Air pollution and the heart

Transcription

1 IN-DEPTH REVIEW Air pollution and the heart Occupational Medicine 2005;55: doi: /occmed/kqi136 H. C. Routledge and J. G. Ayres... Abstract Despite legislation, leading to dramatic decreases in levels of air pollution since the time of the great smogs, a large body of epidemiological evidence has demonstrated that pollution continues to have adverse effects on human health. One striking finding from the epidemiological data is that patients with cardiovascular disease are susceptible to acute rises in ambient pollutants. Mortality and hospital admissions for myocardial infarction, congestive cardiac failure and cardiac arrhythmia all increase with a rise in the concentration of both particulate and gaseous pollutants. Before concluding that this association is a causal one, plausible pathophysiological mechanisms are required. Evidence is accumulating in support of two mechanistic hypotheses: inhalation of pollutants might provoke a local inflammatory response with the consequent release into the circulation of pro-thrombotic and inflammatory cytokines. A systemic response of this nature would put individuals with coronary atheroma at increased risk of cardiac events; exposure to pollutants may have an adverse effect on cardiac autonomic control, leading to an increased risk of arrhythmia in susceptible patients. Clarification of the pollutants involved and the precise mechanisms of action is essential in designing measures by which susceptible individuals might be protected from the adverse cardiovascular effects of air pollution.... Key words Air pollution; autonomic nervous system; cardiovascular disease; inflammation.... Concern regarding the adverse effects of air pollution on health is not new; the use of coal as a fuel was prohibited in London as being prejudicial to health in More substantive legislation, the Clean Air Act of 1956, was triggered by the London Fog Incident of December 1952 and was aimed at reducing pollution from smoke [1]. These measures initially produced a feeling of comfort in the Government, as the air became visibly cleaner, reinforced by scientific advice that air pollution was unlikely to be a problem in the future. In the 1980s, however, work from the USA began to suggest that despite this regulatory framework, emissions now largely from vehicles, were contributing to exacerbation of disease. While the health effects are not usually apparent to clinicians, a large number of epidemiological studies have provided consistent evidence for an increase in death and hospitalization rates in relation to higher levels of pollution. While it would seem intuitively logical that inhaling polluted air could affect individuals with pre-existing lung disease it became obvious from a relatively early stage that cardiac patients were also significantly affected by air pollution. But is this a real effect? If so, what mechanisms are operating? And what Division of Medical Sciences (Cardiology), University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TH, UK. Correspondence to: J. G. Ayres, Department of Environmental & Occupational Medicine, University of Aberdeen, Liberty Safe Work Research Centre, Foresterhill Road, Aberdeen, AB25 2ZP, UK. j.g.ayres@abdn.ac.uk can we learn from an occupational exposure that might contribute to our understanding of this phenomenon? Epidemiology Urban air pollution in westernized cities, and increasingly in the developing mega-cities such as Lagos and Beijing, is primarily derived from fossil fuel combustion mostly via vehicle emissions. It consists of particulate matter as well as gases, notably the primary pollutants sulphur dioxide and carbon monoxide and the secondary pollutants nitrogen dioxide and ozone. Of these, respirable airborne particles have consistently been shown to be associated with mortality and hospital admissions and are generally believed to be the most relevant fraction with respect to cardiovascular health effects. Current air quality standards are based on the mass concentrations of those particles with an aerodynamic diameter of less than 10 mm (PM 10 ). Increasing attention has focused on the fine component (PM 2.5 ) and now the ultrafine fraction (particles, 100 nm in diameter) which are not only able to penetrate deeper into the respiratory tract but also to remain there. Airborne particles are complex mixtures of elemental carbon, organic carbon compounds and reactive components such as transition metals, metal oxides, acid condensates, sulphates and nitrates. Because the components of these particles are site-specific in their source and also vary in a single site q The Author Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please journals.permissions@oupjournals.org

