases have intensified, especially regarding cardiovascular mortality and hospital admission for sudden cardiac events.^19-23 Specifically, Burnett et al. examined the effect of ambient air pollution on cardiac disease exaggeration by relating daily fluctuations in admissions to 134 hospitals for congestive heart failure in the elderly to daily variations in ambient concentrations of CO, NO₂, SO₂, O₃, and the coefficient of haze in Canada’s 10 largest cities for the 11-year period 1981-1991. They found that the daily high-hour ambient CO concentration recorded on the day of admission displayed the strongest and most consistent association with hospitalization rates among the pollutants.¹⁹ The same group studied the ambient air pollution mix on cardiorespiratory disease exacerbation in the summers of 1992, 1993, and 1994, and found that the increase in O₃, NO₂, and SO₂ corresponded to an 11% and 13% increase in daily hospitalizations for respiratory and cardiac diseases, respectively. The inclusion of any one of the particulate air pollutants in multiple regression models did not increase these percentages.²⁰

To examine effect size estimates across large differences in both the levels of potential confounding factors and in their correlation with airborne particle concentration, particle concentration was found to be a significant risk factor for elevated mortality, and the relative risk was for a 100 mg/m³ increase in TSP concentration.²¹ To separate the effects of different air pollutants, daily counts of admissions to all hospitals in Tucson, AZ for cardiovascular disease in persons age ≥ 65 years were analyzed, and indicated that both PM₁₀ and CO were associated with increased risk of cardiovascular hospital admissions with admissions increased by 2.75% for an interquartile range increase (23 mg/m³) in PM₁₀ and by 2.79% for an interquartile range increase (1.66 parts per million) in CO.²³ It is increasingly recognized that exposure to ambient PM contributes to significant adverse health effects and is a risk factor for the development of ischemic cardiovascular events via exacerbation of atherosclerosis, coronary artery disease, and the triggering of myocardial infarction, even within hours following exposure.²⁴ Studies have demonstrated a significant elevation in the incidence of life-threatening myocardial infarctions²⁵ and cardiac arrhythmias²⁶ in the immediate periods (hours to days) following exposure to high levels of atmospheric PM_2.5.

PM pollution is also linked to an increased risk for hospital admission for cardiovascular and respiratory diseases,²⁷ increased risk of myocardial infarction among the elderly,²⁸ triggering of acute cardiac decompensation in heart failure patients,²⁹ and an increase in the rate of hospital admissions for exacerbation of congestive heart failure.³⁰ Recently, variations in the relative risk of hospitalization associated with ambient exposure to PM_2.5 total mass and chemical composition was investigated in the U.S. from 1999 through 2005. This study found a positive statistically significant association between county-specific estimates of the short-term effects of PM_2.5 on cardiovascular and respiratory hospitalizations and county-specific levels of vanadium, elemental carbon, or nickel PM_2.5 content, especially in the Northeast region.^{31, 32} There is a body of literature, as early as the 1970s,³³ indicating a correlation between air pollution and hospital admission for an acute event. Table 1 depicts selected investigations regarding air pollution and hospital admissions, particularly due to sudden cardiac events.

Table 1.

