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(Circulation. 2002;106:933.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

Particulate Air Pollution and Risk of ST-Segment Depression During Repeated Submaximal Exercise Tests Among Subjects With Coronary Heart Disease

The Exposure and Risk Assessment for Fine and Ultrafine Particles in Ambient Air (ULTRA) Study

Juha Pekkanen, MD; Annette Peters, PhD; Gerard Hoek, PhD; Pekka Tiittanen, MSc; Bert Brunekreef, PhD; Jeroen de Hartog, MSc; Joachim Heinrich, PhD; Angela Ibald-Mulli, MSc; Wolfgang G. Kreyling, PhD; Timo Lanki, MSc; Kirsi L. Timonen, MD; Esko Vanninen, MD

From the Unit of Environmental Epidemiology (J.P., P.T., T.L., K.L.T.), National Public Health Institute, Kuopio, Finland; Institute of Epidemiology (A.P., J.H., A.I.-M.), GSF-National Research Center for Environment and Health, Neuherberg, Germany; Environmental and Occupational Health Unit (G.H., B.B., J.d.H.), University of Utrecht, the Netherlands; Institute of Inhalation Biology (W.G.K.), GSF-National Research Center for Environment and Health, Neuherberg, Germany; and Department of Clinical Physiology and Nuclear Medicine (E.V.), University of Kuopio and Kuopio University Hospital, Kuopio, Finland.

Correspondence to Juha Pekkanen, MD, National Public Health Institute, Unit of Environmental Epidemiology, Neulaniementie 4, PO Box 95, FIN-70701 Kuopio, Finland. E-mail Juha.Pekkanen{at}ktl.fi

	Abstract

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Background— Daily variations in ambient particulate air pollution have been associated with cardiovascular mortality and morbidity. We therefore assessed the associations between levels of the 3 main modes of urban aerosol distribution and the occurrence of ST-segment depressions during repeated exercise tests.

Methods and Results— Repeated biweekly submaximal exercise tests were performed during 6 months among adult subjects with stable coronary heart disease in Helsinki, Finland. Seventy-two exercise-induced ST-segment depressions >0.1 mV occurred during 342 exercise tests among 45 subjects. Simultaneously, particle mass <2.5 µm (PM2.5) and the number concentrations of ultrafine particles (particle diameter 10 to 100 nm [NC_0.01–0.1]) and accumulation mode particles (100 to 1000 nm [NC_0.1–1]) were monitored at a central site. Levels of particulate air pollution 2 days before the clinic visit were significantly associated with increased risk of ST-segment depression during exercise test. The association was most consistent for measures of particles reflecting accumulation mode particles (odds ratio 3.29; 95% CI, 1.57 to 6.92 for NC_0.1–1 and 2.84; 95% CI, 1.42 to 5.66 for PM2.5), but ultrafine particles also had an effect (odds ratio 3.14; 95% CI, 1.56 to 6.32), which was independent of PM2.5. Also, gaseous pollutants NO₂ and CO were associated with an increased risk for ST-segment depressions. No consistent association was observed for coarse particles. The associations tended to be stronger among subjects who did not use ß-blockers.

Conclusions— The present results suggest that the effect of particulate air pollution on cardiovascular morbidity is at least partly mediated through increased susceptibility to myocardial ischemia.

Key Words: cardiovascular disease • ischemia • epidemiology

	Introduction

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Several time-series studies have observed an association between particulate air pollution, especially fine particles (particle mass <2.5 µm, PM2.5)¹ and mortality or hospital admissions attributable to cardiovascular diseases.² Despite an intensive search in the last years involving autonomic nervous function^3–8 and blood coagulability^9–11 and acute phase reaction,¹² pathways mediating the effect of particulate air pollution on ischemic heart disease are not known.

See p 890

It is also not known which characteristic of particulate air pollution determine its health effects. Presently, the two dominant hypotheses concern the chemical composition of fine particulate matter or the large number of ultrafine particles (particles <0.1 µm in diameter) in urban air. Ultrafine particles have been associated with respiratory health in panel studies.^13–15 However, presently there is little evidence on the association between exposure to ultrafine particles and cardiovascular health.¹⁶

ST-segment depression during an exercise test indicates with high probability myocardial ischemia.¹⁷ We therefore studied the association between levels of the three main modes of urban aerosol distribution, ultrafine particles (particle diameter 0.01 to 0.1 µm), accumulation mode particles (particle diameter 0.1 to 1 µm), PM1, PM2.5, and coarse particles (particle diameter 2.5 to 10 µm) and the occurrence of ST-segment depressions during repeated submaximal exercise tests among subjects with stable coronary heart disease.

	Methods

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The ULTRA study was carried out in Amsterdam, the Netherlands; Erfurt, Germany; and Helsinki, Finland, during the winter of 1998 to 1999. All methods were performed according to standard operating procedures developed for the ULTRA study.¹⁸

In each city, a panel of subjects with coronary artery disease was followed up for 6 months with biweekly clinical visits and daily symptom diaries. The subjects were characterized by a questionnaire and recording of a 12-lead standard resting ECG. The main inclusion criteria for the study were a self-report on a doctor-diagnosed coronary artery disease, being a nonsmoker, and age >50 years.

The clinical visit included recording of ambulatory ECG during a standardized protocol, which included a 6-minute submaximal exercise with a bicycle ergometer. For each subject, the visit was scheduled for the same weekday and time of day with no changes in daily medication.

In the exercise test, the aim was to achieve a steady state with heart rate of 90 to 100 bpm. If needed for a given participant, a lower target heart rate was set during the first visit and kept for the whole duration of the study. The load was gradually increased to achieve the target heart rate during the first minute of exercise. If the subject had symptoms of angina pectoris or moderate or severe respiratory symptoms during the clinical visit or fever during the preceding week, no exercise test was performed. A common cold or respiratory infection was relative contraindication for the exercise.

The ambulatory ECGs were recorded with Oxford MR-63 tape recorders (V7.5, Oxford Instruments). Two-channel recordings were performed with standard electrode position recommended by the manufacturer. The ST analyses are based on a lead configuration corresponding to standard lead V₅. The ECG recordings were analyzed with the Oxford Medilog Excel II system (Oxford Instruments). Trained research assistants reviewed and when necessary interactively edited the automatically predetermined classification of the QRS complexes.

Only exercise-induced ST depressions were considered. We recorded the start time and end time of both the ST depression and the exercise test and included in the analyses only those ST depressions that had their start time during the exercise test. ST depressions were measured at 63 ms after J-point. Both ST depressions >0.1 mV^19,20 and horizontal or downsloping (ST slope <0.2 mV/s) ST depressions >0.1 mV^17,21 were recorded. In addition, to increase sensitivity, ST depressions >0.053 mV irrespective of slope were also recorded.²²

Because of the lower number of ST depressions observed in Erfurt and Amsterdam, present analyses were limited to Helsinki. In Erfurt, ST-segment depressions >0.05 mV and >0.1 mV were observed in only 17 and 7 of the 416 exercise tests, in Amsterdam 14 and 5 of 328 tests, and in Helsinki in 133 and 78 of 361 exercise tests, respectively. This was mainly attributable to the lower heart rates during the exercise tests in Erfurt and in Amsterdam. The proportion of exercise tests with heart rate >90 bpm and >80 bpm were 59% and 88% in Helsinki, 17% and 56% in Erfurt, and 13% and 41% in Amsterdam. The proportion of exercise tests with an increase in heart rate of at least 20 bpm compared with the rest period was 89% in Helsinki, 28% in Erfurt, and 22% in Amsterdam.

In Helsinki, number concentrations of particles were measured continuously with an Electric Aerosol Spectrometer (EAS) on a fixed urban background-monitoring site. All study subjects lived within a 5-kilometer radius of the monitoring site. EAS has been shown to accurately reflect variations in number counts of ultrafine (0.01 to 0.1 µm; NC_0.01–0.1) and accumulation-mode particles (0.1 to 1.0 µm; NC_0.1–1).^23,24 Six missing days of ultrafine number concentration were imputed based on total particle counts (CPC 3022A, TSI Inc) measured at the same site (correlation 0.98 with NC_0.01–0.1). PM2.5, and PM1 were monitored with single-stage Harvard impactors.^25,26 Thirteen missing days of PM2.5 were imputed using data from a dynamic mass monitor (ESM Eberline, FH 62 I-R) (correlation 0.97 with PM2.5). The data on PM10 and average temperature were provided by the Helsinki Metropolitan Area Council and relative humidity by Finnish Meteorological Institute. PM_2.5–10 was calculated by subtracting PM2.5 from PM10. All variables are 24-hour means from noon to noon.

Ethics committees in each study center approved the study protocol. Written informed consent was obtained from all subjects.

Statistical Analyses
Risk of ST-segment depression was related to levels of air pollution measured during subsequent 24-hour periods from noon to noon. Lag 0 was defined as the 24-hour period from noon of the day of the clinical visit to noon of the previous day, lag 1 as the preceding 24-hour period, ie, from noon of the previous day to noon of the day before, lag 2 as the preceding 24-hour period, and so on. Data were analyzed using logistic regression and generalized additive models in the statistical package S-Plus. A basic model was first built¹⁸ without including particulate air pollution in the model. Shape and lags of the covariates were explored using loess functions. Criteria for building the basic model were Akaike’s information criteria and covariate-response plots. All basic models included a dummy for each subject and either linear terms or nonparametric functions with span 0.5 to 0.8 of time trend, temperature (lag 3), relative humidity (lag 3), and change in heart rate during exercise test.

	Results

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All subjects had doctor-diagnosed coronary heart disease, and half of them had had coronary bypass surgery or percutaneous coronary transluminal angioplasty (Table 1). Altogether, there were 511 visits with 417 exercise tests performed during the study period among 47 subjects. The main reasons for not performing the exercise tests were cardiorespiratory or other symptoms (n=84). Of the 417 exercise tests, 56 were excluded because of substandard quality of the recording and 19 because of missing data on and change in heart rate during exercise test, leaving 45 subjects and 342 (67% of visits) exercise tests for analyses. There was no association between particulate air pollution and missing data on the exercise test. One subject had a ST-segment depression >0.1 mV at every visit, and 21 subjects never had such a ST-segment depression during exercise test.

View this table: [in this window] [in a new window]   Table 1. Characteristics of the Final Study Population

The concentrations of PM2.5 were fairly low, whereas levels of ultrafine particles were similar to those in other parts of Europe (Table 2). All measures of particles reflecting mostly the accumulation-mode particles (NC_0.1–1, PM1, and PM2.5) were highly intercorrelated but were less correlated with ultrafine particles (NC_0.01–0.1) and coarse particles (PM_2.5–10) (Table 3). NO₂ was mainly correlated with NC_0.01–0.1.

View this table: [in this window] [in a new window]   Table 2. Daily Concentrations of Air Pollution, Mean Temperature, and Relative Humidity

View this table: [in this window] [in a new window]   Table 3. Spearman Correlations Between Air Pollutants, Mean Temperature, and Relative Humidity

Consistent and statistically significant associations were observed between increased risk of exercise-induced ST-segment depression >0.1 mV and exposure to measured air pollutants, except PM_2.5–10 (Table 4). The associations were strongest for NC_0.01–0.1 and accumulation-mode particles (NC_0.1–1, PM1, and PM2.5) measured 2 days before the clinic visit (Figure). Associations were more consistent when horizontal or downward-sloping ST-segment depressions during the exercise test were considered but smaller and not as consistent with ST-segment depression >0.05 mV.

View this table: [in this window] [in a new window]   Table 4. ORs* Between Daily Levels of Air Pollution and Occurrence of ST-Segment Depressions During Repeated Mild Exercise Tests

View larger version (15K): [in this window] [in a new window]   Smoothed (span 0.8) association between PM2.5 2 days before the clinic visit and adjusted risk of ST-segment depression >0.1 mV. The broken curves indicate approximate point-wise 95% CIs.

Several sensitivity analyses were performed. Including time and weekday of the clinic visit into the models in general strengthened the associations between air pollutants and exercise-induced ST-segment depression. The association of NC_0.01–0.1 with risk of ST-segment depression was somewhat sensitive to selection of lag of temperature. The association was strongest with lag 3 used in the basic model and weakest with short lags (odds ratio [OR] 1.82; 95% CI, 1.09 to 3.03 for lag 0). Different lags of temperature had little effect on the association with NC_0.1–1. Current day pollen decreased the size of the effect (with pollen OR 2.38 for NC_0.01–0.1, OR 3.18 for NC_0.1–1, and OR 3.55 for PM1, all lag 2), but the associations remained statistically significant. Relative humidity and ambient air barometric pressure had little effect on any of the associations analyzed. This was also true for influenza epidemics, occurrence of supraventricular ectopic beats during exercise test, and excluding those days with pollution levels above the 95th percentile of pollution.

All of the associations were strengthened when subjects with left bundle-branch block, left ventricular hypertrophy, or anterolateral infarction were excluded (Table 5). This was also true when users of digitalis were excluded (data not shown). All associations, but especially associations with accumulation mode particles, tended to be stronger among subjects who did not use ß-blockers. Associations tended to be stronger among women and those without history of past myocardial infarction for NC_0.01–0.1 (NO₂), whereas the opposite was true for PM2.5 (and PM1).

View this table: [in this window] [in a new window]   Table 5. ORs* of Pollutants (Lag 2) With ST Depression >0.1 mV During the Exercise Test in Different Subgroups

In two-pollutant models (lag 2 of all pollutants), the effects of NC_0.01–0.1 (OR 2.55; 95% CI, 1.25 to 5.19) and PM2.5 (OR 2.34; 95% CI, 1.14 to 4.80) were independent of each other. Otherwise the pollutants were quite correlated, so their independent effects are more difficult to separate. However, there was a suggestion that the effects of PM1 and especially NC_0.1–1 were least changed in two pollutant models with other pollutants, like with ultrafine particles (OR 2.70; 95% CI, 1.04 to 6.99 for NC_0.1–1 and OR 1.34; 95% CI, 0.54 to 3.36 for NC_0.01–0.1) or with PM2.5 (OR 3.75; 95% CI, 1.13 to 12.41 for NC_0.1–1 and OR 0.84; 95% CI, 0.23 to 3.02 for PM2.5).

	Discussion

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We observed independent associations of both PM2.5 and ultrafine particulate air pollution with the risk of ST-segment depression during repeated exercise tests among subjects with stable coronary heart disease. The results provide a biological link between ambient particulate levels and mortality and morbidity attributable to ischemic heart disease.

We were able to study all 3 main modes of urban aerosol distribution. Accumulation mode particles (NC_0.01–0.1, PM1, and PM2.5), originating mainly from long-range transport, showed the most consistent independent associations. However, in addition, ultrafine particles produced mainly by traffic showed an effect independent of PM2.5. No consistent association was observed for coarse, mainly soil-derived particles.

There are no previous studies relating particulate air pollution to ischemic ST-segment depressions in humans. However, a consistent association has been observed in time series studies between daily levels of particulate air pollution and mortality or hospital admissions attributable to cardiovascular diseases.² Exposure to particulate air has also been shown to be associated with increased ECG abnormalities like arrhythmia and ST elevation in dogs and rats.²⁷

An association of particulate air pollution with myocardial ischemia could either be attributable to a decrease in the myocardial oxygen supply or an increase in the demand or both. Some studies have suggested an association between particulate air pollution and increased levels of plasma viscosity,⁹ serum fibrinogen,¹⁰ C-reactive protein,¹² and other hemostatic factors,¹¹ which could lead to a decrease in the oxygen supply to the heart. Particulate air pollution could also, like oxidant stress,²⁸ worsen the endothelial dysfunction observed in atherosclerotic coronary arteries.²⁹ Coronary vasculature with endothelial dysfunction is known to respond with paradoxical vasoconstriction to adrenergic stimulation such as exercise,³⁰ which would also lead to a decrease in the oxygen supply to the heart. Particulate air pollution could also increase the oxygen demand of the heart through an increase in the basal heart rate^3,4 or arterial blood pressure,³¹ possibly via an effect on the autonomic nervous system. Several studies also have reported associations with arrhythmia⁵ and different measures of heart rate variability,^6–8,32 which would support an association between particulate air pollution and the autonomic nervous system.³³ The mechanisms linking particulate air pollution and myocardial ischemia are, however, presently unknown.

ST-segment depression >0.1 mV during an exercise test is considered a reliable marker of ischemia among subjects with coronary heart disease.^17,21 Because the exercise test was submaximal in the present study and there is a linear correlation between heart rate response and subendocardial ischemia,²¹ we also evaluated smaller ST changes (>0.05 mV) to increase the sensitivity of the exercise test.²² This less-strict criterion gave less-consistent results, probably because of lack of sufficient specificity for true myocardial ischemia.

We also observed stronger associations when excluding subjects with left ventricular hypertrophy, left bundle-branch block, or anterolateral Q wave infarction, because these ECG abnormalities may obscure ST-segment depressions. The associations of PM2.5, but not ultrafines, were stronger among subjects who did not use ß-blockers, possibly because of the protective effect of ß-blockers on ischemia. The difference was probably not attributable to differences in the average heart rate or increase in heart rate during exercise test, which were 88.1 and 28.7 bpm among those who used and 94.2 and 29.3 bpm among those who did not use ß-blockers. However, because of the low numbers, the ORs need to be interpreted with caution.

An exposure study done in connection with the present study showed that the fixed-site 24-hour PM2.5 measurements correlate well with 24-hour personal exposures (median intraindividual correlation, 0.76).²⁶ Therefore, the present PM2.5 exposure measurements describe well the real variations in personal exposure. There are no similar studies on ultrafine particles. However, we earlier observed in Helsinki that the correlation between different outdoor measurement sites ranged between 0.6 and 0.8 for hourly particle total number concentration.³⁴ The average levels of PM2.5 were low in Helsinki, whereas levels of ultrafine particles were similar to levels measured previously in Finland and other parts of Europe.³⁵

The present study was part of the ULTRA study conducted in 3 centers in Europe. Unfortunately, the heart rate during exercise tests was so low in Erfurt and Amsterdam that the number of exercise-induced ST-segment depressions observed was too low for statistical analyses. The low heart rates were mostly attributable to the fact that the study was done in the community setting and the field workers were very cautious in performing the exercise tests among coronary patients. This same reason also mostly explains the large number of visits with no exercise test performed in Helsinki.

In conclusion, we observed an association between fine and ultrafine particulate air pollution and the risk of exercise-induced ST-segment depression among subjects with coronary heart disease. Ambient particles of different sizes might act independently because of their different sources or potentially through different mechanisms. The present results suggest that the effect of particulate air pollution on cardiovascular morbidity is at least partly mediated through increased susceptibility to ischemia and provide a plausible biological link between ambient levels of particulate matter and risk of mortality and mortality attributable to ischemic heart disease.

	Acknowledgments

 
The study was done within the framework of the Exposure and Risk Assessment for Fine and Ultrafine Particles in Ambient Air (ULTRA) project. The project was funded by the European Union ENVIRONMENT and CLIMATE Research Program contract ENV4-CT97-0568. The project was coordinated by the Unit of Environmental Epidemiology, National Public Health Institute, Kuopio, Finland, with funding also from Academy of Finland.

Received April 2, 2002; revision received June 10, 2002; accepted June 10, 2002.

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