2 440 OCCUPATIONAL MEDICINE over time, the determination of the precise components that impact upon health is difficult. While most recent attention has focused on particles, questions continue to surround the importance of the major gaseous air pollutants. There is convincing evidence that sulphur dioxide (SO 2 ), a substantial proportion of which is derived from industrial sources, is also associated with admissions for cardiovascular disease [2]. Nitrogen dioxide (NO 2 ) and carbon monoxide (CO) and ozone (O 3 ) (an oxidant gas formed by the action of ultra violet light on oxides of nitrogen and hydrocarbon fragments in vehicle emissions) have also been implicated as causes of adverse cardiovascular health effects [3,4]. Whether, at current levels, these gases have a direct health effect, interact with particles or simply act as surrogates for other air pollution metrics remains to be elucidated [5]. Air pollution and health Air pollution may exert adverse effects on health in three ways: Acute effects those temporally related to variation in levels of air pollution on a day-to-day basis Chronic effects or effects of long-term exposures may embrace both initiation of disease and deterioration of established disease, such as progression of atherosclerosis Latent effects such as carcinogenesis, which will not be considered further here. While chronic effects are increasingly recognized as, in all probability, exerting the greatest effect on public health, only a small number of studies have examined the relationship between long-term pollution exposure and cardiovascular health [6]. Data for the impact of air pollution on cardiovascular disease largely concerns acute exposure. Predominantly by use of time-series analyses, which model the relationship between day-today levels of air pollutants and health endpoints, population changes in cardiovascular mortality and hospital admission rates have been linked to variations in ambient pollution. Attributing specific health effects to air pollution is difficult for a number of reasons including confounding by co-exposures, notably meteorological factors. Indeed, there remains some doubt as to whether the effects of temperature have been adequately allowed for in published studies. In addition, lag times (i.e. the likelihood of an acute exposure exerting an effect 1, 2, 3 or more days later), and the presence or absence of a threshold of effect (a concept which exists at an individual level but may not do so at a population level [7]) markedly alter the quantification of the health impact. Lastly, when trying to estimate an average effect size for a specific geographical area, real problems arise as a result of differences between the populations studied and variation in the analytical methods employed. Reported effect sizes thus vary considerably between published time series, but in spite of these difficulties the presence of an effect is remarkably consistent. The association between air pollution and total daily mortality has been established by over 200 time series from geographically distinct areas [8,9] and confirmatory support has now emerged from large multi-location studies notably the APHEA project (Air Pollution and Health, a European Approach). This collaboration was aimed at quantifying the short-term health effects of air pollution using common methodology in 15 European cities, with a total population exceeding 25 million [10]. In western European cities, an increase of 10 mg/m 3 in SO 2 (UK annual level: mg/m 3 ) was associated with a 0.6% increase in daily all cause mortality, the corresponding figure for PM 10 being 0.4%, effect sizes similar to those seen in the US 20 cities study [11]. Effect sizes associated with the particles were greater when examining death specifically from cardio-respiratory disease (0.7% for an increase of 10 mg/m 3 in PM 10 ). This effect was present at low particle levels, was independent of co-pollutants and was not confounded by meteorological factors notably temperature [11]. Air pollution and cardiovascular disease Although the relative risks for pollution-related deaths are greater for respiratory than for cardiovascular causes, meta-analysis of time series data demonstrates that because of the size of the population at risk, the actual number of deaths from cardiovascular diseases is greater [9] (Table 1). A significant number of those with cardiovascular disease are relatively young so that while a death from chronic lung disease brought forward by air pollution might not result in a major degree of loss of life, for the younger individual with cardiac disease, life lost may be substantial. Similar conclusions can be drawn from data on hospital admissions for cardiovascular disease (Table 2). In one London study, the authors suggested that as many as 1 in 50 myocardial infarctions (MI) treated at London hospitals were triggered by outdoor air pollution. Multiplying across the UK, ambient pollution may contribute to as many as 6000 cardiovascular events per year [12]. Further, to this, it has been estimated that a 10 mg/m 3 reduction in 24 h average PM 10 concentration, would result in a 0.8% reduction in cardiovascular admissions [13]. So, can we identify those individuals who are particularly at risk? The identification of susceptible subgroups is of great importance in discerning causal mechanisms and in setting public health policies. At present epidemiological data give us only a limited idea

