Effect of Air Pollution Particulate Matter on Ischemic and Hemorrhagic Stroke: A Scoping Review

Air pollution particulate matter (PM) exposure has been established as a risk factor for stroke. However, few studies have investigated the effects of PM exposure on stroke subtypes (ischemic and hemorrhagic stroke). Ischemic (IS) and hemorrhagic strokes (HS) involve distinctive pathophysiological pathways and may be differentially influenced by PM exposure. This review aims to characterize the effects of PM exposure on ischemic and hemorrhagic strokes. It also identifies subpopulations that may be uniquely vulnerable to PM toxicity. Pubmed was queried from 2000 to 2023 to identify clinical and epidemiological studies examining the association between PM exposure and stroke subtypes (ischemic and hemorrhagic stroke). Inclusion criteria were: 1) articles written in English 2) clinical and epidemiological studies 3) studies with a clear definition of stroke, IS, HS, and air pollution 4) studies reporting the effects of PM and 5) studies that included distinct analyses per stroke subtype. Two independent reviewers screened the literature for applicable studies. A total of 50 articles were included in this review. Overall, PM exposure increases ischemic stroke risk in both lightly and heavily polluted countries. The association between PM exposure and hemorrhagic stroke is variable and may be influenced by a country’s ambient air pollution levels. A stronger association between PM exposure and stroke is demonstrated in older individuals and those with pre-existing diabetes. There is no clear effect of sex or hypertension on PM-associated stroke risk. Current literature suggests PM exposure increases ischemic stroke risk, with an unclear effect on hemorrhagic stroke risk. Older patients and those with pre-existing diabetes may be the most vulnerable to PM toxicity. Future investigations are needed to characterize the influence of sex and hypertension on PM-associated stroke risk.


Introduction And Background
Stroke, a leading cause of morbidity and mortality, can be divided into two main subtypes: ischemic and hemorrhagic [1].Ischemic stroke (IS) is characterized by decreased blood flow and tissue necrosis secondary to vascular obstruction [1].Hemorrhagic stroke (HS) is defined by leakage of blood products into, or around, the brain via damaged blood vessels [1].Stroke burden is expected to increase as the population ages [2].It is therefore important to identify modifiable stroke risk factors.Ambient air pollution (AAP) is composed of particulate matter (PM), metals, and gaseous pollutants including ozone (O3), carbon monoxide (CO), sulphur dioxide (SO2), and nitrogen species (NO2, NOx) [3].PM 2.5 (<2.5µm) may be a significant contributor to AAP-associated toxicity given its small aerodynamic diameter and potential to enter into the systemic circulation after inhalation [3].AAP exposure is a risk factor for stroke [3][4][5][6][7].Air pollution can induce inflammation and oxidative stress, which may impact stroke incidence and/or progression [8].While the association between PM and stroke is well characterized, few studies have investigated the differential effects of PM on IS and HS.The effects of PM may differ by stroke subtype, as IS and HS involve different pathways [1].Patient-based factors may influence the effect of PM on stroke subtype.This review aims to examine the clinical association between PM and stroke subtype (IS and HS).Further, the review describes the influence of patient-based factors (age, comorbidities, sex) on the effects of PM exposure and stroke.

Review Methods
Given the wide scope of this study, a scoping literature review was performed.PubMed was searched between 2000 and 2023 for relevant articles using keywords (Table 1).This review followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISM-ScR) guidelines.The initial search identified 1356 articles.Inclusion criteria were as follows: 1) clinical and epidemiological studies including humans 2) articles written in English 3) studies with a clear definition of stroke, IS, HS, and air pollution 4) studies that included separate analyses per stroke subtype 5) studies on the effects of PM.Studies on all other known air pollution constituents were excluded.

