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Ambient Pollutants and Spontaneous Intracerebral Hemorrhage in Greater Boston

Originally publishedhttps://doi.org/10.1161/STROKEAHA.118.023128Stroke. 2018;49:2764–2766

    Abstract

    Background and Purpose—

    Associations between exposures to ambient air pollution and spontaneous intracerebral hemorrhage (ICH) have been inconsistent, and data on stroke subtypes are currently limited.

    Methods—

    We obtained information on all cases of deep or lobar hematomas from ICH patients who were admitted to the Massachusetts General Hospital in Boston, MA, between 2006 and 2011. We linked the date of admission with 1- to 7-day moving averages of fine particulate matter (PM2.5), black carbon, nitrogen dioxide, and ozone from area monitors. We conducted time-stratified bidirectional case-crossover analyses to assess associations between pollutants and stroke. We also investigated whether associations differed by hemorrhage location and type.

    Results—

    There were 577 cases of ICH (295 deep, 282 lobar). Overall, there was no evidence of elevated ICH risk after increases in PM2.5, black carbon, or nitrogen dioxide in the whole population. However, there was suggestion of heightened risk with higher levels of ozone for averages longer than 1 day although CIs were wide. In models stratified by ICH location, associations with ozone remained positive for patients with lobar (3-day moving average odds ratio, 1.62; 95% CI, 1.18–2.22) but not deep ICH (odds ratio, 0.88; 95% CI, 0.65–1.20). Larger estimates were observed among participants with a probable diagnosis of cerebral amyloid angiopathy (odds ratio, 2.23; 95% CI, 1.25–3.96).

    Conclusions—

    Exposure to ozone may be associated with incidence of lobar ICH, especially among those who have confirmed or probable cerebral amyloid angiopathy.

    Intracerebral hemorrhage (ICH) accounts for ≈10% of strokes in the United States,1 and prognosis is particularly poor. ICH in deep and lobar regions of the brain is often attributed to distinct predominant underlying pathologies. Although ICH related to atherosclerotic mechanisms typically occurs in deep regions of the brain, lobar and subcortical ICH is usually attributed to cerebral amyloid angiopathy (CAA) as β-amyloid protein is deposited within the cortical and leptomeningeal vessel walls.2 However, information about risk factors for ICH remains limited, and whether the risk differs by underlying pathology is not well understood.

    Exposures to ambient air pollution have been associated with incidence of stroke.3 However, most studies have focused on ischemic stroke and particulate matter, and no studies have examined associations between ambient pollutants and ICH subtype. We therefore evaluated associations between exposures to ambient pollutants and ICH in a hospital-based population in Boston, MA, and investigated whether associations differed by ICH location and presumed classification.

    Methods

    Patient Recruitment and Baseline Data Collection

    Participants were drawn from consecutive patients aged ≥18 years, admitted to Massachusetts General Hospital from July 1994 to September 2011 with acute ICH (symptom onset within 1 day of presentation) confirmed by computed tomography scan.4 Lobar ICH was defined as selective involvement of cerebral cortex, underlying white matter, or both. CAA assignment was based on modified Boston criteria. The study protocol was approved by the institutional review boards of Massachusetts General Hospital and Beth Israel Deaconess Medical Center. Written informed consent was obtained from all study participants or their surrogates. Because of the sensitive nature of the data collected for this study, requests to access the data set from qualified researchers trained in human subject confidentiality protocols may be sent to Zora Dipucchio ().

    Pollutants

    Ambient pollutants were assessed at the Harvard Supersite on the rooftop of the Countway Library of Medicine. Fine particulate matter (PM2.5) and black carbon were determined using a tapered-element oscillating microbalance and an Aethalometer, respectively. Nitrogen dioxide and ozone levels came from the Massachusetts Department of Environmental Protection. Meteorologic data were provided by the National Weather Service station at Boston Logan Airport as previously described.5

    Statistical Methods

    Bidirectional time-stratified case-crossover analysis was used to evaluate associations between pollutant concentrations at 1-, 2-, 3-, 5-, and 7-day moving averages and risk of ICH. Exposure preceding ICH was compared with referent period exposures on days of the same month and day of week for each participant. Analyses were adjusted for barometric pressure (continuous), ambient temperature, and dew point temperature (natural cubic splines with 3 df). Pollutants were scaled to differences of 0.01 ppm ozone, 0.01 ppm nitrogen dioxide, 0.5 µg/m3 black carbon, and 2 µg/m3 PM2.5.