3 H. C. ROUTLEDGE AND J. G. AYRES: AIR POLLUTION AND THE HEART 441 Table 1. Associations between mortality and day-to-day changes in air pollutants time series studies Time series study Geography Pollutants Mortality effect Wichmann et al. [15] West Germany 1985 SO 2 TSP Schwartz and Marcus [53] London Black smoke SO 2 Katsouyanni et al. [54] Athens SO 2 Black smoke Kinney and Ozkaynak [55] Los Angeles Particles County CO and NO 2 Schwartz and Dockery [56] Philadelphia SO 2 TSP other than those with pre-existing cardiopulmonary disease. There is, however, some evidence to suggest that those with coronary artery disease and cardiac failure may be most susceptible as may be those who also have diabetes [14]. A persistent (and largely insoluble) problem with mortality data is the accuracy of death certification, so while total mortality is a secure end point, it lacks specificity even though the main driver is cardiovascular deaths. The same is true, though to a lesser extent, for hospital admissions. Breaking down by specific diagnosis is open to error and may be misleading if we use epidemiological studies to try and tease out possible mechanistic clues. The majority of time series studies employ broad categories, relying on retrospective analysis of routine coding for both admissions and mortality. In the largely industrially derived smog episode in the Ruhr 8% " mortality during smog 6% " CVS mortality (15% " admissions) Significant predictors of all cause mortality Higher respiratory and CVS mortality on polluted days Strongly associated with daily CVS mortality 5% " mortality/100 mg " SO 2 7% " mortality/100 mg " TSP 10% " CVS mortality Association between (AMR 1.26) cardiopulmonary Dockery et al. [57] Six US cities Fine particles sulphates mortality and level of pollution in city Schwartz [58] Philadelphia Death TSP RR death ¼ 1.08 on high versus low pollution day Certificates: " heart disease and stroke deaths Schwartz [8] Meta-analysis TSP RR death ¼ 1.06 for 100 mg increase in TSP Anderson et al. [59] London Black smoke 2.5% " daily mortality/ " 7 19mg/m 3 SO 2 SO 2 also significant Ozone 3.6% " CVS mortality/ " 7 36 ppb RR CVS mortality 1.02/ " 50 mg/m 3 4.1% " CVS mortality/ " 10 mg/m 3 9.9% " CVS mortality/ " 20 mg/m 3 Additive effect w/pm 10 and ozone Zmirou et al. [61] 10 European cities Black smoke SO 2 RR CVS mortality 1.04/ " 50 mg/m 3 Ostro et al. [62] Bangkok PM 10 2% " CVS mortality/10 mg/m 3 " Rossi et al. [63] Milan, Italy TSP 7% " heart failure deaths/100 mg/m 3 " 10% " MI mortality/100 mg/m 3 " Ponka et al. [60] Helsinki PM 10 Ozone NO 2 Samet et al. [64] 20 US cities PM 10 (SO 2,CO, ozone NO 2 ) Kwon et al. [4] Seoul PM 10,SO 2,CO, ozone NO 2 " rate of CVS/Resp mortality 0.68% for each " PM 10 of 10 mg/m 3 Weak associations RR mortality1.014/iqr " PM 10 RR mortality1.020/iqr " CO Effect % higher in CCF Katsouyanni et al. [65] 29 European cities APHEA 2 PM 10 " rate of CVS/Resp mortality 0.6% for each " PM 10 of 10 mg/m 3 Effect size greater in elderly; w/high NO 2 or in cold climates Valley in 1985, however, deaths and admissions were coded on the basis of the international classification of diseases for 94% of cases [15]. Deaths due to heart failure, MI and stroke were all significantly higher in the polluted areas compared with the control areas, an effect more pronounced than that on respiratory mortality. Notably, arrhythmia admissions were increased by 50% compared with the periods before and after the smog [15]. A more recent study from the Netherlands considered associations between daily variations in air pollution and specific cardiovascular causes of death over 8 years [16]. Effect estimates were significant for total cardiovascular mortality, MI and other ischaemic heart disease deaths but were most pronounced (three times higher) for deaths from heart failure and arrhythmia. A panel study carried out in 2000 adds further weight to the hypothesis that an increase in cardiac arrhythmia

