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From www.bloodjournal.org by guest on June 18, 2017. For personal use only. Blood First Edition Paper, prepublished online June 10, 2011; DOI 10.1182/blood-2011-04-343111 Thrombogenicity and cardiovascular effects of ambient air pollution Massimo Franchini,1 Pier Mannuccio Mannucci2 1 Department of Transfusion Medicine and Hematology, Carlo Poma Hospital, Mantova, Italy; 2 Scientific Direction, IRCCS Cà Granda Foundation Maggiore Hospital, Milan, Italy. Short title: Air pollution and cardiovascular disease Correspondence: Pier Mannuccio Mannucci, MD Scientific Direction, IRCCS Cà Granda Foundation Maggiore Policlinico Hospital Via Pace 9, 20122 Milan, Italy Tel: ++ 39 02 5503 5414 Fax: ++ 39 02 54 100 125 e-mail: [email protected] 1 Copyright © 2011 American Society of Hematology From www.bloodjournal.org by guest on June 18, 2017. For personal use only. Abstract Exposure to air pollution is associated with adverse effects on health. In particular, a strong epidemiological association is observed between acute and chronic exposure to particulate matter (PM) and the occurrence of cardiovascular events -- coronary artery disease, cerebrovascular disease and venous thromboembolism -- especially among older people, people with diabetes and previous cardiovascular conditions. Multiple mechanisms have been postulated to cause the increase in atherothrombotic and thromboembolic events, including the activation by PM of inflammatory pathways and hemostasis factors, production of reactive oxygen species through the oxidative stress pathway, alterations in vascular tone and decreased heart rate variability (a marker of cardiac autonomic dysfunction and a predictor of sudden cardiac death and arrhythmias). Current knowledge on the biological mechanisms and the clinical impact of short- and long-term exposure to particulate air pollutants is discussed, emphasizing that life expectancy improved significantly in sites where air pollutants were controlled. Key words: air pollution, mortality, cardiovascular disease, acute myocardial infarction, venous thromboembolic disease. 2 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. Introduction Urban air pollution is a leading problem for environmental health.1 Even though much of the early research focused on respiratory diseases, more recent epidemiological studies demonstrated that air pollution substantially contributes to the onset and aggravation of cardiovascular diseases, and that these effects occur at relatively low levels of exposure.2-4 Air pollution definitely increases morbidity and mortality due to atherothrombotic events, causes more frequent hospitalizations and worsens pre-existing cardiac diseases (such as congestive heart failure and arrhythmias).5 In addition, recent preliminary findings suggest an association between air pollution and venous thromboembolism.3 In line with these observations, the World Health Organization (WHO) calculates that urban air pollution is an important cause of global mortality, being responsible for at least 700.000 premature deaths.6 For the individual, the risk of cardiovascular disease triggered by air pollution is relatively small. However, the public health burden is very important, owing to the unavoided exposure of large populations to this risk.7 Both gaseous air pollutants (i.e., ozone, sulfur and nitric oxides, carbon monoxide) and particulate matter (PM) cause adverse effects on health. However, the most serious effects are related to PM, because particles contain a broad range of toxic substances and are considered reliable indicators of other pollutants (such as nitric oxides) and hence of the global adverse impact of air pollution.8-10 Ambient PM is distinguished, according to aerodynamic diameter (AD), in coarse (PM10, AD between 2.5 and <10 μm), fine (PM2.5, AD <2.5 μm) and ultrafine particles (AD <0.1 μm). Upon inhalation, the coarser particles reach only the nasal cavities and upper airways, but fine particles reach the lower airways and alveoli. Composition of PM varies greatly and depends on geographical, meteorological and source-specific variables. In metropolitan areas, primary particles directly emitted in the ambient are a complex and heterogeneous mixture of solid and liquid components, including inorganic substances (sulfates, nitrates, ammonium, chloride, metals), elemental and organic carbon, crustal material and biological components (bacteria, spores, pollens)11. In addition, chemical conversion of gaseous species to aerosol particles in the 3 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. atmosphere leads to the formation of secondary particles. In metropolitan areas the great majority of environmental PM is antropogenic and originates from the combustion of fossil fuels, mainly from automobile traffic and domestic heating.10 There are also soil-related sources of PM that originate from road dust, smokestacks and windblown soil. The latter source can lead to the phenomenon of long-range transport and spread of airborne-suspended PM. This review