The Effect of Air Pollution on Acute Hospital Admission

Author s	Key Findings	Diseases	Poll utan ts	Subj ect	Yea r	Locati on	Ref eren ce
Burnett , et al	Exposure associated with 11% and 13% increased daily hospitalizations for respiratory and cardiac diseases, respectively	Respirato ry and cardiac diseases	PM1 0, O3, NO2 , SO2, CO	Not spe cific	199 2- 199 4	Ontari o, Cana da	20
Domini ci, et al	Short-term exposure to PM2.5 associated with increased hospital admission for cardiovascular and respiratory diseases	Cardiova scular and respirator y disease	PM2. 5	>65 year s	199 9- 200 2	204 US counti es	27
Welleni us, et al	Exposure associated with increased hospital admission for CHF, with	CHF	PM1 0	≥65 year s	198 6- 199 9	7 US cities	30
Bell, et al	Strong relationship between PM2.5 and hospitalization due to respiratory and cardiovascular diseases, especially in the Northeast region, with a 1.49% increase in hospitalizations of cardiovascular diseases per 10-μg/m3 increase in same-day PM2.5,	Respirato ry and cardiovas cular diseases	PM2. 5	≥65 year s	199 9- 200 5	202 US counti es	31
Bell, et al	Higher PM2.5 content of nickel, vanadium, and elemental carbon associated with higher risk of cardiovascular and respiratory hospitalizations	Cardiova scular and respirator y diseases	PM2. 5 & che mic al com posi tion	≥65 year s	199 9- 200 5	106 US counti es	32
Morga n, et al	Exposure associated with increased hospitalization for respiratory and heart disease, with increase in daily maximum 1-hour particulate concentration associated with an increase of 3.01% in COPD and 2.82% in heart disease admissions	Respirato ry and heart disease	PM2. 5, O3, NO2 , PM1 0	All age s	199 0- 199 4	Sydne y, Austr alia	34
Schwa rtz, et al	Exposure associated with hospital admissions for heart disease, with daily variation in PM10 associated with 2.48% increase and daily variation in CO associated with 2.79% increase	Heart disease	PM1 0, CO	≥65 year s	198 8- 199 0	8 US counti es	35
Presco tt, et al	Exposure associated with emergency hospital admission from cardiac and respiratory disease, positive association with PM10 and negative association with O3	Cardiac and respirator y disease	PM1 0, CO, NO2 , O3	All age s	198 1- 199 5	UK	36
Linn, et al	Exposure associated with increased hospitalization for cardiopulmonary illness, with a 25th-75th percentile increase in CO predicted an increase of 4% in cardiovascular admission, and NO2 and PM10 but not O3 showed similar increases in cardiovascular disease	Cardiopul monary disease	PM1 0, CO, NO2 , O3	Adul ts	199 2- 199 5	Los Angel es, US	37
Jansse n, et al	PM10 associated with hospital admissions, especially for cardiovascular disease in 14 cities in summer and winter	Cardiova scular disease	PM1 0	Not spe cific	199 3	14 US cities	38
Wong, et al	Air pollution has similar associations with daily cardiorespiratory admissions in both cities with significant positive association observed with PM10, NO2, SO2, and O3 in both cities	Cardiores piratory disease	PM1 0, O3, SO2, NO2	All age s	199 2- 199 7	Hong Kong, Londo n	39
McGo wan, et al	PM10 exposure associated with cardio-respiratory admission, with 3.37% increase in respiratory admissions and 1.26% rise in cardiac admissions for each interquartile rise in PM10	Cardio- respirator y disease	PM1 0, CO, SO2, NOx	All age s	198 8- 199 8	New Zeala nd	40
Mann, et al	Exposure associated with hospital admission for myocardial infarction, with a 1-ppm increase in CO associated with a 3.60% increase in same-day IHD admissions with a secondary diagnosis of CHF, a 2.99% increase in persons with a secondary diagnosis of ARR, and a 1.62% increase in IHD admissions in persons without either secondary diagnosis	Myocardi al infarction	PM1 0, NO2 , CO	≥40 year s	198 8- 199 5	Califo rnia, US	41
Koken, et al	Exposure associated with increased hospitalization for cardiovascular disease, with O3 associated with an increase in the risk of hospitalization for acute myocardial infarction, coronary atherosclerosis, and pulmonary heart disease, SO2 for cardiac dysrhythmias, and CO for congestive heart failure	Cardiova scular disease	PM1 0, CO, SO2, O3, NO2	>65 year s	199 3- 199 7	Color ado, US	42
Fung, et al	Exposure to SO2 associated with daily cardiac hospital admission, with the percentage increase in daily admission 2.6% for current day SO2, 4.0% for 2-day mean level, and 5.6% for 3-day mean level for an increase in interquartile range of 19.3 ppb, and the contributing effect of SO2 remained significant for all three levels when PM10 included	Cardiac disease	SO2, PM1 0	≥65 year s	199 5- 200 0	Ontari o, Cana da	43
Chang, et al	Exposure, especially to PM10, associated with increased hospital admissions for cardiovascular disease	Cardiova scular disease	PM1 0, O3, NO2 , CO	Not spe cific	199 7- 200 1	Taiwa n	44
Hossei npoor, et al	CO exposure associated with increased hospitalization due to angina pectoris, with each unit increase in CO caused a 1.00 increase in the number of admissions	Angina pectoris	NO2 , CO, O3, SO2, PM1 0	Not spe cific	199 6- 200 1	Iran	45
Mahes waran, et al	Exposure associated with coronary heart disease mortality and hospital admission, with admission rate ratios 1.00, 1.01, and 0.88 to the lowest NOx, PM10, and CO quintile categories, respectively	Coronary heart disease	NOx , PM1 0, CO	≥45 year s	199 4- 199 8	UK	46
Welleni us, et al	Exposure associated with transiently increased ischemia, but not hemorrhagic, stroke, with an interquartile range increase in PM10 associated with a 1.03% increase in admissions for ischemic stroke on the same day	Cardiac ischemia	PM1 0	≥65 year s	199 0	9 US cities	47
Low, et al	Exposure associated with stroke hospital admission, with statistically significant, independent exacerbating effects of SO2 and PM10	Stroke	O3, NO2 , SO2, CO, PM1	Adul ts	199 5- 200 5	New York City, NY	48
Barnett , et al	Exposure associated with adult cardiovascular hospital admissions, with all pollutants except O3 significantly associated with five categories of cardiovascular disease admissions in the elderly	Cardiova scular disease	NO2 , CO, PM2. 5, PM1 0, O3	All age s	199 8- 200 1	Austr alia, New Zeala nd	49
Johnst on, et al	PM10 exposure positively associated with respiratory disease and ischaemic heart disease admissions, especially in indigenous people	Respirato ry disease	PM1 0	All age s	200 0- 200 5	Austr alia	50
Migliar etti, et al	Significant association between the increase in emergency hospital admission for respiratory causes and exposure, with a mean increase in emergency hospital attendance of 2.20% and 2.55% per 10 μg/m3 increase in exposure to SO2 and TSP, respectively, and a mean increase of 5.30% per 1 mg/m3 increase in exposure to CO.	Respirato ry disease	SO2, CO, TSP	Adul ts	199 7- 199 9	Italy	51
Peng, et al	Significant associations between PM10-2.5 and hospital admissions for cardiovascular and respiratory diseases, with a 10-μg/m3 increase in PM10-2.5 associated with a 0.36% increase in cardiovascular disease admissions on the same day	Cardiova scular and respirator y diseases	PM2. 5, PM1 0, PM1 0-2.5	>65 year s	199 9- 200 5	US	52
Yang, et al	CHF admission associated with air pollutants on warm days in the single-pollutant model of PM10, NO2, CO, or O3	CHF	PM1 0, NO2 , CO, O3	Adul ts	199 6- 200 4	Taiwa n	53
Middlet on, et al	Increased risk of hospitalization with PM10 and O3, with every 10 μg/m3 increase in daily average PM10 associated with a 0.9% increase in all-cause and 1.2% increase in cardiovascular admissions	All- cause, especiall y cardiovas cular disease	PM1 0, O3	All age s	199 9- 200 4	Cypru s	54
Lin, et al	Positive association between respiratory hospital admissions and ambient O3 level 2 days prior to admission in 5 of the 11 regions	Respirato ry disease	O3	0-17 year s	199 9- 200 1	New York State	55