4 442 OCCUPATIONAL MEDICINE Table 2. Associations between hospital admissions and day-to-day changes in air pollutants time series studies Time series study Geography Pollutants Effect on admissions Schwartz et al. [66]] Michigan PM 10 CO contributes to the rise in mortality associated with increases in ambient pollution levels [17]. In 100 patients with implantable cardioverter defibrillators in Boston, USA, episodes of defibrillation were related to daily air pollution. The frequency of defibrillator discharges showed a significant correlation with increased levels of PM 10 and PM 2.5, with a lag time of 2 days and with NO 2 on the previous day. In patients with at least 10 interventions to treat ventricular arrhythmia the odds of a discharge tripled with an increase in NO 2 around three times the average mean daily level and increased by 60% for an equivalent rise in PM 2.5. The association between pollutant levels and MI was highlighted recently by the findings of a multicentre case-crossover study. This suggested that a transient elevation in fine particles (increase of 25 mg/ m 3 PM 2.5 ), at levels still below current air quality standards, was associated with a 1.5 times increased risk of MI within 1 2 h of exposure [18]. In addition, high 24 h concentrations of fine particles were associated with an elevated risk of MI. A similar study has confirmed these positive associations between pollution levels and infarction finding an increased risk of MI within 48 h of high levels of NO 2 and CO but describing the strongest and most consistent link with particulate matter [19]. The results at the two separate time periods seem to be independent and additive suggesting the possibility of two, possibly independent mechanisms. " Ischaemic heart disease admissions (RR IQR " PM 10 ) and with heart failure (RR 1.024/IQR " PM 10 and 1.022/IQR " CO) 2.8% " CVS admission/13 mg/m 3 " Burnett et al. [67] Ontario Particulate sulphates Morris et al. [68] Seven US cities CO " Heart failure admissions (RR /10ppm " CO Wordley et al. [69] Birmingham, UK PM 10 " Risk of respiratory (2.4%) or cerebrovascular (2.1%) admission for 10 mg/m 3 " PM 10 Schwartz [70] Tuscon 1997 PM 10 CO Ozone/SO % " CVS admission/iqr " PM % " CVS admission/iqr " CO Little association Burnett et al. [3] 10 Canadian cities CO RR heart failure admission 1.065/IQR " CO 13% " CVS admissions/iqr " gaseous pollutants Burnett et al. [71] Toronto Ozone NO 2 SO 2 Poloniecki et al. [12] London Black smoke NO 2 Schwartz [72] Eight US counties PM 10 CO Le Terte et al. [73] Eight European cities PM 10 (APHEA 2) (black smoke) Sunyer et al. [2] Seven European areas (APHEA 2) 2.5% MI admissions attributable Association with angina admissions Association with arrhythmia admissions 2.48% " CVS admission/iqr " 2.79% " CVS admission/iqr " 0.5% " CVS admission/10 mg/m 3 1.1% " CVS admission/10 mg/m 3 SO 2 0.7% " CVS admission/10 mg/m 3 (for subjects under 65 years) Potential mechanisms Epidemiology has clearly demonstrated an association between increases in particulate air pollution and deaths and admissions due to heart failure, MI and arrhythmia (Figure 1). In order to show that these associations are causal, plausible mechanisms of action are still required. Several hypotheses have been proposed and evidence is accumulating in support of two, possibly interlinked mechanisms, by which low concentrations of particles in inspired air could have adverse cardiovascular effects. Inhalation and interstitialization of fine particles might provoke an inflammatory response in the lungs with the consequent release into the circulation of pro-thrombotic and inflammatory cytokines. A systemic acute-phase response of this nature would put individuals with coronary atheroma at increased risk of plaque rupture and thrombosis. Secondly, exposure to particulate matter may have an adverse effect on cardiac autonomic control, leading to an increased risk of arrhythmia in susceptible patients. A systemic inflammatory response to particulate air pollution was initially suggested in 1995 by Seaton [20], who postulated that such a response might precipitate acute coronary events as a result of an increase in blood coagulability. The relationship between systemic inflammation and adverse coronary events both in patients with coronary artery disease [21,22] and in the general population is now well established [23]. Increases in

5 H. C. ROUTLEDGE AND J. G. AYRES: AIR POLLUTION AND THE HEART 443 Deposition and interstitialization Particles Carbon Acid condensates Transition metals Gases SO 2 / NO 2 CO Ozone? Via upper airway/nasal receptors Lung Inflammation Oxidative stress Liver Synthesis of fibrinogen & clotting factors Plasma viscosity NFKB related gene expression CRP Atheromatous plaques Destabilization / Rupture Thrombosis both plasma viscosity and C-reactive protein have been associated with high levels of particulate pollution in studies of around 4000 healthy adults. During an air pollution episode the odds when compared with the control period, high C-reactive protein concentrations increased by 3-fold and those for plasma viscosity by more than 3.5 [24,25]. These findings are supported both by in vitro and by animal studies. Fine