focuses on the relationship between ambient air pollution, thrombogenicity and cardiovascular diseases through the analysis of the putative biological mechanisms and the strength of the epidemiological evidence. Biological mechanisms Even though the mechanisms by which air pollutants influences the risk of cardiovascular events are still under investigation, a number of plausible explanations are available.10 One possible pathway involves the finest particles (<2.5 nm) that upon inhalation penetrate beyond the upper respiratory tract into the parenchymal region of the lung, where they may be translocated into the circulating blood via interstitium, macrophage phagocytosis as well as epithelial cell endocytosis.12 Following PM inhalation, the lung releases locally and into the systemic circulation pro-oxidative (i.e., reactive oxygen species) and/or pro-inflammatory mediators (i.e., cytokines as interleukin-6 and tumor necrosis factor-α ) and such vasoactive hormones such as endothelins.13-20 Acute phase reactions take place and lead to the increase in plasma of such reactants as C-reactive protein and fibrinogen. In the lung the secretion of adhesion molecules by inflamed endothelial cells results in binding and activation of leukocytes and platelets, formation of platelet-leukocyte conjugates and generation of hemostatically active, tissue factor-bearing microparticles.21-23 A series of studies conducted in animals have demonstrated that acute exposure to proxies of particulate air pollutants leads to the activation of platelets and coagulation enzymes.23 Nemmar et al24 found that in hamsters the intratracheal instillation of ultrafine polystyrene particles enhanced thrombus formation, mainly through a mechanism involving platelet activation. In subsequent 4 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. experiments that employed diesel exhaust as proxy of ambient PM heightened thrombus formation did follow particle penetration into the circulating blood.25 In another study a persistent increase in thrombosis susceptibility to diesel exhaust particles was seen as long as after 24 hours. This prolonged effect was mitigated by pretreatment with sodium cromoglycate (a stabilizer of mast cells and basophil degranulation), suggesting that thrombosis was secondary to histamine release.26 These data provided evidence for a direct link between diesel exhaust, particle-induced release of histamine and pulmonary inflammation, which in turn caused thrombosis through systemic inflammation and platelet activation. However, pulmonary inflammation and thrombosis appeared to be associated events only at the latest time points, because histamine was increased in plasma only 6 and 24 hours after exposure to diesel exhaust and diphenhydramine (a histamine H1-receptor antagonist) mitigated thrombosis at 6 and 24 hours but not at 1 hour.27 It was hypothesized that direct effects of PM constituents reaching the circulation may be responsible for the earlierst prothrombotic effects. Pulmonary instillation of carbon nanotubes triggered neutrophil lung influx and circulating platelet-leukocyte conjugates were elevated 6 hours after exposure, whereas procoagulant microvesicular tissue factor activity and the peripheral thrombotic potential were increased 24 hours later.27 Inhibition of P-selectin (which mediates the adhesion of activated platelets to circulating leukocytes) abrogated these responses, demonstrating that rapid activation of circulating platelets by the pulmonary deposition of PM plays a crucial role.28 This series of experimental studies suggests that the delayed release in the lung of cell–derived mediators (eg, histamine), together with the earlier activation of circulating platelets by lung inflammation via P-selectin-dependent mechanisms, may mediate the prothrombotic effects of the proxies of particulate air pollution. It must be emphasized that the particles used in these studies do reproduce the situation of exposure to ambient PM in terms of size, but not in composition, because ambient PM contains an array of toxic substances that cause adverse effects well beyond their size. For instance, the content of transition metals like iron may be particular toxic through the oxidative 5 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. stress pathways, because they yield highly reactive oxygen species, including the hydroxyl radical through the Fenton reaction. In humans, increased exposure to air pollution is associated with the increase in plasma of several hemostasis components. For instance, in 3256 randomly selected people plasma viscosity increased markedly during an air pollution episode that lasted 13 days.29 Healthy volunteers experimentally exposed to concentrated PM had increased plasma levels of fibrinogen, an acute-phase inflammatory protein, an important determinant of increased viscosity and an established risk factor for venous and arterial thrombosis.18 Another marker of thrombophilia such as plasma homocysteine is positively associated with exposure to traffic-related pollutants, especially PM and black