1 Department of Environmental Health, School of Public Health, University of Washington, Seattle, WA.
2 Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA.
3 Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA.
4 Department of Medicine, School of Medicine, University of Washington, Seattle, WA.
Received for publication July 2, 2002; accepted for publication October 9, 2002.
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ABSTRACT |
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air pollutants; air pollution; heart arrest; heart diseases; environmental exposure
Abbreviations:
Abbreviations: CI, confidence interval; PM1.0, particulate matter 1.0 µm in aerodynamic diameter; PM2.5, particulate matter
2.5 µm in aerodynamic diameter; PM10, particulate matter
10 µm in aerodynamic diameter.
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INTRODUCTION |
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Large epidemiologic studies have suggested that increased levels of air pollutants such as fine particulate matter (particulate matter 2.5 µm in aerodynamic diameter (PM2.5)) and nitrogen dioxide are associated with an increased incidence of myocardial infarction (1315), uncompensated congestive heart failure (15, 16), cardiac arrhythmias (17), and total cardiac mortality in susceptible populations (15, 1720).
One study that was limited to persons without previously identified heart disease did not find an association between primary cardiac arrest and particulate matter levels (21). To further evaluate the potential for particulate matter to trigger primary cardiac arrest, we studied primary cardiac arrest occurring in a different population that included persons with clinically documented heart disease. We hypothesized that an increase in fine particulate matter on the same day as or 1 day preceding an event would be associated with an elevated risk of primary cardiac arrest among persons with preexisting cardiac disease. Moreover, we postulated that persons with recently documented uncompensated congestive heart failure or increasing numbers of angina episodes would be at greater risk.
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MATERIALS AND METHODS |
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Study population
The study population was derived from members of the Group Health Cooperative of Puget Sound, a health maintenance organization that serves approximately 350,000 enrollees in western Washington State, who experienced an episode of out-of-hospital primary cardiac arrest in western Washington between 1985 and 1994. We defined primary cardiac arrest as a sudden pulseless condition in the absence of a noncardiac condition as the cause of cardiac arrest. We reviewed ambulatory care medical records for each potential case to exclude cases with a noncardiac cause of cardiac arrest. Furthermore, we reviewed medical examiner reports, autopsy reports, and emergency medical service incident reports, when available, for all cases with a history of depression, psychosis, and seizure to confirm the absence of evidence of suicide, drug overdose, or status epilepticus as a cause of out-of-hospital arrest. Cases were identified from two sources: emergency medical service databases from Seattle and King County (Washington) and, for those not covered by the paramedic system, the Group Health Cooperative death record.
Our final analysis included 1,206 case days and 4,094 referent exposure days among these case individuals. Case patients were excluded if they lived outside of King County or South Snohomish County, because we did not think that the air pollution data represented exposures for persons residing outside of this geographic area. The personal-level clinical data were abstracted from the ambulatory care medical records; therefore, cases were included in the analysis only if they had received care at the Group Health Cooperative within 12 months of the primary cardiac arrest event.
Medical record review
We determined clinical characteristics from the ambulatory care medical review. Information obtained regarding each patients medical history included the following: physician diagnosis of myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, congestive heart failure, cardiomyopathy, arrhythmias, valvular heart disease, stroke, hypertension, peripheral vascular disease, diabetes mellitus, hypercholesterolemia, chronic obstructive pulmonary disease, and asthma. The record review also provided information on the severity of prior cardiac and lung disease. Information gathered on demographic and risk factors included age, race, gender, blood pressure, heart rate, cigarette smoking, and alcohol use. Smoking was categorized as current smoking, ever smoking, or never smoking. It was further quantified in number of pack-years, and daily consumption was quantified as number of cigarettes smoked per day. The pharmacy record detailed use of cardiac medication, including beta blockers, calcium channel blockers, diuretics, and angiotensin-converting enzyme inhibitors. We also obtained a copy of the results of the most recent 12-lead electrocardiogram taken prior to the index date.
Exposure assessment
The primary exposure metric was 24-hour average particulate matter, as measured by nephelometry from three King County monitoring sites (Lake Forest Park, Duwamish, and Kent). We performed analyses of the association between particulate matter and primary cardiac arrest using 0-day through 2-day lags. Prior studies of the induction of myocardial infarction and cardiac arrhythmia by air pollutants have found associations at lags ranging from 1 hour to 48 hours (17, 18, 20). To allow for comparability with other studies, we converted the nephelometric measure of particulate matter to an equivalent PM2.5 measure (25). In King County, nephelometry data correlate well with gravimetric particle measurements in the 0.11.4 µm/m3 aerodynamic range. They are also highly correlated with PM2.5 levels (Pearsons r2 = 0.85) (26). To adjust for the effects of copollutants, we included 24-hour average measures of sulfur dioxide from the Duwamish site and 24-hour averaged measures of carbon monoxide averaged over four sites in King County. The number of PM10 observations was too small for use in multivariate analyses.