particles have been shown to be capable of penetrating the alveolar epithelium [26], causing local inflammation and oxidative stress [27]. Human bronchial epithelial cells exposed to combustion derived particles in vitro, release pro-inflammatory cytokines such as IL-6, IL-8 and TNFalpha [28,29]. Cytokine secretion in these models is inhibited by the free radical scavenger N-acetyl- L-cysteine [30]. In animals, intratracheal particle instillation studies suggest that the degree of oxidative stress and the release of cytokines are related to size, surface area and to the transition metal content of particles [31 33]. Furthermore, atherosclerotic lesions in rabbits exposed to particulate pollution were noted to display characteristics of unstable plaques (thin plaque caps, presence of inflammatory cells, fewer smooth muscle cells) compared Systemic inflammation Tissue factor Cardiac autonomic Nervous system Cardiac vagal control Arrhythmic susceptibility Sudden death due to acute coronary syndrome or ventricular arrhythmia Tachycardia myocardial ischaemia Figure 1. Potential pathophysiological mechanisms for the adverse effects of air pollutants on the cardiovascular system. with controls a possible mechanism for the longer term effects of air pollution exposure [34]. In healthy human volunteers, increases in neutrophils and platelets in the peripheral blood have been found following exposure to diesel exhaust, in association with an increase in inflammatory cells and expression of endothelial adhesion molecules in bronchial biopsies [35]. While the assumption that local pulmonary inflammation following pollution exposure is the sole trigger of the systemic inflammatory response, there is now evidence to show that inflammation in response to pollution may be initiated at extra-pulmonary sites with particles themselves entering the systemic circulation [36]. While there is gathering belief that these various exposures might share a common final pathway through oxidant damage at a cellular level, evidence for antioxidant abrogation of these effects remains inconsistent. Disturbances in the control of heart rate and rhythm in response to particulate pollution were originally suggested by two observational studies. During an air pollution episode in Central Europe in January 1985, which resulted in an elevated number of hospital admissions for cardiovascular diseases [15], resting

6 444 OCCUPATIONAL MEDICINE heart rates were measured in nearly 3000 subjects. Increases in heart rate were observed during the pollution episode, compared with control periods in relation to both SO 2 and to particles, even after adjusting for cardiovascular risk factors and meteorologic parameters [37]. The second investigation was carried out in Utah in the winter of [38]. In this panel study, oxygen saturation and heart rate using pulse-oximetry were measured daily in 90 elderly subjects. While there was no evidence of pollution-related hypoxia, pulse rate and the odds of the pulse rate being elevated by 5 or 10 beats a minute were associated with PM 10 on the previous 1 5 days. An increase in resting heart rate suggests an alteration in autonomic control of the heart, which is recognized as an independent risk factor for total cardiovascular mortality and sudden death [39,40]. The mechanisms by which abnormal autonomic control influences prognosis are not proven but there is strong animal evidence that increased sympathetic and reduced vagal control results in an increased susceptibility of the ischaemic myocardium to ventricular fibrillation [41]. Experimental animal evidence also supports the hypothesis that the cardiac autonomic nervous system is susceptible to the adverse effects of air pollution. Rats with pulmonary hypertension exposed to particulate matter showed a dose-related increase in incidence and duration of serious arrhythmia, with no preceding hypoxia [42]. Partially coronary ligated dogs exposed to concentrated ambient particles via tracheostomy, showed heart rates rising with increasing PM 10 exposure and alterations in cardiac autonomic control as measured by heart rate variability (HRV) [43]. This non-invasive technique, that describes beat-to-beat changes in heart periodicity and reflects vagal influence on the heart, has recently been used in a number of human studies. Decreased heart rate variability is an independent predictor of cardiac death in patients with established heart disease such as MI and chronic heart failure [44, 45]. Ambulatory ECG monitoring in seven elderly subjects before, during and after particulate pollution episodes from a steel mill showed consistent negative associations between pollution and same day measures of HRV [46]. In two further groups of elderly patients, the risk of an individual having low heart rate variability was significantly increased on high PM 