carbon.30 A study conducted in 1218 healthy individuals found that the degree of chronic exposure to air pollution was associated with the shortening of such a global coagulation test as the prothrombin time.31 The same study confirmed that homocysteine increases in proportion to the degree of exposure to gaseous and particulate air pollutants, albeit only in smokers.32 Bonzini et al demonstrated heightened thrombin formation in workers from a steel-production plant exposed to high concentrations of inhalable particles.33 In these workers the link between inflammation and hypercoagulability was emphasized by the concomitant increase in C-reactive protein.33 The fibrinolytic system is an important regulator of thrombus formation, propagation and vascular occlusion. In a series of double-blind experiments carried out by Mills et al.,34-36 healthy people as well as patients with stable coronary artery disease were randomly exposed to filtered air or high concentrations of diesel exhaust (300 μg/mm3) while performing intermittent exercise. The release from endothelial cells of tissue plasminogen activator, a key player in the regulation of endogenous fibrinolysis, was reduced upon exposure to diesel exhaust. This antifibrinolytic effect persisted for at least 6 hours after exposure, and was of similar magnitude to that seen in heavy smokers. On the whole, these findings in humans indicate that secondary pulmonary inflammation and/or microparticles penetrating directly into the blood cause a hypercoagulable state and 6 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. hypofibrinolysis, that in turn may trigger thrombotic cardiovascular events owing to heightened thrombus formation in blood vessels.37 Another mechanism for the occurrence of cardiovascular disease is perhaps related to the alterations induced by PM to the autonomic control of the heart.38,39 Animals exposed to diesel exhaust had reduced heart rate variability.40,41 These experimental data were substantiated by a number of clinical studies showing an inversely proportional relationship between PM concentration and heart rate variability.42-48 Decreased heart rate variability indicates the existence of a state of cardiac autonomy dysfunction and is a risk factor of sudden cardiac death due to arrhythmias. The adverse effects of particulate pollutants on the cardiac autonomic balance have also been documented through their effects on vascular tone and reactivity, leading to increased blood pressure.49-52 The underlying mechanisms responsible for the increase of the sympathetic drive remain unclear, but may involve activations of pulmonary neural reflex arcs and direct effects of pollutants on cardiac ion channels.53 In addition to these mechanisms, several studies in humans and animals have shown that exposure to PM results in the progression of atherosclerotic lesions through pro-inflammatory mechanisms.54 For instance, intratracheal administration of ambient PM10 in hyperlipidemic rabbits55 or long-term exposure to PM2.5 of genetically susceptible mice (apolipoprotein E-deficient) enhanced atherosclerotic plaque growth.56,57 ApoE-null mice exposed to ultrafine particles exhibited significantly more and larger atherosclerotic lesions than mice exposed to filtered air, through prooxidative effects and the inhibition of the anti-inflammatory capacity of plasma high-density lipoprotein.58 Thus, the forementioned experimental and clinical studies suggest that heightened thrombus formation over atherosclerotic plaques is likely to be an important mechanistic player in the occurrence of cardiovascular events, as supported by the close temporal relationship existing between short-term peaks of pollutants and concomitant increases in atherothrombotic events such as acute myocardial infarction (AMI) and ischemic stroke (see below). Figure 1 summarizes the 7 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. mechanism and pathways that are likely to be involved in the cardiovascular effects of ambient air pollution. Population studies The relationships between ambient air pollution and cardiovascular events are usually represented by dose-response exposure functions that express the relative risk of adverse events for a specified increase in air pollutants. The clinical studies can be broadly divided into short-term and long-term studies. This artificial distinction is justified by the fact that the former investigate the effects of acute transient peaks of exposure to air pollution with emphasis on mortality and hospitalization, and includes mostly time series analyses over a few days of increased PM exposure (changes generally ranging from 10 to 30 μg/mm3). The long-term studies, comprising cohort survival analyses over many years of exposure, evaluate the chronic, persistent impact of exposure to air pollutants on the risk of cardiovascular events.59-61 In terms of putative mechanisms, while shortterm exposure affects mainly endothelium-mediated processes (impaired vasodilation, greater vasoconstriction and hemostasis activation in the specific pulmonary