Note: CHF, chronic heart failure; O₃, ozone; CO, carbon monoxide; NO₂, nitrogen dioxide; BC, black carbon; OC, organic carbon; SO₂, Sulfur dioxide; TSP, total suspended particulate; NO_x, nitrogen oxides. IHD, ischemic heart disease; ARR, arrhythmia

Changes in Heart Rate and Cardiac Function

In an attempt to investigate associations between ambient PM and cardiovascular function in a repeated measures study in Boston residents, exposure to PM_2.5 with an average concentration of 15.5 μg/m³ was associated with decreased vagal tone, resulting in reduced heart rate variability.⁵⁶ In another study that evaluated changes in mean heart rate and heart rate variability in humans, there was an association between exposure to PM₁₀ on a previous day by 100 μg/m³ with significantly increased heart rate by 5-10 beats/min, suggesting that changes in cardiac autonomic function, reflected by changes in mean heart rate and heart rate variability, may be part of the pathophysiological mechanism linking cardiovascular mortality and PM.⁵⁷ In the ULTRA (Exposure and Risk Assessment for Fine and Ultrafine Particles in Ambient Air) study ⁵⁸, elevations in PM predicted risk for exercise-induced ST-segment depression in subjects with coronary artery disease. Another study in 3,827 participants who underwent cardiac magnetic resonance imaging between 2000 and 2002 found that participants living within 50 miles of a major roadway had a higher cardiac function-left ventricular mass index (LVMI) associated with PM_2.5 elevation, indicating chronic vascular end-organ damage from traffic-related environmental exposure.⁵⁹ Several other studies have demonstrated a link between changes in heart rate and PM levels in mice⁶⁰ and elderly humans.⁶¹ The possible mechanisms involved in these events include disturbances in cardiac autonomic control,⁶² reduction in cardiac vagal control,⁶³ decreases in parasympathetic tone,⁶⁴ and an imbalance in cardiac autonomic control.⁶⁵