2.5 days [47,48]. Inan occupational study, the limitations in estimating personal exposure from regional monitoring were overcome by the use of personal exposure monitors in a cohort of 40 boilermakers. In these young industrial workers, half of whom were current smokers, a significant negative association was found between 4 h PM 2.5 exposure and one index of HRV [49]. Experimental laboratory exposure to SO 2 in humans has also recently been shown to exert significant adverse effects on HRV [50]. How inhalation of pollutants and in particular fine particles might exert such effects on the cardiac autonomic nervous system remains to be elucidated. Animal work has demonstrated that stimulation of nasopharyngeal, upper and lower airway receptors can mediate powerful neural influences on the cardiovascular system [51]. Alternatively, and in keeping with the inflammatory hypothesis, inhaled particles might indirectly promote an autonomic stress response as a result of cytokine release. These two mechanistic hypotheses in combination could thus explain the observed effects of air pollution on cardiovascular morbidity and mortality. In susceptible individuals, pollution might increase the likelihood of plaque rupture, promote ischaemia and increase the vulnerability of ischaemic or failing myocardium to arrhythmia [52]. Future research The unpredictable nature of coronary artery disease remains a problem that concerns all cardiologists. Patients with chronic stable angina have a low annual rate of clinical events but sudden death and acute coronary syndromes including acute MI can present without warning both in patients with established disease and in apparently healthy individuals. Surprisingly, little attention has been paid to environmental factors that may influence levels of inflammation and autonomic tone and thus cardiovascular risk. The role of air pollution in determining inflammatory and oxidative status and cardiac autonomic control remains to be determined but it can be seen that the epidemiological evidence for the association of air pollution with cardiac mortality and morbidity is beyond doubt. Research already underway will throw light upon which components of air pollution are important in these respects and help to determine legal standards for these pollutants. In addition, basic research into exactly how air pollution may result in adverse cardiac events is required and may help to improve our understanding of the triggers of plaque rupture and arrhythmia. Further clinical studies are required but cellular and molecular studies in the field of atherosclerosis and arrhythmia should not be limited to the investigation of inherited traits but should also include the impact of environmental factors such as air pollution. References 1. Logan W. Mortality in the London fog incident, Lancet 1953;1: Sunyer J, Ballester F, Tertre AL, et al. The association of daily sulfur dioxide air pollution levels with hospital

7 H. C. ROUTLEDGE AND J. G. AYRES: AIR POLLUTION AND THE HEART 445 admissions for cardiovascular diseases in Europe (The Aphea-II study). Eur Heart J 2003;24: Burnett RT, Dales RE, Brook JR, Raizenne ME, Krewski D. Association between ambient carbon monoxide levels and hospitalizations for congestive heart failure in the elderly in 10 Canadian cities. Epidemiology 1997;8: Kwon HJ, Cho SH, Nyberg F, Pershagen G. Effects of ambient air pollution on daily mortality in a cohort of patients with congestive heart failure. Epidemiology 2001; 12: Sarnat JA, Schwartz J, Catalano PJ, Suh HH. Gaseous pollutants in particulate matter epidemiology: confounders or surrogates? Environ Health Perspect 2001;109: Pope CA 3rd, Burnett RT, Thurston GD, Thun MJ, Calle EE, Krewski D, Godleski JJ. Cardiovascular mortality and long-term exposure to particulate air pollution. Epidemiological evidence of general pathophysiological pathways of disease. Circulation 2004;109: Daniels MJ, Dominici F, Samet JM, Zeger SL. Estimating particulate matter-mortality dose-response curves and threshold levels: an analysis of daily time-series for the 20 largest US cities. Am J Epidemiol 2000;152: Schwartz J. Air pollution and daily mortality: a review and meta analysis. Environ Res 1994;64: Dockery DW. Epidemiologic evidence of cardiovascular effects of particulate air pollution. Environ Health Perspect 2001;109(Suppl. 