Discussion
In this systematic review and meta-analysis, we evaluated the effects of short term exposure to gaseous and particulate air pollution on admission to hospital for stroke or mortality from stroke. We made several important observations. Firstly, in over 6.2 million events across 28 countries throughout the world, our pooled analysis showed robust and clear associations between both gaseous and particulate air pollution and stroke admission or mortality. Secondly, the strongest associations between air pollution and admission or mortality were observed from studies originating in low to middle income countries. Thirdly, these associations persisted when we stratified our pooled analyses by study design, age, or outcome. Thus, we have shown that gaseous and particulate air pollutants have a robust and close temporal association with admission to hospital for stroke or stroke death. We suggest that improvements in air quality could reduce the burden of stroke.
Evidence of Short Term Exposure to Air Pollution and Stroke
Over the past three decades, epidemiological studies including pooled analyses have shown that cardiac, rather than pulmonary, disease is the primary cause of morbidity and mortality associated with exposure to air pollution. Long term exposure studies have already shown strong associations between air pollution and stroke. While the short term effects of air pollution on cardiac disease, including heart failure and myocardial infarction, have received much attention, it is less certain whether acute exposure to air pollution is a trigger for cerebrovascular disease, especially stroke. This is partly because the results of many short term exposure studies evaluating the effect of air pollution on stroke have been inconclusive, reflecting both the nature of the condition and the size of individual studies. Recently meta-analyses, including 12 and 45 studies, reported an association between particulate air pollution and stroke. To our knowledge, our study is the first comprehensive prespecified pooled analysis to examine the short term effects after exposure to gaseous or particulate air pollution and admission to hospital for stroke or mortality from stroke across both time series and case crossover study designs.
Particulate matter and gaseous pollutants both showed a strong temporal relation with mortality from stroke and admission to hospital for stroke. The lag effects of exposure and stroke have to be interpreted with caution. Unlike other cardiac conditions such as acute myocardial infarction, decompensated heart failure, and sudden cardiac death, the timing of onset of stroke symptoms and subsequent admission to hospital or mortality might differ substantially. Lokken and colleagues showed that in cases of acute ischaemic stroke, onset of symptoms occurred at a median of one calendar day before admission, and this delay in presentation is likely to underestimate the overall association between exposure to pollutant and stroke.
Aetiology of Stroke and Exposure to Air Pollution
While our analysis showed consistent associations for ischaemic stroke and air pollution, the association for haemorrhagic stroke was more variable with larger imprecision. Our results were similar to those from a smaller meta-analysis that showed identical patterns with type of stroke and exposure to PM2.5 and PM10. While haemorrhagic and ischaemic stroke share similar risk factors and have a similar clinical presentation, they are different clinical entities. Heterogeneity in the association between air pollution and stroke subtype might be caused by many factors. Firstly, the mechanisms linking exposure to air pollution and haemorrhagic stroke might differ for ischaemic stroke. Secondly, there were fewer estimates for haemorrhagic stroke, reflecting the lower incidence of this subtype, and therefore wider confidence intervals for these estimates. Finally, misclassification of stroke subtype in those studies from countries with limited availability of medical imaging might have contributed to some of the observed heterogeneity.
Particulate Pollution and Stroke
Exposure to PM10 showed weaker associations with admission to hospital for stroke or mortality from stroke than PM2.5, consistent with observations from other meta-analyses for stroke and acute myocardial infarction. This could reflect differences in particle size, with larger particles more likely to exert local pulmonary effects whereas fine or ultrafine particles (PM2.5) or gaseous pollutants could cause additional systemic cardiovascular effects. In contrast, the adverse effect of larger particles in patients with heart failure was more striking, possibly reflecting indirect biological pathways such as the adverse effect of sympathetic nervous activation on the failing heart. We noticed greater heterogeneity for PM2.5 than for PM10. These differences in heterogeneity persisted after subgroup analysis and could reflect variation in study design. We were able to meta-analyse twice as many estimates for PM10 than for PM2.5, with an overall less marked but more consistent effect of exposure on stroke with PM10. There are several biologically plausible reasons for this. While there is a close correlation between PM2.5 and PM10 concentrations, epidemiological studies have shown that the association between PM10 and acute cardiovascular events is primarily driven by the PM2.5 fraction. This fraction is enriched with ultrafine particles derived from the combustion of fossil fuels, which toxicology studies have suggested are the most potent component of particulate matter. These particles are potentially small enough to translocate from the lungs into the circulation and are therefore perhaps more likely to trigger acute cardiovascular episodes. Interestingly, all three gaseous pollutants derived from combustion (nitrogen dioxide, sulphur dioxide, and carbon monoxide) were associated with stroke, and this was consistent with reported associations with admission for heart failure and acute myocardial infarction.