Thrombosis and Other Changes in Hemostasis

PM has been associated with transient increases in plasma viscosity, acute-phase reactants, and endothelial dysfunction, as well as altered autonomic control of the heart. The effect of intravenous or intratracheal administration of ultrafine polystyrene particles, diesel exhaust particles, or PM_2.5 on thrombus formation was investigated, indicating the effects of circulating particles on changes in hemostasis.^66-71 In 3256 randomly selected men and women aged 25-64 years, high concentrations of SO₂, CO, and TSP were associated with increased plasma viscosity.⁷² The Holland group studied approximately 330 deaths during 1986 to 1994 and found that embolisms and thrombotic changes were increased following exposure to CO, O₃, and SO₂.⁷³ In a double-blind randomized crossover study, 20 healthy volunteers were exposed to dilute diesel exhaust and filtered air in UK and Sweden; thrombus formation, coagulation, platelet activation and inflammatory markers were measured post-exposure. These investigators found that diesel exhaust inhalation increased thrombus formation, platelet-neutrophil and platelet-monocyte aggregates.⁷⁴

Other epidemiological data link PM exposure to an augmentation of systemic inflammation, as measured by C-reactive protein (CRP),²⁶ an acute phase protein associated with adverse outcomes in patients with unstable ischemic syndromes. In this prospective cohort survey in 1984/85 with a 3-year follow-up of 631 randomly selected men aged 45 to 64 years free of cardiovascular disease at entry, the odds of observing CRP concentrations above 5.7 mg/L (>90th percentile) tripled at normal ambient PM concentrations, and increases of 26 μg/m³ total suspended particles (mean of 5 days) raised the odds of having a CRP level 50% greater than the 90th percentile.²⁶ Increased levels of fibrinogen, platelets and white blood cell counts were also associated with exposure to TSP.^{75, 76}

The regulation of fibrinolysis is another important aspect of endothelial function. Small areas of endothelial denudation and thrombus deposition are a common finding on the surface of atheromas and are usually subclinical. Therefore, endogenous fibrinolysis of the lesion might prevent thrombus propagation and vessel occlusion.⁷⁷ Nevertheless, under adverse proinflammatory states or imbalances in the fibrinolytic system, microthrombi may progagate and ultimately lead to arterial occlusion and tissue infarction.⁷⁸ In a series of double-blind, randomized crossover studies, both healthy men and patients with stable coronary artery disease were exposed to dilute diesel exhaust (PM 300 μg/m³) for one hour while performing intermittent exercise.^79-81, and were then challenged by intrabrachial bradykinin, acetylcholine, sodium nitroprusside, and verapamil. Although there was a dose-dependent increase in blood flow with each vasodilator, this response was attenuated with bradykinin, acetylcholine, and sodium nitroprusside infusions two hours after exposure to diesel exhaust, which persisted at six hours. Bradykinin caused a dose-dependent increase in plasma tissue plasminogen activator that was suppressed six hours after exposure to diesel.⁷⁹ In a double-blind, randomized, crossover study, 20 men with a prior myocardial infarction were exposed, in two separate sessions, to dilute diesel exhaust (300 μg/m³) or filtered air for one hour during periods of rest and moderate exercise in a controlled-exposure facility. Exercise-induced ST-segment depression was found in all patients, but there was a greater increase in the ischemic burden during exposure to diesel exhaust. Exposure to diesel exhaust reduced the acute release of endothelial tissue plasminogen activator other than aggravating preexisting vasomotor dysfunction.⁸¹ In these studies, the acute release of tissue plasminogen activator (t-PA), which is a key regulator of endogenous fibrinolytic capacity, was reduced after diesel exhaust inhalation. This effect persisted for six hours following initial exposure,⁷⁹ with the magnitude of this reduction comparable to that seen in cigarette smokers.⁸² This antifibrinolytic effect further underscores the prothrombotic potential of air pollution, especially under circumstances of vascular injury.

Baccarelli et al have performed several studies regarding air pollution exposure and changes in blood homeostasis. To investigate the association between pollution levels (PM₁₀, CO, NO₂, SO₂, and O₃) and changes in global coagulation tests, such as prothrombin time (PT) and activated partial thromboplastin time (APTT), 1218 normal subjects from the Lombardia Region, Italy were tested and it was shown that air pollution is associated with changes in global coagulation function, suggesting a tendency towards hypercoagulability after short-term exposure to air pollution.⁸³ The effects of exposure to PM₁₀ on risk of developing deep vein thrombosis (DVT) in 870 patients and 1210 controls from the Lombardy region in Italy between 1995 and 2005 was then tested, with findings suggesting that long-term exposure to PM₁₀ is associated with altered coagulation function and DVT risk.⁸⁴ Using distance from roads as a proxy for traffic exposure to further investigate whether living near major traffic roads increased the risk of deep vein thrombosis, 663 patients with DVT of the lower limbs and 859 age-matched controls from cities with populations >15, 000 inhabitants in the Lombardia Region of Italy from 1995 through 2005 were examined. It was found that the risk of developing DVT was increased for subjects living near a major traffic road compared with those living further away, which was approximately linear over the observed distance range and was not modified after adjusting for background levels of PM, indicating that living near major traffic roads is associated with an increased risk of developing DVT.⁸⁵ A summary of these effects is presented in Table 2.