bed) owing to an increase of the sympathetic drive, more systemic mechanisms (such as oxidative stress, inflammation and hypercoagulability) are likely to be predominant pertaining to long-term effects, through an acceleration of atherosclerosis and a heightened thrombotic tendency.62 Short-term effects Several epidemiological studies have unequivocally shown a strong association between acute peaks of particulate air pollutants and the occurrence of cardiovascular events.63-79 The National Morbidity, Mortality and Air Pollution Study (NMMAPS), that involved 50 million people in the 20 largest cities in the USA, found that total mortality rates were independently associated with particle concentrations and that, on the day before death, each 20 μg/m3 rise in PM10 was associated with a 0.6% increase for cardiopulmonary mortality.64 A stronger association between adverse health outcomes and air pollution was demonstrated by the Air Pollution and Health European 8 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. Approach (APHEA-2) study.67 For 43 million people living in 29 European cities, the estimated daily increase in cardiovascular mortality was 1.5% for each 20 μg/m3 rise in PM10. A recent update of the Meta-analysis of Italian Studies on the short-term effects of Air pollution (MISA),66 that collected data from 9 million people from 15 Italian cities through the period 1996-2002, has shown an increased daily rate of cardiorespiratory mortality associated to increased levels of several air pollutants (NO2, CO, SO2 and PM10). Other studies have analyzed the adverse cardiovascular effects of air pollution in terms of morbidity (i.e., coronary artery disease, arrhythmias and heart failure) rather than mortality. For instance, in a case-crossover study conducted in 691 German patients who had developed AMI, the time spent in cars, public transport, motorcycles or bicycles was consistently linked to the time of onset of symptoms, thus indicating that exposure to air pollution due to road traffic is a risk factor for AMI (odds ratio 2.92).65 The increased risk was somewhat greater in cyclists (odds ratio 3.94) than is automobile users (odds ratio 2.60), suggesting an adverse interaction between physical activity and traffic-related air pollution. In a case-crossover study a 25 μg/mm3 PM2.5 rise within the two hours preceding the event was associated with a 48% increased risk of AMI.63 The acute effect of fine particulate air pollution on elderly people was analyzed by Dominici and colleagues,64 who studied between 1999 and 2002 a U.S. population of 11.5 million individuals aged more than 65 years in order to evaluate whether or not there was an association between daily concentrations of PM2.5 and changes in hospital admissions for cardiovascular and respiratory diseases. The largest association was for congestive heart failure, with a 1.3% increased risk per 10 μg/m3 rise in same day PM2.5 concentration. From 1986 to 1999 the relationship between particulate air pollution and hospital admissions for congestive heart failure was investigated in 7 U.S. cities: a 10 μg/m3 rise in PM10 was associated with a 0.7% increase in the rate of admission with this diagnosis on the same day. In the Intermountain Heart Collaborative Study (IHCS), a rise by 10 μg/m3 of short-term exposure to PM2.5 was associated with a 4.5% increased rate of acute coronary events.70 The association between traffic-borne air pollutants and AMI is also supported by the European HEAPSS (Health 9 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. Effects of Air Pollution among Susceptible Subpopulations) study,71 air pollution being associated with an increased risk of cardiac readmission to hospital in patients with pre-existing AMI.72 In a study on the relationship between air pollution and emergency room admissions in Boston, a positive association was found between NO2, PM2.5 and the risk of hospitalization for AMI.73 A higher incidence of ischemic and hemorrhagic stroke has also been reported, with higher mortality and more hospital admissions related to short-term increases in airborne PM.74 For instance, in the US Medicare population of elderly patients, there was an increase in hospitalization for stroke on the same day of exposure to higher PM2.5 levels.68 A study in nine US cities of people aged 65 or more confirmed this association, with a daily rise of 1.03% in hospital admissions for ischemic stroke for every 23 μg/m3 increase in PM10.75 A positive association between stroke mortality and daily concentrations of fine particles was also found in individuals aged 65 years or more from Helsinki.76 A more recent study conducted in Denmark confirmed also for ultrafine particles the association with hospital admissions for stroke.77 While all the forementioned epidemiological studies provide solid and unequivocal evidence of a positive relationship between short-term peaks of air pollution and atherothrombotic disease, the evidence for an effect on venous thromboembolism is more preliminary and less established.78 Dales et al reported that the