Statistical methods
The data were analyzed using the statistical packages SAS (version 8.0; SAS Institute, Inc., Cary, North Carolina) and SPSS (version 10; SPSS, Inc., Chicago, Illinois). We performed simple descriptive analyses including summary statistics and graphic plots of the exposure and demographic data. Levels of correlation between covariates were assessed using Pearsons correlation coefficient and simple linear regression of covariates.
Case-crossover index and referent days were selected on the basis of previous methodological work (23). Air pollution exposures occurring on index days were compared with exposures that occurred on all referent days in the same time stratum as the index date. There were 840 time strata in our study. These were defined as all observations made on a single day of the week during one month and year. This time-stratified referent selection scheme minimizes bias due to nonstationarity of air pollution time-series data (2224).
We then performed conditional logistic regression analysis to obtain estimates of odds ratios and 95 percent confidence intervals. The primary outcome was incident primary cardiac arrest, and the primary exposure variable was exposure to fine particulate matter, defined as the interquartile increase in 24-hour average light scattering as measured by nephelometry. In secondary analyses, we evaluated day-of-event and 2-day lags, as well as other pollutant variables (PM10, carbon monoxide, sulfur dioxide). Lagged analyses used time strata defined by the lagged index date. Relative humidity and temperature were included as confounding variables and were entered as both linear and quadratic terms in the conditional logistic regression models. We performed stratified analyses to assess effect modification of the association between primary cardiac arrest and particulate matter. We considered age, gender, race, smoking status, preexisting disease (chronic obstructive pulmonary disease or heart disease), alcohol use, and activity level. To assess potentiation of effect by known risk modifiers for primary cardiac arrest, we performed further subanalyses among persons with preexisting heart disease, assessing the effects of smoking and medication use. Smoking status was categorized as current smoking versus not smoking at the last clinic visit prior to the event (never smoker or ex-smoker). To determine whether severity or type of heart disease influenced the association between primary cardiac arrest and particulate matter level, we used separate models to consider all forms of heart disease as a single variable or covariates of subtypes of heart disease (ischemic heart disease, congestive heart failure, supraventricular tachycardia, bradycardia). Supraventricular tachycardia is represented by cases with atrial fibrillation (n = 45), paroxysmal supraventricular tachycardia (n = 14), or paroxysmal atrial tachycardia (n = 9) but without established coronary artery disease, cardiomyopathy, or congestive heart failure. Moreover, to better define susceptible subpopulations, we performed analyses that stratified the data by severity of ischemic heart disease (unstable angina at the last clinic visit prior to primary cardiac arrest) and severity of congestive heart failure.
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RESULTS |
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Medication use did not change the absence of association between lagged 0- to 2-day fine particulate matter levels and primary cardiac arrest among all cases with heart disease (data not shown). However, smokers with heart disease who were not using any cardiac medication had an increased risk of primary cardiac arrest from an increase in fine particulate matter 2 days prior to the event as compared with those using these medications. Persons not using an angiotensin-converting enzyme inhibitor (n = 136) had an odds ratio of 1.39 (95 percent CI: 1.12, 1.72), as compared with an odds ratio of 0.97 (95 percent CI: 0.60, 1.54) among those using angiotensin-converting enzyme inhibitors (n = 26). Those not on calcium channel blockers (n = 136) had an odds ratio of 1.31 (95 percent CI: 1.07, 1.61), as compared with an odds ratio of 1.17 (95 percent CI: 0.65, 2.09) among those taking calcium channel blockers (n = 26). Persons who were not on diuretics (n = 70) had an odds ratio of 1.46 (95 percent CI: 1.05, 2.03), as compared with an odds ratio of 1.19 (95 percent CI: 0.94, 1.51) among those taking diuretics (n = 92). In contrast, this same pattern of association was not found for use of beta blockers and beta agonists.
We repeated the detailed single-pollutant analyses with carbon monoxide as the exposure. In these models, in which data were stratified by disease status and primary cardiac arrest risk factors, we did not find an association between increased carbon monoxide levels and primary cardiac arrest (data not shown).
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DISCUSSION |
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Our study was designed to discern an association between primary cardiac arrest and increased particulate matter levels in a new case series that included persons with and without preexisting cardiac and lung disease. A previous study by Levy et al. (21) had not found such an effect among cases without prior clinically recognized heart or lung disease. Our analysis found the suggestion of an effect among persons with prior heart disease and not lung disease, but the effect appeared to be limited to current smokers and to increases in fine particulate matter 2 days prior to the event. These stratum-specific findings were not expected and may be a result of multiple comparisons. However, it is possible that current smokers with preexisting cardiac disease are particularly susceptible to the effects of particulate matter air pollution.
It is difficult to posit an additive effect of particulate matter among current smokers, since they would be exposed to an order-of-magnitude-greater level of particulate matter from smoking than from outdoor air. However, cigarette smoking may enhance the sensitivity of persons with heart disease to the proarrhythmic effects of particulate matter. Epidemiologic studies have demonstrated that current smoking status is associated with elevated risk of primary cardiac arrest among persons with and without heart disease (27). Potentiation of the proarrhythmic effect could also be explained by cigarette smoke-induced increases in platelet aggregation (28, 29), nicotine-associated increases in catecholamine levels and decreases in heart-rate variability (30), and free-radical amplification of pulmonary inflammation (29, 30).
We had anticipated finding an association between same-day or prior-day elevated particulate matter levels and primary cardiac arrest. However, it is plausible that an elevated level of particulate matter 2 days prior to an event results in the induction of an inflammatory cascade in the lungs of susceptible persons that is followed by amplification of systemic proinflammatory cytokine levels and endothelial vasoconstrictors. This may lead to alterations in heart rate and blood pressure or amplification of the release of local inflammatory mediators and increased recruitment of T lymphocytes and monocytes with resultant plaque rupture and arrhythmia (4, 3134). Interestingly, Peters et al. (17) found that 2-day lagged elevations in nitrogen dioxide and fine particulate matter levels were associated with increased automated implantable cardiac defibrillator firings.
The absence of a strong association between elevated particulate matter levels and primary cardiac arrest among persons with preexisting heart disease contrasts with studies performed in Massachusetts which demonstrated consistent associations between elevated particulate matter levels and cardiac events (14, 17). We speculate that these differences may be explained by the composition of particulate matter in the Seattle air shed or methodological differences in referent sampling between the case-crossover studies. The National Morbidity, Mortality, and Air Pollution Study found differences between cities for cardiac mortality and overall mortality due to particulate matter, with the greatest increase in cardiac mortality being observed in the northeastern United States (1820). Although prior time-series studies in Seattle have documented an increase in respiratory disease exacerbations from increased levels of particulate matter, they failed to find an increase in cardiac morbidity or mortality. The Seattle air shed contains particulate matter that is relatively sparse in transition metals and sulfates (19). Recent in vivo data suggest that transition metals can catalyze an oxidative stress reaction in the lung, leading to inflammatory lung injury (33, 34) and increased arrhythmia (32, 34). Moreover, compositional analyses of ambient air in Quebec suggest that particulate matter with high sulfate fractions is more strongly associated with increased hospitalizations for cardiac and respiratory diseases (15, 35).
This study had several strengths. We were able to study the effect of fine particulate matter on the risk of out-of-hospital primary cardiac arrest in a large number of cases accumulated over a long period of time in an extensively characterized air shed. This was done with a well-characterized study population in a western US city with a long history of air monitoring. Moreover, our referent selection strategy was based on a sound theoretical foundation. This strategy has been shown to perform well in simulation studies (23). Last, studies of primary cardiac arrest contrast with studies that have examined the outcome of total cardiac mortality. The prevention of primary cardiac arrest in otherwise healthy vulnerable adults may lead to a dramatic savings in quality years of life (24).
However, our study had several limitations. First, this analysis utilized a 24-hour average measure of particulate matter that may have underestimated the effect of shorter peak exposures. For instance, Peters et al. (14) recently documented a relation between increased particulate matter levels and onset of myocardial infarction symptoms. Second, our analysis did not examine the potential proarrhythmic effects of elevated nitrogen dioxide levels because of the absence of available nitrogen dioxide exposure data over the period of study. Third, small numbers of persons using cardiac medications in our subgroup analyses may have led to an underestimation of the modulating effect of medications (e.g., beta blockers and sympathomimetics) on the association between particulate matter and primary cardiac arrest. Furthermore, the absence of a protective effect with use of beta blockers may have resulted from the indication for use, that is, worsening ischemic heart disease or prior myocardial infarction. Fourth, information on the use of statins, aspirin, and antioxidants, as well as recent lipoprotein level, was not readily available from the data set. Moreover, our analyses did not include information on socioeconomic status or educational level, both of which are known risk factors for primary cardiac arrest. Last, the proportion of cases with each preexisting cardiovascular disease reflected the population under study. It is possible that we may have found different overall results in a population containing a larger proportion of persons with advanced congestive heart failure or active angina.
In conclusion, the results of this study suggest that elevated levels of particulate matter are not consistently associated with out-of-hospital primary cardiac arrest among persons with preexisting heart or lung disease. A similar study carried out in an air shed with higher ambient levels of sulfates and metals would be of interest. To clarify recent research suggesting that very short-term elevations in particulate matter levels are associated with onset of myocardial infarction, further research is needed to examine the effect of short-term peak exposures (1-hour and 4-hour) on the risk of out-of-hospital primary cardiac arrest in populations with preexisting heart disease.
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ACKNOWLEDGMENTS |
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The authors thank Bill OBrien for his assistance with data management.
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NOTES |
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REFERENCES |
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