TABLE 1: Search Criteria
Two independent reviewers performed the initial screen and reviewed the title and abstract of articles.The full text was read for articles that passed the initial screen.The initial screen included 250 articles.This review includes 50 articles (Figure 1).
Moderate PM exposure may impact the IS risk.Moderate PM 2.5 exposure (15-40µg/m 3 ) increased IS risk by 34% when compared to light PM 2.5 exposure (≤15µg/m 3 ).PM 2.5 levels were linearly associated with stroke risk and the association between PM 2.5 and IS onset was strongest within 12 hours of exposure [19].PM 2.5 is neurotoxic at levels within the US National Ambient Air Quality Standards [39].The effect of PM on IS may vary by stroke severity.Higher levels of ultrafine particle (UFP) (<0.1µm) exposure increased hospital admissions by 21% for mild IS without atrial fibrillation.There was no association between UFP exposure and severe IS admissions [31].
Other studies have found no association between PM exposure and IS [17,28,[32][33][34][35][36][37][38].The Health Professionals Follow-up Study (HPFS) demonstrated that daily changes in PM 10 , but not PM 2.5 , were associated with IS events.Subjects were mostly Caucasian men, and results, therefore, may not be generalizable to the entire population [32].In the Women's Health Initiative, no association was demonstrated between PM 2.5 /PM 10 and IS risk [34].Similarly, there was no association between PM 2.5 /PM 10 and incident IS in the South London Stroke Register [35].Exposure assessment, stroke ascertainment, and statistical approaches varied among studies, which could contribute to result heterogeneity.

Long-Term Particulate Matter Exposure
Fewer studies have investigated the effects of long-term PM exposure on IS (Table 3).Long-term PM exposure is defined as PM exposure for one year or longer.A meta-analysis by Yuan et al. identified four studies that stratified analyses by stroke subtype [40].Pooled results suggested no association between IS incidence and PM 2.5 exposure (per 5µg/m 3 increase, Hazard Ratio (HR): 1.62, 95% Cl: 0.88-2.97)[40][41][42][43][44].In the Danish Nurse Cohort, IS risk increased by 17% (95% Cl: 1.01-1.34)per 5µg/m 3 increase of one-year mean PM 2.5 .A 3µg/m 3 increase of one-year mean PM 10 showed a positive, but nonsignificant, association with IS risk (HR: 1.04, 95% Cl: 0.96-1.13).A linear dose-response relationship between PM 2.5 /PM 10 and stroke incidence was noted.A threshold was found, above which an effect between PM and increased stroke risk was not observed (PM 2.5 , PM 10 : 20µg/m 3 ) [45].These results suggest that PM exposure can increase IS risk in a region with lower pollutant concentrations.Subjects were female nurses aged 44 years and older, limiting the study's generalizability [45].In contrast, PM 2.5 exposure was not associated with IS incidence in the South London Stroke Register [46].In Seoul, Korea, every 1µg/m 3 increase in PM 2.5 /PM 10 exposure increased IS incidence [42].The Atherosclerotic Cardiovascular Disease Risk in China (China-PAR) project demonstrated that every 10µg/m 3 increase in PM 2.5 increased IS incidence by 20% (95% Cl: 15-25%) [47].An almost linear association between PM 2.5 exposure and incident IS was noted [47].Higher air pollution levels in Korea and China relative to Western countries may account for the increased risks of PM exposure [29].An association between short-term PM 2.5 /PM 10 exposure and HS incidence was observed in the HPFS study on the day before stroke [32].This association was not consistent across exposure days [32].Gu et al. noted similar results, with an association between PM 2.5 and HS hospital admissions that was significant with specific single-day exposures or moving average exposures [30].Interestingly, same-day PM 10 exposure decreased HS incidence in London after adjusting for NO x .As PM 2.5 and NO x are strongly correlated, this association may be secondary to collinearity [35].
No association between one-or three-year mean PM 2.5 or PM 10 and incident HS was demonstrated in the Danish Nurse Cohort [45].Similarly, no association between daily PM 2.5 /PM 10 exposure and incident HS was noted in the Women's Health Initiative [34].In contrast, Kim et al. demonstrated that every 1µg/m 3 increase in long-term PM 2.5 and PM 10 concentration increased HS incidence [42].In the China-PAR project, every 10µg/m 3 increase in long-term PM 2.5 increased incident HS by 12% (95% Cl: 5-20%) [47].

Comparison of particulate matter effects on ischemic and hemorrhagic stroke
The association between PM exposure and IS is well established, while the association between PM exposure and HS is less clear.Most studies reported stronger associations of PM with IS than HS, while few reported the opposite effect [6,9,10,13,21,23,36,42,45,47,52,53] (Table 4).PM 10 levels were associated with same-day IS, but not HS, admissions among Medicare recipients [20].In China, every 10µg/m 3 increase in PM 2.5 concentration, increased years life lost by 0.31% (95% Cl: 0.15-0.46)for IS and 0.23% (95% Cl: 0.09-0.36)for HS [53].The differential effect of PM on stroke subtypes may be secondary to the distinctive underlying mechanisms.

Pathophysiology behind air pollution-associated stroke
The exact mechanisms underlying air pollution-associated ischemic and hemorrhagic stroke are still unknown.PM exposure activates neuroinflammatory and oxidative stress pathways in both clinical and animal studies [8,[60][61][62][63].In addition, PM exposure contributes to endothelial dysfunction, which is a risk factor for stroke [7,62,64].Atherosclerosis is an important mechanism underlying IS development [65].PM exposure contributes to the formation and progression of atherosclerosis [62].Furthermore, PM exposure is associated with increased plaque instability [62].PM exposure increases sympathetic nervous system activity [66].These effects may cause increases in blood pressure and risk of thrombosis [67].Thrombus formation may contribute to IS pathogenesis, while hypertension increases HS and IS risk [58].Proposed mechanisms behind air pollution particulate matter and ischemic and hemorrhagic stroke have been outlined in Figure 2.

Effect of particulate matter on stroke in susceptible populations
The effect of PM exposure on IS and HS may depend on patient-based factors, such as sex, age, and comorbidities.This study investigated the influence of sex, age, and comorbidities (hypertension and diabetes) on the association between PM exposure and stroke.

Sex
Studies have produced inconsistent results with regards to the influence of sex on PM exposure and stroke risk (Table 5).PM 2.5 exposure (nonsignificantly) increased stroke incidence and mortality in females compared to males across China.Chinese females have a higher prevalence of diabetes and hypertension, which may render them vulnerable to PM neurotoxicity [10,68].In contrast, the effect of PM 10 on daily IS deaths was stronger in males than females in Changzhou, China.Study authors suggested that males may spend more time outdoors and be exposed to higher PM 10 levels [14].Globally, males had a higher burden of PM-attributable stroke (stroke-related DALYs and deaths) in 2017 [5].Risk factors for stroke, such as smoking, tend to be more prevalent in men [69].

Age
Older individuals are susceptible to air pollution toxicity [70].Likewise, a stronger association between PM and stroke may be observed in older populations (Table 6).Chinese adults aged ≥75 years had an increased stroke mortality risk after PM 2.5 exposure compared to individuals <75 years.However, the association between PM 2.5 and stroke incidence increased in adults aged <75 years compared to adults ≥75 years [10].
The average age for first-ever stroke ranges from 60.9 to 63.4 years in China [68].Therefore, the effect of PM 2.5 on stroke incidence may be greatest in individuals aged ≥60 years and not ≥75 years.Similarly, the association between PM 2.5 and IS admissions was increased (nonsignificantly) in Chinese adults aged 65-74 compared to adults aged <65 [30].A greater effect of PM 2.5 on IS admissions was demonstrated in adults ≥75 years in Yancheng, China [11].For HS, PM 2.5 exposure increased fatal ICH incidence among Chinese adults >65 years but not in adults <65 years [50].It is possible that individuals aged ≥60 years are more vulnerable to PM toxicity [10].In London, the strongest IS risk per 10µg/m 3 increase in PM 10 occurred in adults aged 65-79 years (rate ratio 1.96, 95% Cl: 1.10-3.13)compared to adults aged 45-64 years (1.12, 95% Cl: 0.55-2.28)and adults older than 80 (0.5, 95% Cl: 0.19-1.32).The data used for census counts of individuals >80 years may have been inaccurate in the study's small region.This may contribute to the lack of association between PM 10 and IS in adults >80 years [17].There was no association between PM 10 exposure and HS incidence across age ranges [17].

Findings
Several studies have reported no effect of age on PM and stroke [13,32].In Changzhou, China, PM 10 -related IS mortality risk was greater in individuals <65 years compared to individuals ≥65 years.Young individuals may spend more time outdoors and be exposed to higher PM 10 levels than elderly individuals [14].

Hypertension and Diabetes
Individuals with underlying comorbidities, such as diabetes and hypertension, may be vulnerable to the adverse effects of PM (Table 7).PM 2.5 exposure increased IS risk by 10.6% among patients with diabetes (95% Cl: 0.8-21.5%) in Canada, a region with low air pollution levels.No association was demonstrated between PM 2.5 and IS among patients without diabetes [37].PM 2.5 exposure increased fatal ICH by 26% (95% Cl: 9-46%) among patients with diabetes in Shanghai.This association was significantly stronger when compared to subjects without diabetes (5% increase, 95% Cl: -2-12%) [50].The exact mechanisms behind why patients with diabetes may be more vulnerable to PM exposure are still unknown; however, inflammation may play a key role.Diabetes can increase vascular inflammation and cause endothelial dysfunction, which may contribute to an individual's susceptibility to PM 2.5 neurotoxicity [71].
exposure and HS risk is less clear and may depend on the level of ambient air pollution present in a country.
Older patients and patients with pre-existing diabetes may be uniquely susceptible to the adverse effects of PM.Future studies are needed to determine the effect of PM exposure on HS and the influence of sex and hypertension on PM-associated stroke risk.Improving air quality standards and monitoring those most vulnerable to PM toxicity may mitigate the detrimental health effects of PM and reduce healthcare costs.

FIGURE 2 :
FIGURE 2: Mechanisms Underlying Particulate Matter Exposure and Ischemic and Hemorrhagic Stroke Figure created with BioRender.com

TABLE 2 : Short-term Particulate Matter Exposure and Ischemic Stroke
*Results include short-and long-term PM exposure.Abbreviations: PM: particulate matter; IS: Ischemic stroke; HS: hemorrhagic stroke; ns: nonsignificant; UFP: ultrafine particle A recent meta-analysis by Fu et al. (2019) demonstrated a stronger association between PM 2.5 exposure and IS incidence than the meta-analyses conducted by Shah et al. and Wang et al.

TABLE 4 : Short-and Long-Term Particulate Matter Exposure and Hemorrhagic Stroke
*After adjustment for nitrogen oxides (NOx).†Resultsinclude short-and long-term PM exposure.Abbreviations: PM: particulate matter; IS: ischemic stroke; HS: hemorrhagic stroke; SAH: subarachnoid hemorrhage; ns: nonsignificant; ICH: intracerebral hemorrhage; DALYs: disability-associated life years Ban et al., 2021 [10] PM 2.5 stronger association with stroke incidence and mortality in females Hu et al., 2021 [11] PM 2.5 stronger association with IS admissions in females

TABLE 5 : Influence of Sex on Particulate Matter Exposure and Stroke
*No sex differences indicate that sex differences were examined in each study, and sex did not influence the association between particulate matter exposure and stroke Abbreviations: PM: particulate matter; IS: ischemic stroke; HS: hemorrhagic stroke Ban et al., 2021 [10] PM 2.5 stronger association with stroke mortality in people ≥75 yrs and stroke incidence in people 64-74 yrs Hu et al., 2021 [11] PM 2.5 stronger association with IS admissions in people ≥75 yrs Tian et al., 2018 [12] PM 2.5 stronger association with IS admissions in people ≥75 yrs PM 2.5 stronger association with IS incidence in people ≥60 yrs Chen et al., 2019 [49] PM 1 stronger association with fatal IS in people ≥75 yrs Sade et al., 2015 [23] PM 10 , PM 2.5 stronger association with IS admissions in people <55 yrs Huang et al., 2016 [24] No effect Qian et al., 2019 [45] PM 2.5 stronger association with fatal ICH in people ≥65 yrs

TABLE 6 : Influence of Age on Particulate Matter Exposure and Stroke
*No effect indicates that age was examined in each study and did not affect the association between particulate matter exposure and stroke Abbreviations: PM: particulate matter; IS: ischemic stroke; HS: hemorrhagic stroke; ICH: intracerebral hemorrhage; yrs: years