Air Quality, Stroke, and Coronary Events
Results of the Heinz Nixdorf Recall Study From the Ruhr Region
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Background: Studies have shown that air pollution is associated with cardiopulmonary mortality, but there has been less research of the possible effect of air pollution on stroke and non-fatal coronary events. The Heinz Nixdorf Recall (HNR) study addressed the question of the effect of long-term air pollution on stroke and coronary events. Ambient acoustic noise was also considered as a risk factor.
Methods: The HNR study, initiated in 2000, is a prospective, population-based cohort study in the Ruhr region of Germany. Long-term exposure to fine-particle dust (PM10, PM2.5 and PM2.5abs [carbon black content]) and traffic noise at the subjects’ home addresses were determined using land-use regression and dispersion models, respectively. Strokes and coronary events were ascertained from patient records by an independent end-point committee on the basis of predefined study criteria. The adjusted hazard ratio (HR) was calculated using Cox regression analysis for an increase in concentration from the 5th to the 95th percentile for each exposure.
Results: Data from 4433 subjects were evaluated. The incidence of stroke was 2.03 per 1000 person-years (PY), and that of coronary events was 3.87 per 1000 PY. The highest hazard ratios for stroke were seen for PM10 (HR 2.61, 95% confidence interval [CI] 1.13–6.00) and PM2.5 (HR 3.20, 95% CI 1.26–8.09). The highest hazard ratios for coronary events were found for PM10 (HR 1.07, 95% CI 0.56–2.04) and for PM2.5abs (HR 1.37, 95% CI 0.80–2.36).
Conclusion: Long-term exposure to fine-particle dust is associated with a higher risk of stroke, regardless of the subject’s exposure to noise at his or her home address. The results for coronary events are less clear, but still suggest increased risk.
In Germany, the times of great smog episodes are largely things of the past. But even today, air quality thresholds are frequently exceeded and discussions of solutions range from low emission zones, bypass roads, industrial restrictions, etc., to personal lifestyle interventions. In addition, the quality of air pollution has changed significantly due to a number of factors including effective filtering of larger particles, which has led to a relative increase of smaller, respirable particles. The rapidly increasing body of evidence for the adverse health effects of particulate matter that has emerged in recent years (Box) (1) prompted the U.S. Environmental Protection Agency to revise its standards in 2013. Thus, the long-term threshold for respirable particulate matter with an aerodynamic diameter of under 2.5 µm (PM2.5) was lowered from 15 µg/m3 to 12 µg/m3 (2). In the European Union (EU), the roughly comparable value is currently 25 µg/m3 (3).
Although in recent years numerous studies have reported correlations between air pollution and total mortality as well as cardiovascular and respiratory mortality (4–12), the association with stroke incidence has been less frequently studied and with conflicting results (13–16). In addition, several studies have shown an association between cardiovascular disease and chronic noise exposure, which often coexists with high levels of air pollution (17). Studies examining both environmental stressors simultaneously remain uncommon (18).
Because of its substantial relevance at the population level, this topic deserves worldwide attention from the research and public health communities (19). To investigate the health impact of long-term exposure to the concentrations of air pollutants currently found in Europe, the EU, through its Framework Programme 7, funded a large, multicenter study: the European Study of Cohorts on Air Pollution Effects (ESCAPE). One particular goal of the ESCAPE study was to provide epidemiological evidence for the modification of European thresholds. The incidences of stroke and coronary events were examined as two key endpoints of the ESCAPE study (20, 21).
The German Heinz Nixdorf Recall (HNR) study is one of the cohort studies making a substantial contribution to this European project. Because of the location of the study in the Ruhr region, a densely populated and still recently highly industrialized area, the studied cohort is highly suitable to evaluate the effects of long-term air pollution. The goal of the current study is to extend the HNR-specific results regarding stroke and coronary events by accounting for concomitant chronic noise pollution.
The HNR is a population-based prospective cohort study involving a random sample of 45- to 74-year-old inhabitants of the Ruhr region cities of Bochum, Essen, and Mülheim/Ruhr (22). During the years 2000 to 2003, 4814 people took part in the baseline investigation (participation rate: 55.8%) (23). All subjects provided written informed consent. The study was approved by the Ethics Committee of the University of Duisburg–Essen.
Subsequent to the baseline examination, annual questionnaire-based follow-up was performed. In cases where stroke or coronary events were suspected, the medical records or other sources were investigated (22). For the endpoints of the current analysis, clearly documented incidents of stroke and coronary events (infarction, sudden cardiac death, and fatal coronary heart disease [CHD]) were considered. These endpoints are defined according to a protocol harmonized among the individual European cohorts: diagnoses with ICD-10 I61, I63, or I64 and cause of death I61 to I64 apply for stroke (21), diagnoses with ICD-10 I21, I23, I20.0, or I24 and cause of death I20 to I25 apply for coronary events (20).