Table 2.

The Effect of Air Pollution on Changes in Blood Homeostasis

Author s	Key Findings	Pollut ants	Subj ect	Yea r	Locatio n	Ref eren ce
Peters, et al	Exposure associated with increased plasma viscosity, with the odds ratio 3.6 for plasma viscosity above the 95th percentile of the distribution comparing measurements during the air pollution episode with non-episode measurements in men and the odds ratio 2.3 for women	TSP, SO2, CO	25- 64 year s	198 4- 198 5	Augsbu rg, Germa ny	72
Hoek, et al	Exposure associated with increased embolism, thrombosis, and mortality, with heart failure deaths responsible for about 30% of the cardiovascular deaths related to PM10, SO2, CO, and NO2	PM10, CO, SO2, NO2	All age s	198 6- 199 4	The Netherl ands	73
Luckin g, et al	Exposure associated with increased ex vivo thrombus formation and in vivo platelet activation, with increased thrombus formation under low- and high-shear conditions by 24% and 19%, respectively	Diesel exhau st	21- 44 year s	200 8	UK, Swede n	74
Mills, et al	Exposure associated with inhibition of endogenous fibrinolytic capacity, with a greater increase in the ischemic burden during exposure to diesel exhaust	Diesel exhau st	59- 61 year s	200 7	UK	81
Baccar elli, et al	Exposure associated with changes in global coagulation function, with PT shorter with higher PM10 and NO2	PM10, NO2, SO2, CO, O3	11- 84 year s	199 5- 200 5	Italy	83
Baccar elli, et al	Exposure associated with altered coagulation function and DVT risk, with each increase of 10 μg/m3 in PM10 associated with a 70% increase in DVT risk	PM10	18- 84 year s	199 5- 200 5	Italy	84
Baccar elli, et al	Living near major traffic roads is associated with increased risk of DVT, with the increase in DVT risk approximately linear over the observed distance range from 718 to 0 meters	Not specifi c (dista nce from major roads)	18- 84	199 5- 200 5	Italy	85
Ray, et al	Exposure associated with activated circulating platelets and increased leukocyte-platelet aggregates, with the MFI of CD11b on the surface of circulating monocytes and PMN of biomass users increased by 50 and 68%, respectively, and a 62 and 48% increase in MFI observed in CD18 expression on the surface of these cells in biomass users	PM2. 5, PM10	21- 60 year s	200 3- 200 4	India	86

Note: DVT, deep venous thrombosis; O₃, ozone; CO, carbon monoxide; NO₂, nitrogen dioxide; SO₂, Sulfur dioxide; TSP, total suspended particulate; MFI, mean fluorescence intensity; PMN, polymorphonuclear leukocytes; PT, prothrombin time

Atherosclerosis

The main pathway by which PM contributes to increased cardiac risk is by initiating and promoting atherosclerotic progression, the underlying cause of most cardiovascular diseases.^87-89 Atherosclerotic lesions can lead to ischemia of the heart, brain, or extremities. The disruption of a vulnerable but not necessarily stenotic atherosclerotic plaque in response to hemodynamic stress has been suggested as a mechanism that can trigger a myocardial infarction. Air pollution may induce atherosclerosis in the peripheral arteries, coronary arteries and aorta. Acute exposure to elevated PM has been associated with increased acute cardiovascular mortality, especially with an at risk subset of the population, whereas prolonged exposure has been considered as a causative factor for atherosclerosis.¹ In an epidemiological study, Pope et al reported that PM_2.5 exposure is a risk factor for cause-specific cardiovascular disease mortality via mechanisms that likely include pulmonary and systemic inflammation, accelerated atherosclerosis, and altered cardiac autonomic function.⁷ The precise pathway through which PM induces initiation and progression of atherosclerosis has not been determined, but two hypotheses have been proposed and assessed experimentally. The original hypothesis proposed that inhaled particles provoke an inflammatory response in the lungs, with consequent release of prothrombotic and inflammatory cytokines into the circulation.⁹⁰ The alternative pathway proposed that inhaled, insoluble PM_2.5 or PM_0.1 could rapidly translocate into the circulation, with the potential for direct effects on homeostasis and cardiovascular integrity.⁹¹ The ability of PM_0.1 to cross the lung-blood barrier is likely to be influenced by a number of factors including particle size and charge, chemical composition, and propensity to form aggregates.³ Once in the circulation, PM_0.1 can interact with the vascular endothelium or have direct effects on atherosclerotic plaques, causing local oxidative stress and pro-inflammatory effects similar to those seen in the lungs. Either through direct translocation into the circulation or via secondary pulmonary-derived mediators, PM augments atherogenesis and causes acute adverse thrombotic and vascular effects.