4): Katsouyanni K, Touloumi G, Spix C, et al. Short-term effects of ambient sulphur dioxide and particulate matter on mortality in 12 European cities: results from time series data from the APHEA project. Air pollution and health: a European approach. Br Med J 1997;314: Samet JM, Dominici F, Curriero FC, Coursac I, Zeger SL. Fine particulate air pollution and mortality in 20 US cities, N Engl J Med 2000;343: Poloniecki JD, Atkinson RW, de Leon AP, Anderson HR. Daily time series for cardiovascular hospital admissions and previous day s air pollution in London, UK. Occup Environ Med 1997;54: Anderson HR. Association Between Ambient Particles and Daily Admissions for Cardiovascular Diseases. London: Department of Health, Goldberg MS. Particulate air pollution and daily mortality: who is at risk? J Aerosol Med 1996;9: Wichmann HE, Mueller W, Allhoff P, et al. Health effects during a smog episode in West Germany in Environ Health Perspect 1989;79: Hoek G, Brunekreef B, Goldbohm S, Fischer P, van den Brandt PA. Association between mortality and indicators of traffic-related air pollution in the Netherlands: a cohort study. Lancet 2002;360: Peters A, Liu E, Verrier RL, et al. Air pollution and incidence of cardiac arrhythmia. Epidemiology 2000;11: Peters A, Dockery DW, Muller JE, Mittleman MA. Increased particulate air pollution and the triggering of myocardial infarction. Circulation 2001;103: D Ippoltti D, Forastiere F, Ancona C, Agabiti N, Fusco D, Michelozzi P, Perucci CA. Air pollution and myocardial infarction in Rome: a case-crossover analysis. Epidemiology 2003;14: Seaton A, MacNee W, Donaldson K, Godden D. Particulate air pollution and acute health effects. Lancet 1995;345: Ferreiros EB, Boissonnet CP, Pizarro R, Merletti PF, Corrado G, Cagide A, Bazzino OO. Independant prognostic value of elevated C-reactive protein in unstable angina. Circulation 1999;100: Biasucci LLG. Elevated levels of C-Reactive Protein at discharge in patients with unstable angina predict recurrent instability. Circulation 1999;99: Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342: Peters A, Frohlich M, Doring A, et al. Particulate air pollution is associated with an acute phase response in men; results from the MONICA-Augsburg Study. Eur Heart J 2001;22: Peters A, Doring A, Wichmann HE, Koenig W. Increased plasma viscosity during an air pollution episode: a link to mortality? Lancet 1997;349: Donaldson KLX, MacNee W. Ultrafine (nanometre) particle mediated lung injury. J Aerosol Sci 1998;29: Donaldson K. Studies on the inflammatory potential of fine and ultrafine particles of carbon black, titanium dioxide and polystyrene/latex. Am J Respir Crit Care Med 2000; 161(Part 2):A Veronesi B, Oortgiesen M, Carter JD, Devlin RB. Particulate matter initiates inflammatory cytokine release by activation of capsaicin and acid receptors in a human bronchial epithelial cell line. Toxicol Appl Pharmacol 1999; 154: Jimenez LA, Drost EM, Gilmour PS, Rahman I, Antonicelli F, Ritchie H. PM(10)-exposed macrophages stimulate a proinflammatory response in lung epithelial cells via TNF-alpha. Am J Physiol Lung Cell Mol Physiol 2002;282:L237 L Quay JL, Reed W, Samet J, Devlin RB. Air pollution particles induce IL-6 gene expression in human airway epithelial cells via NF-kappaB activation. Am J Respir Cell Mol Biol 1998;19: Ghio AJ, Richards JH, Carter JD, Madden MC. Accumulation of iron in the rat lung after tracheal instillation of diesel particles. Toxicol Pathol 2000;28: Frampton MW, Ghio AJ, Samet JM, Carson JL, Carter JD, Devlin RB. Effects of aqueous extracts of PM(10) filters from the Utah valley on human airway epithelial cells. Am J Physiol Cell Physiol 1999;277:L960 L Costa DL, Dreher KL. Bioavailable transition metals in particulate matter mediate cardiopulmonary injury in healthy and compromised animal models. Environ Health Perspect 1997;5: Ogami A. The effect of PM10 on atherosclerotic lesions in rabbits. Am J Respir Crit Care Med 2000;161:A Salvi S, Blomberg A, Rudell B, et al. Acute inflammatory responses in the airways and peripheral blood after shortterm exposure to diesel exhaust in healthy human volunteers. Am J Respir Crit Care Med 1999;159:

8 446 OCCUPATIONAL MEDICINE 36. Nemmar A, Hoet PH, Vanquickenborne B, et al. Passage of inhaled particles into the blood circulation in humans. Circulation 2002;105: Peters A, Perz S, Doring A, Stieber J, Koenig W, Wichmann HE. Increases in heart rate during an air pollution episode. Am J Epidemiol 1999;150: Pope CA 3rd, Dockery DW, Kanner RE, Villegas GM, Schwartz J. Oxygen saturation, pulse rate, and particulate air pollution: a daily time-series panel study. Am J Respir Crit Care Med 1999;159: Dyer AR, Persky V, Stamler J, et al. Heart rate as a prognostic factor for coronary heart disease and mortality: findings in three Chicago epidemiologic studies. Am J Epidemiol 1980;112: Hjalmarson A, Elmfeldt D, Herlitz J, et al. Effect on mortality of metoprolol in acute myocardial infarction. A double-blind randomised trial. Lancet 1981;2: Schwartz PJ, Vanoli E, Stramba-Badiale M, De Ferrari GM, Billman GE, Foreman RD. Autonomic mechanisms and sudden death. New insights from analysis of baroreceptor reflexes in conscious dogs with and without a myocardial infarction. Circulation 1988;78: Watkinson WP, Campen MJ, Costa DL. Cardiac arrhythmia induction after exposure to residual