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Air Pollution and Ischaemic Stroke

Air pollution is a significant contributor of cardiovascular diseases, including ischaemic stroke (IS), with substantial mortality and morbidity. However, associations between air pollution and IS remain unclear. Limited data are available on the relationship between IS and individual air pollutants. In this systematic review, we present an overview of the current literature about various individual ambient air pollutants that are believed to contribute towards incidence of hospitalization and mortality related to IS.

emissions. The concentration of ozone increases in warm weather due to sunlight exposure, increasing the rate of photochemical reactions. [1] Inhaled ozone can penetrate deeply into the lungs, causing respiratory and cardiac deaths. [7] Carbon monoxide (CO) CO is a colourless, odourless gas produced from incomplete combustion of fossil fuels, for example from motor vehicles. Due to its higher affinity for haemoglobin than oxygen, CO can cause hypoxia and ischaemia related cardiovascular and cerebrovascular diseases. [8,9] Nitrogen dioxide (NO 2 ) NO 2 is produced principally by combustion processes in road traffic, power generation and heating. [1] It is a free radical that when inhaled, is absorbed by the respiratory tract and deposited in the lung peripheries, leading to increased respiratory diseases. [10] Sulphur dioxide (SO 2 ) SO 2 is a colourless gas with sharp odour, produced from fossil fuel burning and smelting of mineral ores containing sulphur. [1] As an irritant, SO 2 causes bronchitis, bronchospasm and has been associated with worsening of cardiovascular diseases. [11] It is also associated with acid rain, leading to deforestation and environmental damage. [1] shoRt-teRM aIR PollutIon and stRoke Short-term exposure to air pollution is associated with increased risk of stroke and related mortality, which may have a lag of several days. Studies from countries across all continents except Antarctica found the strongest short-term association of PM with stroke. [12,13] CO, SO 2 , NO 2 and O 3 were also associated with cerebrovascular disease. [12] The results of recent meta-analyses are presented in Table 1.

Stroke incidence
The incidence of stroke is associated with PM 2.5 , PM 10 , SO 2 , NO 2 , CO and O 3 in several meta-analysis and cohort studies. [12] Across 3 meta-analyses, every 10 µm/m 3 increase in PM 2.5 was significantly associated with increased incidence and admission with stroke (HR 1.008-1.012). [13][14][15] This was consistently observed in time-series analysis and case-crossover studies based in Europe, Asia, North and South America, [16][17][18] especially in studies on ischaemic stroke. [19] Similarly, two meta-analyses of 15 and 21 studies each found a significant association of PM 10 with incidence or admission with stroke (HR 1.004-1.006 per 10 µm/m 3 increase). [14,15] The Asian dust storm events, mainly driven by PM10, were significantly associated with ischaemic stroke admission in Taiwan. [20] In Korea, a national study on 13,535 patients found that PM 10 and SO 2 were independently associated with cardioembolic stroke when compared to large artery atherosclerosis and non-cardioembolic stroke. [21] Another study in Italy found an association of PM 10 with lacunar stroke. [22] Other studies in China, [23] US, [24] UK [25] and Italy [26] confirmed the relationship between PM 10 and stroke incidence or admission.
For gaseous pollutants, NO 2 is most associated with stroke incidence and admission. Meta-analysis of 15 studies by Niu et al. [14] and 24 studies by Yang et al. [15] found a 2.2-2.3% increase in stroke with every 10 µm/m 3 increase in NO 2 concentration. The study of lag effect showed that the association was the strongest on the day of stroke (lag 0) and diminishes with increasing lag. [12] The relationship between O 3 and stroke is inconsistent, with the meta-analysis by Niu et al. and Yang et al. who reported a significant association, which was not seen in the meta-analysis by Shah et al. [12,14,15] O 3 was associated with stroke in several studies in China, [23] Korea, [27] Iran, [28] US, [29] France [30] and Iceland. [31] The effect of air pollution on stroke appeared higher in Asian countries than European or North American countries, which could be due to the higher prevalence of low-or middle-income countries in Asia. [15] However, the geographical variation could have contributed to the high heterogeneity between studies. [13,14] Integrated markers of air pollution are also associated with stroke incidence. In Singapore, a city-state with seasonal exposure to the Southeast Asian haze, the Pollution Standards Index (PSI) was associated with stroke occurrence, and the escalated risk persisted up to lag 5. [32] Furthermore, in Canada, the Air Quality Health Index, CO and NO 2 were positively associated with emergency department presentations with ischaemic stroke. [33]
Short-term exposure to SO 2 , NO 2 , and CO increases stroke mortality. Two previous meta-analysis showed 0.6-2.5% increase in risk of stroke mortality with every 10 µm/m 3 of SO2 and a 0.9-1.5% increase with NO2 [14,15] CO was significant associated with stroke mortality in a meta-analysis of 16 studies by Yang et al. but not in the meta-analysis of 5 studies by Niu et al. [14,15] However, O 3 was consistently shown to be not associated with stroke mortality by Niu et al., Yang et al. and Shah et al. [12,14,15] Studies on CO and O3 were mostly performed in Asia, particularly in China [34,41] and Korea, [35,42] with few studies from other regions such as Iran [28] and Finland. [39] There was significant heterogeneity for all gaseous pollutants, [15] and significant publication bias with the literature on O 3, [14] suggesting that more research is needed on the association of short-term exposure to gaseous pollutants and stroke mortality.

long-teRM aIR PollutIon and stRoke
Long-term exposure to air pollution, often measured as the mean annual concentration, is also associated with stroke incidence and mortality in previous studies [13,43,44] The results of meta-analysis on this relationship is presented in Table 2.
Stroke incidence PM 2.5 is the most investigated air pollutant, whereas long-term exposure to PM 2.5 remains most strong association with stroke incidence or admission. Three meta-analysis were performed between 2019 and 2021, which showed that long-term 10 µm/m 3 increase in PM 2.5 was associated with 2-13% increase in stroke. [13,43,44] They included large population-based cohorts in China, [6] US, [45] Canada [46] and Europe. [47] Ischaemic-stroke specific analysis confirmed the relationship between PM2.5 and stroke incidence in a cohort of 115,575 patients, with an almost linear exposure-response relationship. [6] In Ontorio, Canada, interquartile range increments in 5-year mean concentrations of PM 2.5 , NO 2 and O 3 were associated with atrial fibrillation (AF) and stroke incidence. [48] A study of 11 cohorts in Europe found that both PM 2.5 and PM 10 were associated with incident stroke, and 5 µm/m 3 increase in PM 2.5 was linked to a 19% increase in stroke, even at low levels <25 µm/m. [3,47] Long-term exposure to PM 10 was also associated with stroke in Israel, [49] Sweden, [50] Germany [51] and UK, [52] however, studies in low-and middle-income countries are lacking. Annual mean traffic-related PM 10 was associated with stroke in Stockholm, Sweden, [50] and both exhaust and non-exhaust PM 10 were associated with total anterior circulation infarcts in South London. [52]  Several studies investigated long-term exposure to gaseous air pollutants with stroke incidence, but no meta-analysis has been published so far. A population-based cohort of 5 million residents in Ontorio, Canada found a significant association of interquartile increase in NO 2 (HR 1.04) and O 3 (HR 1.05) with stroke. [48] On a follow-up of 9.8 years, interquartile increase in NO 2 was associated with ischaemic stroke and severe stroke followed by death within 30 days. [53] However, studies in Korea and Stockholm did not find a significant relationship between long-term NO 2 levels and ischaemic stroke. [54,55] Long-term exposure to ambient air pollution determined by distance to a roadway was not associated with subclinical cerebrovascular disease on magnetic resonance imaging. [45] Due to the differences in measurement of pollutant concentration (e.g., annual mean, monthly mean, proxy by distance to roadway) comparisons between studies and therefore meta-analysis is challenging. Future research should develop consistent methods to measure exposure and standardise reporting.

Stroke survival
Similar to stroke incidence, PM 2.5 is most investigated and most strongly associated with stroke survival. [13,43,44] Three meta-analysis of 17 studies, 13 studies and 6 studies, respectively, reported a 3%-24% increase in stroke mortality associated with an increase in long-term PM 2.5 concentration by 10 µm/m. [3,13,43,44] In China, PM 2.5 and PM 1 (ultrafine particles) were associated with 1-year mortality after ischaemic stroke but not with PM 10 or NO 2 . [56] Similarly, studies in the US [57,58] and UK [59] found significant associations of PM 2.5 with stroke mortality. In contrast, the study in Australia found no significant association between PM 2.5 and NO 2 with stroke mortality, which was attributed to the low pollutant level and baseline incidence of stroke in Australia. [60] PM 10 and CO was associated with stroke mortality in the UK, [25] and NO 2 was shown to be associated with stroke mortality in Denmark [53] and UK. [25] Studies on long-term SO 2 and O 3 with stroke mortality are lacking, and further research is needed to explore this potential relationship.

effect ModIfIcatIon of aIR PollutIon-assocIated stRoke
Consistently high heterogeneity in the effect sizes of the impact of air pollution on stroke incidence or mortality suggest variable susceptibility to air pollution-induced stroke in the general population. Previous studies have studied subgroups and effect modifiers that may increase the vulnerability to adverse health effects of air pollution.

Socioeconomic status and income
At the country level, national income may affect the impact of air pollution on stroke. The meta-analysis performed by Shah et al. [12] in 2015 found that pooled estimates from studies performed in middle-or low-income countries, a majority of which from China, showed stronger associations between NO 2 and PM 10 and stroke than studies from high-income countries.
The mean concentrations of NO 2 and PM 10 were higher in middle-and low-income countries than high-income countries, which may explain the stronger association. [12] There is a paucity of studies from Africa and the Indian subcontinent, and with the increasing stroke incidence and mortality in developing nations, research in these areas is needed.
Individual socioeconomic status may also modify the effect of air pollution on stroke. In the US, higher levels of PM 2.5 were associated with higher odds of severe stroke in those with higher disadvantage scores than those from lower disadvantage areas. [61] In another study performed in the US, PM 2.5 was no longer significantly associated with stroke risk after accounting for socioeconomic status. In Canada, the long-term average NO 2 and CO levels were associated with higher stroke risk, but this was strongly attenuated by household income levels. [46] The reasons underlying this is unclear, and qualitative research to identify root causes for the increased air pollution-associated stroke in areas with lower socioeconomic status may be useful to inform targeted interventions in these areas.

Demographic characteristics
Age, sex and ethnicity have been explored as effect modifiers in previous studies on stroke and air pollution. A majority of studies with subgroup analysis based on age found that older age was associated with increased vulnerability to air pollution-associated stroke. This included studies performed in large cities in China, [34,62] Singapore, [32] UK, [63] Spain, [64] 11 cohorts in Europe [47] and Canada. [33] In contrast, one study in Chongqing, China, on O 3 and NO 2 contrasted this and found a higher risk in those age <60 years, [65] which might be due to behavioural differences where older individuals were more likely to stay at home when air quality was poor. The effect of gender is not well-established. Some studies found a stronger association in women, [32,42,66] whereas others found a stronger association with men. [65,67,68] Ethnic differences were suggested by a study in the US, which found that O 3 was associated with greater odds of ischaemic stroke for Mexican Americans than non-Hispanic Whites. [69] However, another study investigating O 3 did not find any differences between African American and European Americans with regards to ischaemic stroke. [29]

Recurrent stroke
Patients with previous stroke may be more vulnerable to air pollution-associated stroke. An interquartile range increase in PM 10 concentration was associated with 2.3% increase in ischaemic stroke events in those with previous stroke, but not in those without any previous stroke. [70] This was also observed with short-term O 3 in a study performed in France, where there was a linear relationship with recurrent stroke and large artery stroke only. [71] The association of short-term NO 2 with ischaemic stroke was stronger in those with a history of stroke in a Canadian study. [72] In contrast, the study on patients with recurrent ischaemic stroke found no association with PM 2.5 and O 3 , but the study may be underpowered due to a limited variability in exposure levels in Corpus Christi, Texas, US. [73]

Cardiovascular risk factors
Diabetes mellitus was associated with increased stroke associated with PSI, PM 2.5 , PM 10 and nitrogen oxides in several studies, for both short-and long-term exposures. [32,68,[74][75][76] Stroke admission associated with NO 2 , CO, SO 2 was also increased in patients with hypertension and heart disease. [77] Hypertension was found to be a possible mediator between PM 2.5 and stroke, [37] and was also seen in stroke associated with PSI. [32] Similarly, obesity was also associated with increased air pollution-associated stroke. [37,66,68] However, studies on hyperlipidaemia are conflicting, [32,[77][78][79] necessitating better designed and powered studies to evaluate the association. Interestingly, non-smokers seemed more vulnerable to air pollution-associated stroke, which was shown in a study on PM 2.5 and PM 10 [79] and PSI. [32] Pre-existing cardiac disease was also associated with increased air pollution-associated stroke in two studies on short-term exposure to NO 2 , CO, SO 2 , O 3 and PM. [77,80] MechanIsMs MedIatIng the assocIatIon of aIR PollutIon and stRoke Acute exposure to air pollutants can promote stroke through a variety of proposed mechanisms that can largely be divided into two main categories, including activation of the thrombosis pathway and systemic vascular dysfunction. On the contrary, atherosclerosis progression, peripheral artery disease and systemic vascular dysfunction are thought to be the main underlying mechanisms during chronic exposure to air pollutants.

Hypercoagulopathy and thrombosis
Independent studies performed in patients with chronic obstructive pulmonary disease collectively found short-term exposure to a range of air pollutants (NO 2 , CO and PM 10 ) to correlate with increased plasma fibrinogen. [81,82] Others have found elevated ambient NO 2 or CO in the previous day of blood sampling to be associated with a 1.5% increase in plasma fibrinogen in a population based study. [83] Similarly, acute exposure to ambient air pollution is associated with elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) [84] and soluble platelet selectin (sP-selectin), which is a marker associated with platelet activation. [85] Studies conducted around the 2008 Beijing Olympic Games, where there was a decrease in air pollution due to strict restriction policies, found plasma sP-selectin and von Willebrand factor (vWF) to be reduced in relation to improved air quality. [86,87] A prothrombotic state through elevated plasma levels of prothrombotic factors and direct platelet activation have been associated with increased stroke incidence and mortality, [88][89][90] providing a potential mechanistic link between air pollution and stroke.

Endothelial dysfunction and blood pressure
Exposure to air pollution can result in systemic vascular dysfunction due to vasoconstriction and increasing blood pressure. Critically, hypertension is a key risk factor associated with increased incidence and worse outcomes in both ischaemic and haemorrhagic stroke. [91,92] Short-term exposure to PM 2.5 and O 3 at ambient concentrations in healthy volunteers under experimental settings led to acute arterial vasoconstriction in a small study. [93] The endothelium plays key roles in modulating arterial tone, and endothelial dysfunction results in vasoconstriction due to reduced NO. [94] Episodic PM 2.5 exposure in healthy adults correlated with endothelial cell apoptosis, along with increased circulating monocytes and CD4 + and CD8 + T cells, which is consistent with systemic inflammation. [95] Importantly, the pathogenic roles of T cells in stroke are well documented through a plethora of animal and human studies. [96,97] In addition, many studies have related both short and long term PM 2.5 exposure to increased blood pressure. [98] A randomised crossover trial found that reduced short-term exposure to ambient air pollutants in Beijing through the use of facemasks resulted in significantly lower ambulatory blood pressure in patients with coronary artery disease. [99] Overall, although several studies identified air pollution exposure to be associated with a range of stroke risk factors, further mechanistic studies are required to better elucidate the mechanisms underlying air pollution and stroke predisposition.