For all end points, the independent endpoint committees of the HNR study evaluated patient records containing laboratory values, ECG, and pathology results. In cases of deceased participants, death certificates were evaluated and interviews with treating physicians, relatives, and witnesses were conducted as needed.
As part of the ESCAPE project, exposure to particulate matter was measured using a standardized protocol at 20 locations in the studied region over the time from August 2008 to July 2009 (24, 25). The pollutants measured were PM10 (aerodynamic diameter of ≤ 10 µm), PM2.5 (≤ 2.5 µm), PM2.5–10, and PM2.5abs (the absorbance [abs] of PM2.5 is a measure of the soot content). Using land-use regression (LUR) models (eBox), the levels of pollutants at the home residence were allocated for each participant. Traffic from busy roads (>5000 vehicles/day) within a 100 m radius of the residence was considered as an additional exposure. Chronic noise pollution from road traffic near the home was determined using noise models prepared according to the European guidelines. The results of the noise pollution models were made available by the cities and then assigned to the home addresses of the study participants.
The following covariates collected during the baseline examination were considered (Table 1):
- Marital status
- Employment status
- Smoking status, including duration and intensity
- Blood pressure
- Type 2 diabetes mellitus
- Categorical variables for body mass index (BMI)
- Physical activity
- Alcohol consumption.
In addition, the unemployment rate for the residential district was considered as an indicator of socioeconomic status. This is because this factor, independent of personal socioeconomic status, affects cardiovascular disease, access to healthcare, and lifestyle factors (26). In the final model, we did not adjust for cholesterol because there was no significant impact on the effect estimates, and there was a significant reduction in sample size when using it, since not all subjects had blood samples, and thus cholesterol values, available.
Cox regression analysis was performed with age as a time scale to determine the association between exposure and event incidence. 4433 participants reporting no history of coronary events or stroke at baseline and offering complete information regarding the confounding variables, were included in the study. We analyzed the most recent complete data set, from February 2012. (Table 1).
A combined endpoint of stroke and coronary events was defined as the main outcome, but each end point was also evaluated independently.
A priori defined sets were used for the adjustment of the confounding variables:
- Model 1: adjustment for sex and recruitment year.
- Model 2: additional adjustment for marital status, education, employment status, smoking status, smoking duration and intensity, and unemployment rate in the residential district.
- Model 3: additional adjustment for BMI, physical activity, and alcohol consumption.
- Model 4: additional adjustment for night traffic noise.
The effects were specified for an increase corresponding to the difference in concentration from the 5th to 95th percentiles of each pollutant exposure within the study region. Thus, it becomes possible to compare effects of different pollutants within the study area.
In a sensitivity analysis based on Model 2, those individuals who had lived at least five years in their residence prior to the baseline examination and who had not changed address during follow up were investigated. All analyses were performed using STATA Software (www.stata.com).
The profile of this at-risk study population, with no history of stroke nor coronary events at baseline, is listed in Table 1. The analysis population for whom information regarding covariates are available (N = 4433) represent 90% of the total population of the HNR study (N = 4814), and 97% of the study participants who at the time of the baseline examination reported neither stroke nor coronary event (N = 4465). Over an average observation period of 7.9 ± 1.5 years, there were 206 events in a total of 34 644 at-risk person-years (PY), of these 135 coronary events in 34 909 PY and 71 strokes in 34 941 PY. Thus, the incidence was 5.95/1000 PY for all events, 3.87/1000 PY for coronary events, and 2.03/1000 PY for stroke. A detailed description of the study population including risk scores is given in the study by Erbel et al. (27). The individual pollutant exposure was on average 27.8 µg/m3 for PM10 and 18.4 µg/m3 for PM2.5 (Table 2).
An analysis of the combined endpoint of stroke and coronary events yielded increased point estimates for all investigated exposures in the fully adjusted model (Model 4), particularly for PM10 (hazard ratio [HR] = 1.41; 95% confidence interval [CI]: 0.85 to 2.36]), PM2.5 (HR = 1.45; 95% CI: 0.84 to 2.52), and with soot content of the particulate matter PM2.5abs (HR = 1.51; 95% CI: 0.99 to 2.31) (Table 3). When subjects who had moved within five years prior to the baseline study were excluded, the HR increased for PM2.5abs to 1.65 (95% CI: 1.07 to 2.55) and for a high traffic load to 1.27 (95% CI: 0.97 to 1.66).