short-term increase in hospital admissions for venous thrombosis and pulmonary events in Santiago (the capital city of Chile) was proportional to the concentration of particulate and gaseous air pollutants.79 These findings are not surprising, because there is evidence that venous and arterial thromboses are not distinct entities but share a number of common risk factors.80 Thus, given that acute peaks of exposure to air pollution contribute to pulmonary and systemic inflammation and hypercoagulability, an epidemiological link between short-term PM peaks and changes in venous thrombosis events is plausible, but additional evidence is warranted. In all, these findings demonstrate that short-term elevations in ambient PM (that are also a proxy for gaseous pollutants) are capable of triggering atherothrombotic events and perhaps also clinical manifestations of venous thromboembolism such as deep vein thrombosis and pulmonary 10 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. embolism. Table 1 shows the detailed results of the largest short-term studies. It must be emphasized that the degree of elevation in ambient PM that, according to these studies, causes a substantial increase in mortality and morbidity for cardiovascular disease may indeed occur very frequently in metropolitan areas, especially where and when there is a combination of intense automobile traffic, high atmospheric pressure and air stagnation. Long-term effects Also chronic exposure to airborne PM enhances the risk of cardiovascular diseases or mortality.81 In more than 8000 adults from six USA cities (HSCS, Harvard Six Cities Study) followed for 14-16 years, overall mortality was 1.26 times higher in the most polluted than in the least polluted cities.82 In an extended follow-up of this study for eight additional years,83 a significant increase in risk of death was found for every 10 μg/m3 rise in PM2.5, with a relative risk (RR) of 1.28 for cardiovascular death. The American Cancer Society (ACS) who conducted a study between 1982 and 1989 in order to investigate individual health risks for 552,138 residents of 151 U.S. cities in relation to local ambient air quality, found a RR of 1.17 for all-cause mortality owing to increased levels of PM2.5.84 The extended 16-year follow-up of the ACS study demonstrated that each rise of 10 μg/m3 in the mean PM2.5 daily concentration was associated with a 12% increased risk of death from cardiovascular causes,85 and that death from coronary artery disease was the single largest cause of mortality (18%). Mortality from long-term exposure to air pollution was also investigated through the follow-up of 22,905 subjects residing in the Los Angeles urban area during the years 1982-2000.86 Cardiopulmonary mortality and deaths for coronary artery disease increased by 20% and 49% per 10 μg/m3 rise in PM2.5 exposure. A study conducted in Sweden on 176,309 male construction workers exposed to PM and compared with 71,778 unexposed workers found that their occupational PM exposure was associated with an increased RR for coronary artery disease (1.13).87 A large Dutch cohort study showed that living near a major road was associated with total mortality (RR 1.41), an even more significant relationship being found for cardiopulmonary mortality (RR 1.95).88 Miller et al89 reported that exposure to air pollution over a 6-year period 11 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. increased the risk of cardiovascular events by 24% and cardiovascular-related death by 76% for every 10 μg/m3 PM2.5 rise. Similarly, the same PM2.5 rise was associated with a 35% and 83% increase in risk for stroke and stroke-related mortality, respectively. In the frame of a retrospective cohort study carried out in residents of South London who survived a first stroke,90 a positive association was seen between estimated exposure to ambient air pollution and subsequent poststroke mortality. In addition to the forementioned strong and consistent evidence that long-term exposure to air pollution is associated with an increase in atherothrombotic clinical events, markers of subclinical atherosclerosis are more frequently found in communities chronically exposed to high levels of ambient air pollution. For instance, Künzli and colleagues measured carotid intima–medial thickness in 800 residents of Los Angeles.91 Personal air pollution exposures were estimated with a geostatistical model that mapped their area of residence to PM values recorded by local pollutionmonitoring stations. For every 10 μg/m3 rise in PM2.5, intima-media thickness increased by 4% after adjustment for potential confounding variables. The same authors reported an association between air pollution and progression of atherosclerosis (measured as the annual rate of increase in the carotid artery intima-media thickness) following the analysis of 5 double-blind randomized trials.92 Similar effects have also been reported for coronary artery calcium content, a biomarker of coronary atherosclerosis. In a prospective cohort study of 4,494 individuals, living close to a major urban road increased coronary artery calcium scores by 60%.93 The strong evidence supporting the association between atherothrombosis and air pollution is complemented by fewer studies on venous thromboembolism. Baccarelli et al94 examined the relationship between exposure to PM10 and venous thrombosis in a case-control study of 870 patients and 1210 healthy individuals, and found that for each 10 μg/mm3 rise in PM10 there was a 70% increase of venous thrombosis, independently of other clinical and environmental variables.95 In the same study, exposure to PM was associated with a shortened prothrombin time, extending previous observations based upon a shorter time window of exposure to pollution.31 The increased 12 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. risk of venous thrombosis was nearly linearly associated with living in proximity to major traffic roads, extending findings by other investigators who had shown the same association for arterial cardiovascular events.96 However, these results on the risk of venous thromboembolism were not replicated by two prospective cohort studies, indicating the need of further studies in this field.97,98 Table 2 summarizes the findings of the largest studies on long-term cardiovascular effects of particulate air pollution. Taken together, they demonstrate that prolonged exposure to particulate air pollution is associated with adverse cardiovascular events, even when PM10 concentrations become only modestly higher than the thresholds established as target by regulatory agencies (for instance, 20 μg/mm3 by the World Health Organization). 99 Conclusions From an array of experimental, epidemiological and clinical studies it emerges that air pollution is an important acquired cardiovascular risk factor that adds to the traditional ones. Alterations induced by exposure to particulate air pollution contribute in the long-term to the development and progression of atherosclerosis and, in the frame of short-term exposures, to triggering thrombosis and acute cardiovascular events. The two most frequent cardiovascular diseases (i.e., coronary artery disease and cerebrovascular disease) are definitely and consistently increased by particulate exposure. There is preliminary evidence that PM exposure may be a risk factor also for venous thromboembolism. A recent evaluation of the public health relevance of triggers of acute myocardial infarction found that exposure to automobile traffic had the greatest population effect on this event, being an ongoing factor to which a huge number of individuals are exposed.7 Further studies on the mechanisms of cardiovascular effects related to air pollution are necessary and changes in the hemostatic system warrant special attention. For instance, the role of platelets in thrombus formation has been relatively poorly studied in humans,100 at variance with the evidence gained in animal models, that however were based upon artificial proxies of ambient air pollutants. The many toxic substances contained in the anthropogenic PM (such as, for instance, metals) may 13 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. cause oxidative stress and platelet hyperactivity. Of the other components of hemostasis, coagulation and fibrinolysis are more thoroughly investigated, but more adequate models of PM exposure in humans and animals are needed, because the different particles used in these models failed to mimic the complex composition of PM that are present in the urban ambient owing to traffic and domestic heating. What can be done to control these adverse effects of air pollution? The American Heart Association has recently delivered the following statement:39 “the overall evidence is consistent with a causal relationship between PM2.5 exposure and cardiovascular morbidity and mortality”. A large number of metropolitan areas around the world have PM concentrations well above the WHO target of 20 μg/mm3, especially in Eastern and Southern Europe and Asia. PM exposure is a modifiable risk factor.39 It has been calculated that a reduction by only 10 μg/mm3 in the daily mean concentration of PM10 would decrease by 1.6% the incidence of new cases of myocardial infarction, the decrease being as large as 4.8 % if PM10 concentration were decreased by as much as 30 μg/mm7. Because it has been shown that the decrease of air pollution clearly leads to a parallel increase in life expectancy,83,101 it is a community responsibility to adopt the necessary measures. Efforts directed to manage local air quality should aim to reduce not only PM from anthropogenic but also from soil sources, even if anthropogenic particles appear to have a higher impact on cardiovascular events due to their stronger production of pro-inflammatory cytokines. Yet, also the single citizen can adopt simple measures to reduce his /her individual risk, such as to avoid walking in the most trafficked roads, performing strenuous outdoor exercise in busy roads and exposing small children to the high concentration of air pollutants that are present next to the ground. 14 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. Acknowledgments This works was supported in parte by grants to PMM by the Lombardy Region. Drs. Baccarelli and Bertazzi are thanked for helpful discussion and advice. Conflict of interest The authors declare no conflict of interest. Legend to Figure 1. Adverse effects of air pollution exposure: possible mechanisms of action of cardiovascular events. 15 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. References 1. Brunekreef B, Holgate ST. Air pollution and health. Lancet. 2002;360(9341):1233-1242. 2. 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Air pollution and markers of inflammation and coagulation in patients with coronary heart disease. Am J Respir Crit Care Med. 2006;173(4):432-441. 23. Vermylen J, Hoylaerts MF. The procoagulant effects of air pollution. J Thromb Haemost. 2007;5(2):250-251. 24. Nemmar A, Hoylaerts MF, Hoet PH, et al. Ultrafine particles affect experimental thrombosis in an in vivo hamster model. Am J Respir Crit Care Med. 2002;166(7):998–1004. 25. Nemmar A, Hoet PH, Dinsdale D, Vermylen J, Hoylaerts MF, Nemery B. Diesel exhaust particles in lung acutely enhance experimental peripheral thrombosis. Circulation. 2003;107(8):1202–1208. 26. Nemmar A, Hoet PH, Vermylen J, Nemery B, Hoylaerts MF. Pharmacological stabilization of mast cells abrogates late thrombotic events induced by diesel exhaust particles in hamsters. Circulation. 2004;110(12):1670–1677. 27. Nemmar A, Nemery B, Hoet PH, Vermylen J, Hoylaerts MF. 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Baccarelli A, Zanobetti A, Martinelli I, et al. Air pollution, smoking, and plasma homocysteine. Environ Health Perspect. 2007;115(2):176-181. 33. Bonzini M, Tripodi A, Artoni A, et al. Effects of inhalable particulate matter on blood coagulation. J Thromb Haemost. 2010;8(4):662-668. 34. Mills NL, Törnqvist H, Robinson SD, et al. Diesel exhaust inhalation causes vascular dysfunction and impaired endogenous fibrinolysis. Circulation. 2005;112(25):3930-3936. 35. Mills NL, Törnqvist H, Gonzalez MC, et al. Ischemic and thrombotic effects of dilute dieselexhaust inhalation in men with coronary heart disease. N Engl J Med. 2007;357(11):10751082. 36. Mills NL, Törnqvist H, Robinson SD, et al. Air pollution and atherothrombosis. Inhal Toxicol. 2007;19(1 Suppl):81-89. 37. Mannucci PM. Fine particulate: it matters. J Thromb Haemost. 2010;8(4):659-661. 38. Sun Q, Hong X, Wold LE. Cardiovascular effects of ambient particulate air pollution exposure. Circulation. 2010;121(25):2755-2765. 39. 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Air pollution-related prothrombotic changes in persons with diabetes. Environ Health Perspect. 2010;118(2):191-196. 101. Pope CA 3rd, Ezzati M, Dockery DW. Fine-particulate air pollution and life expectancy in the United States. N Engl J Med. 2009;360(4):376-386. 25 Table 1. Summary of the largest population studies on short-term cardiovascular effects of ambient air pollution. First author, year (study Population Many findings Reference Peters, 2001 Case cross-over study of 772 patients with AMI A PM2.5 increase of 25 μg/m3 within the 2 hours preceding the event was 63 associated with a 48% increased risk of AMI Dominici, 2003 (NMMAPS) Time series study including 50 million people from 20 U.S. cities 0.6% daily increase of cardiorespiratory deaths for each 20-μg/m3 PM10 64 increase Peters, 2004 (AMIR) Case cross-over study of 691 patients with AMI Increased risk of AMI (OR 2.92) associated with acute exposure to car traffic 65 one hour before the event Biggeri, 2004 (MISA) Meta-analysis of 9 million people from 15 Italian cities 0.4% daily increase of cardiovascular deaths for each 10 μg/m3 increase in 66 NO2, of 0.9%, for each 1mg/m3 increase in CO, of 1.1%, for each 10 μg/m3 increase in SO2,, and of 0.5% for each 10 μg/m3 increase in PM10 Analitis, 2006 (APHEA-2) Dominici, 2006 Wellenius, 2006 Pope, 2006 (IHCS) Time series study of 43 million people from 29 European cities 1.5% daily increase in cardiovascular deaths for each 20 μg/m3 PM10 increase 67 Time series study of 11.5 million U.S. 1.3% daily increase in the risk of congestive heart failure, and 1.2% increase in 68 people aged more than 65 years the risk of stroke for each 10 μg/m3 PM2.5 increase. Time series study on 292,918 admissions for congestive heart 0.7% increase in the rate of admission for heart failure for each 10 μg/m3 PM10 failure in 7 U.S. cities increase Case cross-over study on 12,865 U.S. patients undergoing 4.5% daily increase of acute coronary events for each 10 μg/m3 PM2.5 increase From www.bloodjournal.org by guest on June 18, 2017. For personal use only. acronym) 69 70 26 coronary arteriography Lanki, 2006 (HEAPPS) 26,854 cases of first AMI in 5 European cities A positive association with AMI of the same day CO (RR 1.021) per 0.2 71 von Klot, 2005 (HEAPPS) 22,066 AMI survivors in 5 European cities Rate ratio for cardiac readmissions was 1.021 for each 10 μg/m3 in PM10 72 increase Zanobetti, 2006 Wellenius, 2005 Kettunen, 2007 Andersen, 2010 Dales, 2010 15,578 admission for cardiovascular and respiratory