Possible Mechanisms Explaining Relation Between Stroke and Air Pollution
Several large cohort studies have shown a positive association between long term exposure to ambient air pollution and coronary and cerebrovascular events. Staffogia and colleagues showed that even in high income countries, where annual mean air pollution concentrations meet current international standards, small increases in PM2.5 were associated with a 19% increase in the risk of cerebrovascular disease, including both ischaemic and haemorrhagic events. Long term exposures to PM2.5 accelerate carotid atherosclerosis. The underlying pathophysiological mechanisms after acute exposure to air pollutants in triggering stroke, however, remain unclear and might differ for haemorrhagic and ischaemic stroke. Previous controlled exposure studies have shown that air pollution can adversely affect the vascular endothelium and increase activity of the sympathetic nervous system, resulting in vasoconstriction, increases in blood pressure, ischaemia, and risk of thrombosis. Indeed, even minor increases in PM2.5 concentrations are associated with changes in cerebrovascular haemodynamics, including increased cerebrovascular resistance and reduced cerebral blood flow. Another potentially important effect of air pollution that is pertinent to stroke is the risk of atrial arrhythmias, which could predispose to thromboembolic events. It is plausible that the association between short term exposure to air pollution and cerebrovascular events are a result of these important mechanistic pathways.
Air Pollution and Stroke by Income of Nation
Most of the studies used to derive our pooled estimates originated from high income countries. The smaller number of studies from low and middle income countries is probably a result of less cohesive policies on air quality, inadequate environmental monitoring, and less robust disease surveillance. This is particularly concerning as it is these countries that bear a disproportionate burden of the global morbidity and mortality from stroke. More concerning are the trends for cerebrovascular disease, where the incidence is falling by 12% in high income countries and increasing by 12% in low and middle income countries. Urban cities in low and middle income countries not only experience high levels of ambient air pollution but also have larger daily fluctuations in levels. Our pooled estimates stratified by region showed larger associations in low and middle income countries than in high income countries. Our estimates from low and middle income countries, however, predominantly come from East Asia, mainly mainland China followed by Latin America, South East Asia, and South Africa. There still remains a paucity of data from other highly populated regions including the Indian subcontinent and north and central Africa.
Limitations
Several limitations of our study should be considered. Firstly, unlike other cardiac conditions such as myocardial infarction, case definition for stroke, especially when administrative data are used, might be less reliable. Secondly, many studies measured concentrations of air pollution at remote monitoring sites, and it is therefore likely there will be some degree of misclassification of exposure. While there might be good correlations in measurements between pollutant concentrations at patient specific locations compared with those measured at remote stations, it is likely that highly urbanised city centres will not only experience higher concentrations but also greater fluctuations in concentrations. Therefore such ecological studies might underestimate the overall associations reported for stroke and air pollution. Thirdly, we did not have access to primary data and were not able to determine whether patients were included across multiple studies if there was partial temporal overlap between studies from the same geographical location. We did, however, exclude studies with complete geographical and temporal overlap during meta-analysis. Finally, we noticed significant heterogeneity (except for PM10) across all pollutants. This could be because of systemic differences in the baseline characteristics of the underlying population in addition to misclassification of both the measurement of pollutant and outcome. Our sensitivity analysis after exclusion of studies with a high risk of bias, however, showed similar results to the overall effect estimates.
Conclusion
Stroke remains the second most common cause of death and third most important cause of disability worldwide. Over the past 20 years many environmental studies have evaluated the association between outdoor air pollution and stroke, with varying conclusions. Our pooled estimates now show a marked and close association between exposure to pollutants and adverse stroke outcomes. Only a few studies originated from low or middle income countries and yet these countries experience the highest levels of air pollution and bear a disproportionate burden of global stroke mortality and morbidity. Public and environmental health policies that aim to reduce air pollution levels might reduce the burden of stroke.