The fully adjusted risk for stroke in all particulate matter fractions was markedly increased, particularly for PM10 (HR = 2.61; 95% CI: 1.13 to 6.00) and PM2.5 (HR = 3.20; 95% CI: 1.26 to 8.09). The effect estimate for PM2.5abs was 1.86 (95% CI: 0.94 to 3.66). Traffic exposure in proximity to the home was not clearly linked to the risk of stroke. When subjects who had moved within five years prior to the baseline survey were excluded, the risks did not significantly change.
The fully adjusted risks for coronary events were less markedly increased. Only for PM2.5abs was there a not significantly increased effect estimate with HR of 1.37 (95% CI: 0.80 to 2.36), which increased to 1.61 (95% CI: 0.93 to 2.78) when the people who had moved were excluded. The estimate for high traffic load in the home vicinity was also increased (HR = 1.35; 95% CI: 0.98 to 1.86) after the participants who had moved within five years prior to the baseline study were excluded.
The concentration of air pollution today is only about a quarter of the value common during the 1970s. The present study shows an association between long-term air pollution and stroke regardless of the presence of noise pollution, and this even at current, lower pollution concentrations. The results of the HNR study indicate that the occurrence of stroke is associated with PM10 and PM2.5, the two currently EU wide regulated PM fractions. In addition, the soot content of the particulate dust, which is currently not legally regulated in the EU, appears to be associated with risk for both stroke and coronary events. These results were robust to changes in various model assumptions and adjustment variables.
The present analysis of the HNR study is based on the multi-center European ESCAPE project that used data from approximately 100 000 test subjects and calculated that a concentration change of 5 µg/m3 PM2.5 led to an increased risk for stroke of 19%, and for coronary events of 13% (20, 21). In addition to the main results of the ESCAPE study, our analysis considered chronic noise exposure, which is known as a potentially important variable influencing the effects of air pollution. When noise is considered during the analysis for stroke, there is a trend towards an increase in the effect estimate for particulate matter. By contrast, the effect estimate decreases slightly when evaluating coronary events. Further results from the HNR study indicate a correlation between long-term concentrations of particulate matter at the home and high-sensitivity C-reactive protein (CRP) levels in serum (28, 29), arterial blood pressure (30), and the degree and progression of intima-media thickness of the common carotid artery (a measure for subclinical atherosclerosis) (31, 32). In addition, proximity to busy streets was associated with the degree of coronary artery calcification as measured with electron beam computed tomography (32).
There is no clear explanation for the markedly higher HR for stroke compared to coronary events in the HNR study. It is possible that the selected endpoint of coronary events incompletely reflects the presence of CHD, thanks to the increasingly improved and earlier treatments for the disease. Thus, interventions such as dilatation or stents that prevent events from manifesting should also be considered as endpoints when appropriate. This will be performed in further analyses.
The results of the ESCAPE and HNR studies show linear exposure–effect relationships (20, 21, 29, 31). Also, the associatons between particulate matter and the health sequelae listed above also occur beneath the currently valid European thresholds for particulate matter concentrations (20, 21). Thus, if the long-term exposure to particulate matter is reduced, health improvements in the population may be expected, regardless of current levels of exposure. A large U.S. study has already demonstrated that life expectancy increases by 0.6 years when long-term PM10 concentration is decreased by 10 µg/m3 (33).
- Endothelial dysfunction and vasoconstriction
- Increased blood pressure
- Prothrombotic changes
- Systemic inflammatory processes and oxidative stress
- Autonomic disequilibrium and arrhythmias
- Progression of atherosclerosis .
The effects of short-term increases in particulate matter concentrations—causing acute events for example through the induction of arrhythmias and atrial fibrillation as well as triggering of inflammatory and procoagulative processes (1)—are differentiated from the effects of long-term exposure, which accelerate the development of the underlying atherosclerotic disease (31, 32).
The size of the associations found in this study are comparable to known risk factors. For stroke, the HR is approximately 2.0 for smoking, 1.5 for atrial fibrillation, and 1.4 for diabetes mellitus (34). These risk factors, however, are only present for subgroups of the population. On the other hand, the entire population is exposed to greater or lesser concentrations of air pollution. In addition, personal exposure can be only relatively minimally controlled by the individuals themselves. This explains why these findings have such enormous significance for public health.
The American Heart Association (AHA) has produced a comprehensive statement describing the marked effect of air pollution (1, 34). The AHA recommends that practicing physicians should educate patients regarding the risks of particulate matter. This applies particularly for people at risk, for example because of diabetes mellitus, increased age, or multiple cardiovascular risk factors. Such individuals should restrict extra physical activity on days with higher loads of dust pollution or do so protected in a less polluted indoor area. Overall, the prevention potential for individuals is considered to be very low, so a setting approach for prevention by environmental regulation is necessary. The current recommendations of the World Health Organization (WHO) are annual averages of 20 µg/m3 for PM10 or 10 µg/m3 for PM2.5 and are thus markedly lower than the levels measured currently in many urban centers in Germany.