diseases in Significant association between NO (12.7% increase) and PM2.5 (8.6% Boston increase) and the risk of emergency hospitalization for AMI 155,503 ischemic and 19,314 hemorrhagic stroke admissions in One interquartile range increase in PM10 was associated with a 1.03% daily people aged 65 years or more from 9 US cities increase in hospitalization for ischemic stroke 3265 deaths from stroke among people aged 65 years or more Daily stroke mortality was positively associated with current and previous day from Finland PM2.5 levels Case cross-over study on 7485 admissions for hemorrhagic and Exposure to ultrafine particles led to a 21% increase in hospitalization for ischemic stroke in Denmark ischemic stroke Times series study on a population of 5.4 million residents in The relative risk of hospitalization for venous thrombosis was 1.05 for a 20 Santiago (Chile) μg/m3 PM2.5 increase 73 75 76 77 79 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. mg/m3 and particle number concentration (RR 1.058) per 10,000 particles/cm2 PM, particulate matter; OR, odds ratio; RR, relative risk; NMMAPS, National Morbidity, Mortality and Air Pollution Study; APHEA, the Air Pollution and HealthEuropean Approach; MISA, Meta-analysis of Italian Studies on the short-term effects of Air pollution; IHCS, Intermountain Health Collaborative Study; AMIR, Ausburg Myocardial Infarction Registry; CHF, congestive heart failure; HEAPSS, Health Effects of Air Pollution among Susceptible Subpopulations; AMI, acute myocardial infarction 27 Table 2. Summary of the largest population studies on long-term cardiovascular effects of particulate air pollution. First author, year (Study) Key findings Reference Increase in cardiovascular death (RR 1.28) for each 10 μg/m3 PM2.5 increase 83 Prospective cohort of 500,000 residents 12% increased risk of cardiovascular deaths and 18% increased risk of 85 in 150 U.S. cities followed for 16 years coronary artery disease for each 10 μg/m3 increase in long-term PM2.5 Prospective cohort of 8,111 people from 6 U.S. cities followed for 28 years Pope, 2004 (ACS) exposure Jerrett, 2005 Prospective cohort of 22,905 residents in the Los Angeles area 20% and 49% increase in the risk for cardiopulmonary and coronary artery 86 disease deaths for each 10 μg/m3 increase in long-term PM2.5 exposure Toren, 2007 Hoek, 2002 (NLCS) Prospective cohort of 176,309 PM exposed construction workers Increased risk for coronary artery disease (RR 1.13) associated with and 71,778 PM unexposed construction workers occupational exposure to particulate air pollution 4492 Dutch participants Increased risk of cardiopulmonary mortality (RR 1.95) associated with 87 88 living near a major traffic road Miller, 2007 Prospective cohort of 65,893 postmenopausal women in 36 U.S. 24% and 76% increase in the risk for cardiovascular events and cities followed for 6 years cardiovascular mortality for each 10 μg/m3 increase in long-term PM2.5 89 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. Laden, 2006 (HSCS) Population exposure. Maheswaran, 2010 Retrospective cohort study on 3320 patients with stroke residents Each 10 μg/m PM10 increase was associated with a 52% increase 3 90 28 in south London between 1995 and 2005 Kunzli, 2005 Measurement of carotid intima-media thickness in 798 resident in Each 10 μg/m3 PM2.5 increase was associated with a 5.9% increase Los Angeles of carotid intima–media thickness 4494 German study participants Compared with participants living more than 200 m away from a major Nixdorf Recall Study) 91 93 road, participants living within 50, 51 to 100, and 101 to 200 m had odds ratios of 1.63, 1.34, and 1.08, respectively, for a high coronary artery calcium content Baccarelli, 2008 Baccarelli, 2009 870 patients with deep-vein thrombosis and 1210 controls in Each 10 μg/m PM10 increase was associated with a 70% increase in Northern Italy the risk of venous thrombosis 663 patients with deep vein thrombosis and 859 controls in The risk of venous thrombosis was increased (OR 1.47) for subjects living Northern Italy near a major traffic road 3 94 95 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. Hoffmann, 2007 (Heinz post-stroke mortality PM, particulate matter; HSCS, Harvard Six Cities Study; RR, relative risk; ACS, American Cancer Society; WHI, Woman’s Health Initiative; NLCS, Netherlands Cohort Study; DVT, deep vein thrombosis. 29 From www.bloodjournal.org by guest on June 18, 2017. For personal use only. Prepublished online June 10, 2011; doi:10.1182/blood-2011-04-343111 Thrombogenicity and cardiovascular effects of ambient air pollution Massimo Franchini and Pier Manuccio Mannucci Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml Advance online articles have been peer reviewed and accepted for publication but have not yet appeared in the paper journal (edited, typeset versions may be posted when available prior to final publication). Advance online articles are citable and establish publication priority; they are indexed by PubMed from initial publication. 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