In a series of animal models, mice fed high fat chow and exposed to ambient PM_2.5 demonstrated marked increases in plaque area, macrophage infiltration, expression of the inducible isoform of nitric oxide synthase, increased generation of reactive oxygen species, and greater immunostaining for the protein nitration product 3-nitrotyrosine, indicating that exposure to low concentrations of PM_2.5 altered vasomotor tone, induced vascular inflammation, and potentiated atherosclerosis.^{92, 93} Consistently, Chen and Nadziejko exposed the ApoE knockout mice and ApoE, LDLr-deficient mice to ambient PM_2.5 ⁹⁴ and demonstrated that subchronic exposure to ambient PM in these mice had a significant impact on the size, severity, and composition of aortic plaque. The PM_0.1 component could have a greater atherogenic effect than the PM_2.5 fraction. Araujo et al compared the proatherogenic effects of ambient particles of <0.18 μm (ultrafine particles) with particles of <2.5 μm in apoE knockout mice.⁹⁵ Ultrafine PM-exposed mice exhibited significantly larger early atherosclerotic lesions than mice exposed to PM_2.5 or filtered air. Also, exposure to ultrafine particles resulted in an inhibition of the anti-inflammatory capacity of plasma high-density lipoprotein and greater systemic oxidative stress. Their data showed that exposure to concentrated ultrafine PM rich in polycyclic aromatic hydrocarbons produced more inflammation, systemic oxidative stress, and atheroma formation than the fine fraction in apoE-knockout mice. In the Watanabe heritable hyperlipidemic rabbit model, four-week exposure to ambient PM₁₀ resulted in dose-dependent alveolar and systemic inflammatory responses and progression of atherosclerosis in the coronary arteries and the aorta.⁸⁹ The volume fraction of coronary atherosclerotic lesions was increased in response to PM₁₀ exposure. The atherogenic effects correlated with the extent of PM phagocytosed by alveolar macrophages in the lung and coupled with an enhanced release of bone marrow monocytes. These precursors of macrophages play a key role in atherogenic inflammatory responses. In addition, exposure to PM₁₀ also caused an increase in plaque cell turnover and extracellular lipid pools in coronary and aortic lesions, as well as in the total amount of lipids in aortic lesions. Therefore, progression of atherosclerosis and increased vulnerability to plaque rupture may underlie the relationship between PM and increased cardiovascular death.

A panel study in Los Angeles provided the first evidence of a link between chronic PM exposure and atherosclerosis in humans.⁹⁶ This study using data from 798 participants of two clinical trials found that a 10-μg/m³ increase in PM_2.5 was associated with an increase in carotid intima-media thickness (CIMT), an ultrasonic measure of atheroma. For a cross-sectional exposure contrast of 10 μg/m³ PM_2.5, CIMT increased by 5.9% (95% confidence interval, 1-11%). Adjustment for age reduced the coefficients, but further adjustment for covariates indicated robust estimates in the range of 3.9-4.3%. Among older subjects (≥60 years of age), women, never smokers, and those reporting lipid-lowering treatment at baseline, the associations of PM_2.5 and CIMT were larger with the strongest associations in women 60 years of age (15.7%, 5.7-26.6%), suggesting that chronic ambient PM exposure may affect the development of atherosclerosis in humans. In a study examining the role of traffic-related, long-term exposure to PM_2.5 (mean concentration 22.8 μg/m³) in 4494 adult participants from the Heinz Nixdorf Recall Study, , a 50% reduction in the distance between the residence and a main road resulted in a 10.2% increase in coronary artery calcification.⁹⁷ These studies support the concept that air pollution causes a progression of atherosclerosis. In a cross-sectional analysis, Allen et al investigated exposure to PM_2.5 and residential proximity to major roads in relation to abdominal aortic calcification, a sensitive indicator of systemic atherosclerosis.⁹⁸ Aortic calcification was measured by computed tomography among 1147 persons, in five US metropolitan areas, enrolled in the Multi-Ethnic Study of Atherosclerosis. They found a slightly elevated risk of aortic calcification with a 10 μg/m contrast in PM_2.5, and the PM_2.5-associated risk of aortic calcification was stronger among participants with long-term residence near a PM_2.5 monitor and among participants not recently employed outside the home. Their findings revealed a strong relationship between ambient PM and systemic atherosclerosis. A summary of these effects on the development of atherosclerosis is presented in Table 3.