Limitations and strengths of the study
The present study is limited by the fact that disease events had partly already occurred when the air pollution measurements took place and the resulting exposure models were created. However, studies have confirmed that the procedure used for the land-use regression models does provide valid exposure values for the long-term. Concentration differences within the study region, on which our analyses are based, have been reliably reproduced (35, 36). When exposure values were extrapolated back to the time of the baseline examination, using air pollution concentrations from routine monitoring sites, the risk estimates of the HNR study do not change significantly.
The strength of this study lies in the detailed assessment of exposure, which contrasts to most previous studies, in that the pollutant exposure was assessed with a high spatial resolution and that the noise exposure of each individual residence was taken into account. In addition, the HNR is a large, population-based study, for which an external committee of experts regularly assessed the endpoints of CHD and stroke. Thus, misclassification of events was minimized. A number of potential confounding variables for the investigated correlations were carefully recorded and considered.
The results suggest that long-term home exposure to particular matter, both PM2.5 and PM10, even at current levels as measured in the Ruhr area, increases the risk of stroke. The results for coronary events are less clear, but still indicate—corresponding with findings in the literature and in the European ESCAPE study—increased risk. The role of other dust particles, currently not yet regulated in Europe but possibly also increasing risk, should be investigated in the future. This includes—particularly important in proximity to roads—exposure to soot particles. Concerted action is needed across Europe to further reduce exposure to particulate matter and minimize the health consequences for the population.
We would like to thank the Heinz Nixdorf Foundation (Heinz Nixdorf Stiftung) (Chairman: Martin Nixdorf; former Chairman: Dr. Jur. G. Schmidt [†]), for its generous support of this study. The study was also funded by the Federal Ministry of Education and Research (BMBF: Bundesministerium für Bildung und Forschung). We thank also Prof. Dr. K. Lauterbach (Institute of Health Economics and Clinical Epidemiology, University of Cologne [Abteilung für Gesundheitsökonomie und Epidemiologie, Universität Köln]) for his valuable contribution at an early phase of the study. The compilation of psychosocial factors and the residential district-level information was supported by the German Research Foundation (DFG, Deutsche Forschungsgemeinschaft; Projects SI 236/8–1 and SI 236/9–1). In addition, we thank Sarstedt AG & Co. (Nümbrecht) for assisting with laboratory materials. The air pollution portion was funded by the DFG (DFG HO 3314/2–1 and JO170/8–1) and the 7th Framework Programme of the European Union (FP7/2007–2011: Project ESCAPE [grant number: 211250]).
We thank all study participants as well as the investigating group and the staff in the study center of the Heinz Nixdorf Recall study, particularly U. Roggenbuck, S. Slomiany, E. M. Beck, A. Öffner, S. Münkel, M. Bauer, S. Schrader, R. Peter, H. Hirche, and A. Buschka. Scientific advisory board: T. Meinertz, Hamburg (Chairman); C. Bode, Freiburg; P. J. de Feyter, Rotterdam/Netherlands; B. Güntert, Hall i.T., Austria; F. Gutzwiller, Bern, Switzerland; H. Heinen, Bonn; O. Hess, Bern, Switzerland; B. Klein, Essen; H. Löwel, Neuherberg; M. Reiser, Munich; M. Schwaiger, Munich; C. Steinmüller, Bonn; T. Theorell, Stockholm, Sweden; S. N. Willich, Berlin. Endpoint committee: C. Bode, Freiburg (Chairman); K. Berger, Münster; HR. Figulla, Jena; C. Hamm, Bad Nauheim; P. Hanrath, Aachen; W. Köpcke, Münster; EB. Ringelstein, Münster; C. Weimar, Essen; A. Zeiher, Frankfurt. In addition, we thank our colleagues Giulia Cesaroni and Massimo Stafoggia from Rome, who produced the large majority of analysis codes used here for the ESCAPE project.
Conflict of interest statement
Prof. Hoffmann was remunerated for the review of a related project from the Health Effects Institute. She received research funding from the Volkswagen Foundation (Volkswagenstiftung).
Prof. Dragano received funding from the Volkswagen Foundation (Volkswagenstiftung) for a research project he initiated.
Prof. Erbel received funding from the Heinz Nixdorf Foundation (Heinz Nixdorf Stiftung) for a research project he initiated.
The remaining authors declare that no conflicts of interest exist.
Manuscript received on 2 June 2014, revised version accepted on
9 December 2014.
Prof. Dr. med. Barbara Hoffmann MPH
IUF – Leibniz Research Institute of Environmental Medicine
at the Heinrich Heine University Düsseldorf gGmbH
Auf’m Hennekamp 50
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