oil fly ash particles in a rodent model of pulmonary hypertension. Toxicol Sci 1998;41: Godleski JJ, Verrier RL, Koutrakis P, et al. Mechanisms of morbidity and mortality from exposure to ambient air particles. Res Rep Health Eff Inst 2000;98: La Rovere M, Bigger JT Jr, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) investigators. Lancet 1998;351: Nolan J, Batin PD, Andrews R, et al. Prospective study of heart rate variability and mortality in chronic heart failure: results of the United Kingdom heart failure evaluation and assessment of risk trial (UK-heart). Circulation 1998;98: Pope CA 3rd, Verrier RL, Lovett EG, et al. Heart rate variability associated with particulate air pollution. Am Heart J 1999;138: Liao D, Creason J, Shy C, Williams R, Watts R, Zweidinger R. Daily variation of particulate air pollution and poor cardiac autonomic control in the elderly. Environ Health Perspect 1999;107: Gold DR, Litonjua A, Schwartz J, et al. Ambient pollution and heart rate variability. Circulation 2000;101: Magari SR, Hauser R, Schwartz J, Williams PL, Smith TJ, Christiani DC. Association of heart rate variability with occupational and environmental exposure to particulate air pollution. Circulation 2001;104: Tunnicliffe WS, Hilton MF, Harrison RM, Ayres JG. The effect of sulphur dioxide exposure on indices of heart rate variability in normal and asthmatic adults. Eur Respir J 2001;17: Yeates DB, Mauderly JL. Inhaled environmental/occupational irritants and allergens: mechanisms of cardiovascular and systemic responses. Introduction. Environ Health Perspect 2001;109(Suppl. 4): Zareba W, Nomura A, Couderc JP. Cardiovascular effects of air pollution: what to measure in ECG? Environ Health Perspect 2001;109(Suppl. 4): Schwartz J, Marcus A. Mortality and air pollution in London: a time series analysis. Am J Epidemiol 1990;131: Katsouyanni K, Karakatsani A, Messari I, et al. Air pollution and cause specific mortality in Athens. J Epidemiol Community Health 1990;44: Kinney PL, Ozkaynak H. Associations of daily mortality and air pollution in Los Angeles County. Environ Res 1991; 54: Schwartz J, Dockery DW. Increased mortality in Philadelphia associated with daily air pollution concentrations. Am Rev Respir Dis 1992;145: Dockery DW, Pope CA 3rd, Xu X, et al. An association between air pollution and mortality in six US cities. N Engl J Med 1993;329: Schwartz J. What are people dying of on high air pollution days? Environ Res 1994;64: Anderson HR, Ponce dla, Bland JM, Bower JS, Strachan DP. Air pollution and daily mortality in London: Br Med J 1996;312: Ponka A, Savela M, Virtanen M. Mortality and air pollution in Helsinki. Arch Environ Health 1998;53: Zmirou D, Schwartz J, Saez M, et al. Time-series analysis of air pollution and cause-specific mortality. Epidemiology 1998;9: Ostro B, Chestnut L, Vichit-Vadakan N, Laixuthai A. The impact of particulate matter on daily mortality in Bangkok, Thailand. J Air Waste Manag Assoc 1999;49: Rossi G, Vigotti MA, Zanobetti A, Repetto F, Gianelle V, Schwartz J. Air pollution and cause-specific mortality in Milan, Italy, Arch Environ Health 1999;54: Samet JM, Dominici F, Curriero FC, Coursac I, Zeger SL. Fine particulate air pollution and mortality in 20 US cities N Engl J Med 2000;343: Katsouyanni K, Touloumi G, Samoli E, et al. Confounding and effect modification in the short-term effects of ambient particles on total mortality: results from 29 European cities within the APHEA2 project. Epidemiology 2001;12: Schwartz J, Morris R. Air pollution and hospital admissions for cardiovascular disease in Detroit, Michigan. Am J Epidemiol 1995;142: Burnett RT, Dales R, Krewski D, Vincent R, Dann T, Brook JR. Associations between ambient particulate sulfate and admissions to Ontario hospitals for cardiac and respiratory diseases. Am J Epidemiol 1995;142: Morris RD, Naumova EN, Munasinghe RL. Ambient air pollution and hospitalization for congestive heart failure among elderly people in seven large US cities. Am J Public Health 1995;85: Wordley J, Walters S, Ayres JG. Short term variations in hospital admissions and mortality and particulate air pollution. Occup Environ Med 1997;54:

9 H. C. ROUTLEDGE AND J. G. AYRES: AIR POLLUTION AND THE HEART Schwartz J. Air pollution and hospital admissions for cardiovascular disease in Tucson. Epidemiology 1997; 1997: Burnett RT, Cakmak S, Brook JR, Krewski D. The role of particulate size and chemistry in the association between summertime ambient air pollution and hospitalization for cardiorespiratory diseases. Environ Health Perspect 1997; 105: Schwartz J. Air pollution and hospital admissions for heart disease in eight US counties. Epidemiology 1999;10: Le Tertre A, Medina S, Samoli E, et al. Short-term effects of particulate air pollution on cardiovascular diseases in eight European cities. J Epidemiol Community Health 2002; 56: