- Become familiar with the findings and limitations of previous research on the association between outdoor air pollution and cardiac arrest.
- Summarize the new findings on the relationship between air pollutant levels and out-of-hospital cardiac arrest in a Japanese city, including the relevant lag times.
- Identify the effects of specific pollutants, including differences in susceptibilities by sex and age group.
A number of studies have shown associations between short-term exposure to air pollution and cardiovascular disease.1 Specific cardiovascular events considered to be associated with air pollution include ischemic heart disease, heart failure, cerebrovascular disease, peripheral arterial and venous disease, and cardiac arrhythmia/arrest.1 Indeed, a recent study from Japan using hourly air pollution monitoring data demonstrated that outdoor air pollution had adverse impacts on emergency hospital visits owing to cardiovascular and cerebrovascular events.2
Although there is growing evidence to support an association between outdoor air pollution and cardiovascular disease, the number of studies focusing on cardiac arrest remains small and their findings are inconsistent. Cardiac arrest is defined as an “abrupt cessation of cardiac pump function which may be reversible by a prompt intervention but will lead to death in its absence,” and is estimated to cause between 200,000 and 450,000 deaths annually in the United States owing to sudden cardiac death.3 Given that cardiac arrest leads directly to sudden cardiac death, and that its consequences result in a significant burden for both individuals and society, prevention of cardiac arrest is a major public health priority. Although cigarette smoking, diabetes, and hypertension are well-known risk factors for sudden cardiac death, the influence of air pollution on cardiac arrest has recently gained greater attention.4
To date, a total of 10 studies evaluating the impacts of outdoor air pollution on cardiac arrest have been conducted in the United States,5–9 Europe,10–12 and Australia.13,14 All of these studies examined the effect of exposure to particulate matter (PM), with seven suggesting a positive association with the onset of cardiac arrest.4–7,11,12,14 In addition, five of these studies examined the effect of ozone,5,6,10,11,14 with three of them demonstrating adverse effects.5,10,11 Only two of these studies provided evidence on other pollutants, however.12,13
The results of these previous studies, which were conducted in the United States, Europe, or Australia, may not be generalizable to an Asian context for a number of reasons, including differences in residents' health characteristics and the constituents of local air pollution.15 This study evaluated the associations between short-term exposure to outdoor air pollution and the risk of out-of-hospital cardiac arrest among residents of Okayama, Japan, who had visited hospital emergency departments between January 2006 and December 2010.
Study Area and Subjects
Anonymized data on all ambulance calls made during the study period were provided by the Ambulance Division of the Fire Bureau in Okayama City, a city located in the western part of Japan with population of 709,584 and area of 790 km2 (in 2010).2 Data were available for calls made either by the patients themselves or by others to request an ambulance. Using the data, we selected 110,110 residents who had been brought to an emergency department in Okayama City by ambulance between January 2006 and December 2010.
We initially restricted the study to 2181 patients who had been administered an electrocardiogram by ambulance personnel and who presented signs of cardiac arrest (ie, ventricular fibrillation, asystole, and pulseless electrical activity).3 To identify cardiac arrest owing to cardiac etiology, we used diagnoses made by physicians at the hospitals to which patients were admitted. Because the diagnoses were coded in accordance with the 10th International Classification of Disease (ICD-10), we restricted our analysis only to those subjects who were diagnosed with cardiac disease by medical doctors on arrival at a hospital (ICD-10: I20-I52). Data from a total of 558 individuals (ie, cardiac arrest cases owing to cardiac etiology) were included in our final analysis.
Air Pollution Monitoring and Meteorological Data
We obtained data from the Okayama Prefectural Government on hourly concentrations of suspended particulate matter (SPM), ozone, nitrogen dioxide (NO2), sulfur dioxide (SO2), and carbon monoxide (CO) during the study period as measured at monitoring stations in Okayama City. In Japan, measures of PM are typically expressed in term of SPM and account for PM with an aerodynamic diameter of less than 7 μm (PM7). During the period studied, 11 stations were used for SPM measurements, 8 for ozone, 11 for NO2, 7 for SO2, and 2 for CO. The entire area of Okayama City was covered within a 30-km radius of each monitoring station. We then calculated city-representative hourly average concentrations of each air pollutant from hourly concentrations recorded at each monitoring station. Although there were no missing data for city-representative hourly average concentrations of SPM, NO2, and SO2 over the entire study period, 502 hourly mean concentration readings for ozone (1.15% of eligible hours) and 26 for CO (0.06% of eligible hours) were unavailable.
Finally, we obtained hourly data on temperature and relative humidity for the entire study period from one weather station managed by the Japan Metrological Agency located in Okayama City. There were no missing data for either temperature or relative humidity.
Our analysis used a time-stratified case-crossover design, which can be considered as a case-control version of a crossover study and can adjust for time-invariant confounders.16 The design uses cases only; for each individual case, exposure before a given event (case period) is compared with exposure during other control (or “referent”) periods. Time-stratified referent selection of subjects is recommended for use with this study design to ensure unbiased estimates from resulting conditional logistic regression models and to avoid bias resulting from any time trend in the outcome measure.16 We therefore selected control periods from the same times on other days, on the same days of the week in the same months and years.
When we examined the association between each individual air pollution exposure and cardiac arrest owing to cardiac etiology, we considered four lag periods before the case event using hourly pollutant monitoring data and the time of the emergency calls (0 to 24, 24 to 48, 48 to 72, and 72 to 96 hours). We conducted conditional logistic regression analyses to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between exposure to pollutants and cardiac arrest. We used exposure data as continuous variables on the basis of the previous studies5–14 and estimated adjusted ORs for an interquartile range (IQR) increase in each air pollutant during the study periods. In all analyses, we adjusted for hourly ambient temperature using a natural spline with 6 df and hourly relative humidity with 3 df. We selected the number of df on the basis of a previous study of air pollution in Japan,17 and both covariates were generated using data at the time of the case event.
We then conducted further analyses on those pollutants associated with cardiac arrest at any lag to determine whether their effects were modified according to patients' characteristics—including age (<65 years vs ≥65 years),4 sex, time of onset (8 AM to 7 PM vs 8 PM to 7 AM), and season of onset of cardiac arrest (April to September vs October to March). Interaction terms with P values of less than 0.05 (two-sided) were considered significant.
All statistical analyses were conducted using the statistical package R, version 22.214.171.124 The Institutional Review Board of the Graduate School of Medicine, Dentistry and Pharmaceutical Sciences at Okayama University granted approval for this study on June 26, 2012 (Review No. 556 and No. 851).
The characteristics of the study subjects are shown in Table 1. While 78.0% of the subjects were more than 65 years of age, 58.9% were male and 58.6% had experienced cardiac arrest during the cold season. About 10% of the subjects had a medical history of coronary heart disease or hypertension.
During the period studied, the IQRs of air pollutants were 20.6 μg/m3 for SPM, 25.8 ppb for ozone, 11.1 ppb for NO2, 2.3 ppb for SO2, and 0.3 ppm for CO. The mean values and Pearson correlation coefficients for hourly air pollutant concentrations and temperatures in both the warm and cold seasons are shown in Table 2. As expected, the recorded mean concentration of ozone was higher in the warm season. Although the concentration of SPM was also higher in the warm season, the mean concentration of NO2 was higher in the cold season. In both seasons, SPM was moderately correlated with all other pollutants except ozone. By contrast, concentrations of ozone showed a weak positive correlation with SO2 in the warm season and a negative correlation with NO2 and CO in the cold season. Our results also showed that NO2 was correlated with SO2 and CO in both seasons.
When we examined the effect of each pollutant at different lags, exposure to SPM, ozone, NO2, and SO2 was associated with an increased risk of cardiac arrest (Table 3). The ORs representing the increase in the risk of cardiac arrest in response to an IQR increase in exposure were 1.17 (95% CI, 1.02 to 1.33) for SPM (48- to 72-hour lag), 1.40 (95% CI, 1.02 to 1.92) for ozone (72- to 96-hour lag), 1.24 (95% CI, 1.01 to 1.53) for NO2 (24- to 48-hour lag), and 1.16 (95% CI, 1.00 to 1.34) for SO2 (48- to 72-hour lag). CO exposure was not associated with the increased risk of cardiac arrest.
When we stratified our analyses by patients' characteristics (Table 4), those in the younger age group had a higher effect estimate for SPM exposure compared with the older age group (P = 0.15) whereas the older group had a higher effect estimate for ozone compared with the younger age group (P = 0.04). Furthermore, the OR for cardiac arrest among male subjects in response to an IQR increase in SPM was higher than that for female subjects (P = 0.03). Although the effect estimate for SPM was higher in the warm season and the effect estimate for NO2 exposure was higher in the cold season, no significant seasonal differences were detected for any of the pollutants analyzed.
In this study, we evaluated the associations between short-term exposure to outdoor air pollution and out-of-hospital cardiac arrest owing to cardiac etiology in Okayama, Japan. We found that exposures to SPM (48- to 72-hour lag), ozone (72- to 96-hour lag), NO2 (24- to 48-hour lag), and SO2 (48- to 72-hour lag) were all associated with a higher risk of cardiac arrest. We also observed different susceptibilities to SPM and ozone exposures by sex and age group.
The observed effect of SPM (which corresponds to PM7) on the risk of cardiac arrest is consistent with findings obtained from seven previous studies conducted in the United States, Europe, and Australia.5–7,11–14 In addition, the adverse effect of ozone exposure is also consistent with the findings from three studies conducted in the United States and Europe.5,10,11 Although the evidence for effects of exposure to ozone on cardiovascular disease risk remains inconsistent, a recent large-scale study of 11,677 cases of cardiac arrest in Houston, Texas, demonstrated adverse effects of ozone both on the day of the event and in the 1 to 3 hours before onset.5 These findings, as well as those of this study, support the hypothesis that exposure to both PM and ozone increases the risk of cardiac arrest.
Different susceptibilities to SPM and ozone exposures by age category and different lags between SPM and ozone merit consideration. Cardiac arrest has a variety of causes, including coronary heart disease, arrhythmia, and cardiomyopathy.3 In a recent study, Rosenthal et al11 examined the effect of exposure to PM2.5 (with an aerodynamic diameter <2.5 μm) and ozone on the risk of cardiac arrest as a result of myocardial infarction or other cardiac causes. Their results showed that the same-day PM2.5 exposure was associated with cardiac arrest caused by myocardial infarction and that lagged exposure to ozone was associated with cardiac arrest caused by other cardiac etiologies. This suggests that air pollution may induce cardiac arrest via two distinct pathways: one in which exposure to PM results in myocardial infarction and another in which ozone exacerbates other cardiac conditions such as arrhythmia to increase the risk of cardiac arrest.11 These results may also provide an explanation for our findings that susceptibilities to SPM and ozone exposures differed by age category and that the effects of exposure to SPM and ozone had different lags.
We also observed that NO2 and SO2 were associated with the risk of cardiac arrest. This result may reflect the different toxicological effects of each pollutant. Nevertheless, because SO2 has been shown to have more spatial variability compared with other pollutants (eg, NO2)19 and that concentrations of SO2 were correlated with those of NO2 and CO in this study, the effects of SO2 should be interpreted with care. SO2 might work as a maker of NO2, which reflects local traffic-related air pollution.20 A previous work by Wichmann et al12 has also shown a positive association between nitrogen oxides and cardiac arrest in Copenhagen, Denmark.
Our observation that exposure to SPM had a stronger effect in male than in female subjects is consistent with the results of previous studies conducted in Houston, Texas,5 and Melbourne, Australia.14 Although the cause is unclear, one explanation may be that men spend more time outdoors, or that they are more likely to have comorbidities and partake in unhealthy behaviors such as smoking when compared with women. Indeed, among the 54 subjects with a medical history of coronary heart disease (Table 1), 41 (76%) were men in this study.
The major strength of this study was the availability of hourly data on both air pollution and emergency department visits, which enabled us to determine an exact temporal relationship between air pollution exposure and disease onset. Nevertheless, because the exact timing of disease onset was unavailable, we used the time of emergency calls as a proxy for disease onset. Given that health care in Japan is widely available and easily accessible owing to a universal health insurance system that covers all of its citizens and provides ambulance transport free of charge, it is likely that the lag between the timing of disease onset and the time of emergency calls was negligible for the majority of cases.
Restricting the study subjects to those diagnosed as cardiac disease by physicians could have reduced the misclassification of cardiac outcomes. By contrast, we could not evaluate effect modifications by preexisting disease probably because of the small sample size owing to this restriction.
A further limitation was our assumption that all residents were exposed to the same concentrations of pollutants without considering their spatial distribution. This exposure measurement error may widen CIs but may lead to little or no bias (ie, Berkson error21).
Finally, there may be a possibility of residual confounding because of other clinical factors, which can change during a month within each subject.
This study provides further evidence to support the hypothesis that short-term exposure to outdoor air pollution exposure increases the risk of cardiac arrest in a Japanese context. Furthermore, our results suggest that SPM and ozone may impact upon hospitalization owing to cardiac arrest via different mechanisms.
We thank Toshihide Tsuda for his assistance in obtaining data and Saori Irie for helping us to prepare the manuscript.
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