Atherosclerosis
During chronic exposure to air pollutants, stroke predisposition is mainly thought to be due to progression of atherosclerosis. Using a variety of surrogates, including carotid intima-media thickness and coronary artery calcification, independent studies found PM 2.5 and PM 10 to be associated with atherosclerosis. [100][101][102][103] Residents that live in closer proximity to major roads with presumed increased exposure to traffic-related air pollution, have increased risk of atherosclerosis and peripheral artery disease as measured by arterial calcification, carotid-intima-media thickness and ankle brachial index. [102,104,105] Finally, increased blood pressure due to air pollution exposure may facilitate subsequent plaque rupture, leading to thrombosis and stroke. [106]

PotentIal InteRventIons and futuRe ReseaRch dIRectIon
Behavioural factors may modify the effects of air pollution exposure on stroke, thus allowing means of intervention through education and enforced regulations. A recent study found the increase in blood pressure associated with long-term exposure to air pollution (PM 2.5 , PM 10 or NO 2 ) is more pronounced in individuals who consume 75 g of more meat per day. [107] On the contrary, daily consumption of 500 g or more vegetable and fruits did not affect risk of high blood pressure associated with air pollutants but these subjects had lower odds of stroke associated with PM 2.5 . [108] These results suggest that education and public health awareness may reduce the detrimental effects of air pollution on stroke, but more studies are needed to confirm these findings.
Reduction in ambient air pollution has measurable effects on stroke. This was evident when temporary reduction in air pollution during the Beijing 2008 Olympics, was associated with reduced plasma vWF, [86,87] an important risk factor for stroke due to its prothrombotic functions. [109,110] Implementation of public transport can also reduce air pollution and associated stroke risk. Residents living in surrounding areas of the light rail transit in Houston had significantly reduced daily stroke mortality, which mirrors the lower acetylene levels after LRT implementation. [111] Intriguingly, the contemporary COVID-19 pandemic provided a unique opportunity to study the potential effects of air pollution intervention on stroke. A modelling study found nationwide lockdown measures due to COVID-19 across China and Europe and the resultant 29.7% and 17.1% reduction in population-weighted PM 2.5 , respectively, was associated with significantly reduced premature mortality related to multiple cardiovascular and respiratory conditions, including stroke. [112] Similarly, a study in Pakistan found significantly improved air quality during the COVID-19 pandemic, to be associated with reduced stroke-related hospital admissions potentially due to reduced incidence. [113] Finally, face coverings may reduce short-term exposure to ambient air pollution. Given the association of hypertension to stroke, facemask-wearing led to increased heart rate variability and reduced mean arterial blood pressure during prescribed walks in a randomised crossover trial. [99] Altogether, these observations suggest that interventions against air pollution may be effective in reducing stroke risk or mortality.
There are several limitations to the methodology of the current literature. The date of admission to hospital or presentation to emergency department is often used as the date of onset of stroke, and a study by Lokken et al. [114] found that assessing exposure based on hospitalization date could underestimate the strength of associations compared to date of presentation. There are also concerns that the date of onset of stroke may differ from date of presentation, and there may be significant recall bias. However, in a study that compared using the date of onset as reported by the patient and the date of presentation, more then 70% of patients experienced stroke onset on the same day as presentation to hospital, and this was an unlikely source of error. [115] Many studies also used ICD 9 or ICD 10 to identify patients who had a stroke from large databases, and although the change from ICD 9 to ICD 10 may not significantly affect the effects of air pollution, [116] the use of coding systems may cause an over-or under-capture of cases. [117] There is also a lack of clinical detail associated, increasing the challenge of identifying relationships with stroke subtypes.

conclusIon
There is strong evidence that short-and long-term exposure to air pollution is linked to increased stroke incidence and mortality. The mechanism behind the association of air pollution and stroke may be related to hypercoagulopathy, endothelial dysfunction, increased blood pressure and atherosclerosis. Although the incidence of stroke and levels of air pollution are decreasing in developed countries, the stroke burden and air pollution is constant or increasing in developing countries. Further research from middle-and low-income countries is needed, especially regarding long-term exposure to air pollutants. It is important to reduce levels of air pollution globally, to reduce the associated adverse health effects.

Financial support and sponsorship
Nil.

Conflicts of interest
There are no conflicts of interest.