Table 3.

The Effect of Air Pollution on the Development of Atherosclerosis

Author s	Key Findings	Polluta nts	Subje ct	Year	Location	Refer ence
Pope, et al	Exposure associated with acute ischemic coronary events (unstable angina and myocardial infarction), with PM2.5 elevated by 10 μg/m3 associated with increased risk of acute ischemic coronary events equal to 4.5%	PM2.5	Adults	1994- 2004	US	8
Kunzli, et al	Exposure associated with an increase in carotid intima-media thickness, with a cross-sectional exposure contrast of 10 μg/m3 PM2.5, CIMT increased by 5.9%	PM2.5	≥40 years	1998- 2003	California , US	96
Hoffma nn, et al	Long-term residential exposure associated with coronary atherosclerosis, with a reduction in the distance between the residence and a major road by half associated with a 7.0% higher CAC	PM2.5	45-74 years	2000- 2003	Germany	97
Allen, et al	Associations with systemic atherosclerosis stronger among participants with less exposure, with elevated risk of aortic calcification with a 10 μg/m contrast in PM2.5	PM2.5	45-84 years	2000- 2002	US	98

Note: CIMT, carotid intima-media thickness; CAC, coronary artery calcification

Vasomotor Tone Alterations and Hypertension

The effect of air pollution on vascular dysfunction and blood pressure change has been investigated in both humans and animals for years. In 2607 men and women aged 25 to 64 years who participated in the Augsburg Monitoring of Trends and Determinants in Cardiovascular Disease survey in association with air pollution episodes in Europe in January 1985, continuous concentrations of TSP and SO₂ were associated with an increase in systolic blood pressure.⁹⁹ To investigate the associations between PM_2.5 and blood pressure during 631 repeated visits for cardiac rehabilitation in 62 Boston residents with cardiovascular disease, data analyses indicated that for an increase from the 10th to the 90th percentile in mean PM_2.5 levels during the 5 days prior to the visit (10.5 μg/m³), there was a 2.8-mm Hg increase in resting systolic, a 2.7-mm Hg increase in resting diastolic, and a 2.7-mm Hg increase in resting mean arterial blood pressure. The mean PM_2.5 level during the two preceding days (13.9 μg/m³) was associated with a 7.0-mm Hg increase in diastolic and a 4.7-mm Hg increase in mean arterial blood pressure during exercise in persons with resting heart rate ≥70 bpm, but not associated with an increase in blood pressure during exercise in persons with heart rate <70 bpm.¹⁰⁰ In a study conducted in Italy comparing 68 traffic policemen and 62 controls (all male) at rest and during a symptom-limited incremental exercise test, 26 traffic policemen and none of the controls experienced exercise-induced ECG abnormalities or hypertension, along with the traffic exposed group demonstrated a number of significant changes in cardiorespiratory measures on exercise testing, suggesting that chronic occupational exposure to urban pollutants reduces resistance to physical effort and increases the risk of cardiovascular and respiratory effects.¹⁰¹

In an investigation of 40 healthy white male nonsmokers spontaneously breathing ambient air in Paris, France, gaseous pollutants were found to affect large artery endothelial function, whereas PM exaggerated the dilatory response of small arteries to ischemia.¹⁰² In detail, reactive hyperemia was significantly and positively correlated with PM_10-2.5. An increase in PM, 2 weeks apart, was significantly correlated with an increase in reactive hyperemia. Endothelial function was impaired by ordinary levels of pollution in healthy young males, in an urban area, and may be reduced by 50% between the least and the most polluted day.¹⁰² Potential mechanisms for PM-associated changes in blood pressure have been suggested to include an increase in sympathetic tone and/or the modulation of basal systemic vascular tone.¹⁰³ Two studies showing associations between air pollution and blood pressure followed subjects with chronic obstructive pulmonary disease (COPD). Linn et al found that an increase of 33 μg/m³ ambient PM₁₀ was associated with a 5.7 mmHg increase in systolic blood pressure.¹⁰⁴ In contrast, Brauer et al studied 16 non-smoking COPD patients residing in Vancouver equipped with a PM_2.5 monitor for seven 24-h periods, and found that although no associations between air pollution and lung function were statistically significant, weak associations were observed between particle concentrations and increased supraventricular ectopic heartbeats and with decreased systolic blood pressure. No consistent associations were observed between any particle metric and diastolic blood prressure, heart rate, heart rate variability (r-MSSD or SDNN), symptom severity, or bronchodilator use. Of the pollutants measured, ambient PM₁₀ was most consistently associated with health parameters.¹⁰⁵ In nonsmoking healthy and asthmatic volunteers exposed to concentrated fine ambient particulates (CAP) compared to filtered air (FA), systolic blood pressure was decreased in asthmatics and increased in healthy subjects during CAP exposure relative to FA. Cardiovascular (but not respiratory) symptoms increased slightly with CAP in both groups.¹⁰⁶ However, in 25 healthy adults exposed to two-hour inhalation of approximately 150 μg/m³ of CAP plus O₃, exposure to CAP plus O₃ caused a significant brachial artery vasoconstriction compared with FA inhalation,¹⁰⁷ suggesting that PM_2.5 CAP exposure (with/without O₃) were found to be inversely associated with systolic blood pressure in asthmatics, but positively associated in healthy subjects.^{106, 107}

In addition to the epidemiological and clinical studies, animal studies have provided evidence regarding the mechanism of action of air pollution exposure-induced changes in blood pressure. In an angiotensin II-induced hypertensive Sprague-Dawley rat model, exposure to concentrated ambient PM_2.5 for 10 weeks induced prolonged blood pressure recovery compared to the filtered air (FA)-exposed group.¹⁰⁸ In this study, aortic vasoconstriction to phenylephrine was potentiated with exaggerated relaxation to the Rho-kinase (ROCK) inhibitor Y-27632 and an increase in ROCK-1 mRNA levels and superoxide production in the PM_2.5-exposed group, suggesting that short-term PM_2.5 exposure exaggerates hypertension through superoxide-mediated upregulation of the Rho/ROCK pathway.¹⁰⁸ Subsequently, in a murine model exposed to concentrated ambient PM_2.5 for 12 weeks followed by a 14-day angiotensin II infusion in conjunction with fasudil, a Rho kinase antagonist, PM_2.5 exposure was found to potentiate angiotensin II-induced hypertension, which was abolished with fasudil treatment.¹⁰⁹ In addition, PM_2.5 exposure increased angiotensin II-induced cardiac hypertrophy, collagen deposition, and cardiac and vascular RhoA activation, suggesting that cardiovascular health effects are indeed the results of air pollution exposure.¹⁰⁹

Other Cardiovascular-Associated Events

Air pollution exposure has been shown to be linked to cerebrovascular diseases, such as stroke. In a study conducted in England and Wales in the early 1980s, stroke mortality showed strong correlations with atmospheric pollution levels, both in the winter and summer. These correlations were strengthened by standardization for season and for temperature.¹¹⁰ By examining death certificates in Philadelphia on 5% of the days with the highest particulate air pollution and 5% of the days with the lowest particulate air pollution during the years 1973-1980, the relative risk of dying from a stroke was elevated on days of high pollution.²² The effect of air pollution exposure on stroke has also been confirmed in Japan in 1980-1995 during the summer season.¹¹¹ In a recent investigation examining the association of long-term exposure to PM_2.5 with cardiovascular events, 65,893 postmenopausal women without previous cardiovascular disease in 36 U.S. metropolitan areas from 1994 to 1998 were studied. The results showed that each increase of 10 μg/m³ was associated with a 24% increase in the risk of a cardiovascular event and a 76% increase in the risk of death from cardiovascular disease. The risk of cerebrovascular events was also associated with increased levels of PM_2.5.⁹

Air pollution has recently been linked to diabetes and obesity. In a study conducted in 270 Boston residents by measuring 24 hour average ambient levels of air pollution (PM_2.5, particle number, black carbon, and sulfates) approximately 500 m from the patient examination site, it was found that diabetes confers vulnerability to effects of particles associated with coal-burning power plants and traffic.¹¹² Recently, in a high fat diet-induced obesity mouse model, PM_2.5-exposed mice exhibited marked whole-body insulin resistance, systemic inflammation, and an increase in visceral adiposity, which was associated with abnormalities in vascular relaxation to insulin and acetylcholine, increased adipose tissue macrophages and inflammatory cell adhesion in the microcirculation, providing a new link between air pollution and type 2 diabetes mellitus.¹¹³

Conclusion

Cardiovascular diseases have caused significant human and public health burden, with sustained reductions in air pollution exposure associated with increased life expectancy.¹⁰ Although significant improvements have been achieved in terms of air quality in the past decades, “clear sky visibility” over land has decreased globally over the past 30 years (except in Europe),¹¹⁴ indicating that we still have a long way to go in reducing air pollution levels and associated diseases. Future investigations on air pollution-induced cardiovascular diseases must not only include more studies to determine the mechanisms of action, but also examine the role of each specific component of air pollution in order to determine what combination of particles is to blame for this sudden increase in environmental-induced health concerns. This information is paramount for policy makers to determine acceptable levels of air pollution and to design ways to minimize the harmful effects of particles on the body.