    Sensitivity analyses separately stratified by season (warm: April to September), restricted to probable cases of CAA, incident ICH cases with no prior hemorrhage, and residents of Massachusetts. Nonlinearity in associations was evaluated using natural splines with 3 df. A 2-sided P<0.05 was considered statistically significant. Analyses were conducted in SAS 9.4 and R version 3.2.4.

    Results

    Participant characteristics are described in the Table. In multivariable-adjusted models including all ICH cases, there was no clear pattern of association for PM2.5, black carbon, or nitrogen dioxide. Associations with ozone were positive but had wide CIs. However, ozone was associated with higher odds of ICH among patients with a lobar but not deep ICH. A 3-day moving average of ozone was associated with 1.62 (95% CI, 1.18–2.22) higher odds of lobar ICH and odds ratio, 0.88 (95% CI, 0.65–1.2) for deep ICH (Figure). Associations were of larger magnitude in models restricted to patients with CAA (odds ratio, 2.23; 95% CI, 1.25–3.96; n=99). Results remained consistent when we stratified by season, restricted to incident events (n=538), or patients with residential addresses in Massachusetts (n=496). There was no evidence of deviation from linearity for ozone associations.

    Table. Population Characteristics of 577 Cases of Intracerebral Hemorrhage, Mean [SD], or n (%)

    All (577)Deep (295)Lobar (282)
    Age76 [19]74 [21]79 [15]
    Men304 (53%)171 (58%)133 (47%)
    Race
     White489 (85%)269 (82%)297 (87%)
     Black37 (7%)22 (7%)22 (6%)
     Asian32 (6%)23 (8%)9 (3%)
     Other/unknown19 (3%)12 (4%)7 (2%)
     Hispanic31 (5%)21 (7%)10 (4%)
    History of hypertension465 (81%)257 (87)208 (74)
    History of coronary artery disease120 (21%)64 (22%)56(20%)
    History of atrial fibrillation122(21%)63(22%)59 (21%)
    Previous hemorrhage37 (5%)12 (4%)23 (7%)
    Previous ischemic cerebrovascular accident64 (11)36 (12)28 (10)
    Alcohol >3 oz/d10 (1%)5 (1%)5 (1%)
    Smoking
     Current58 (11%)27 (9%)31 (12%)
     Former191 (33%)92 (31%)99 (35%)
    Figure.

    Figure. Analyses were adjusted for ambient temperature and dew point temperature with natural cubic splines with 3 df and barometric pressure modeled continuously for the same time window as the moving average of interest. Pollutants were scaled to differences of 0.01 ppm ozone, 0.01 ppm nitrogen dioxide (NO2), 0.5 µg/m3 black carbon (BC), and 2 µg/m3 particulate matter (PM2.5).

    Discussion

    We found that patients with lobar ICH had greater odds of stroke after recent exposure to ozone. This is the first study to examine differences by hematoma location/presumed underlying cause. The findings suggest that ozone could have an impact on fragile small vessels affected by CAA. Across the limited number of studies that have evaluated associations between stroke and ozone in the United States and Europe, no clear associations have been reported.6–8 In contrast, among 41 746 hemorrhagic stroke cases from 14 cities in China, an interquartile range difference in 6-day average of exposure to ozone was associated 2% higher (95% CI, −0.2 to 4.3) admissions and consistently positive estimates for lags 0 to 5 days, although associations did not achieve nominal statistical significance.9 However, this study did not report on differences related to lobar or deep ICH or presumed cause.

    Although no prior studies directly examined associations between air pollution and CAA pathology, ozone may lead to neuroinflammation10 or accumulation of and conformational changes in β-amyloid.11 In humans, short-term exposures to ozone have been associated with hospital admissions because of dementia,12 whereas long-term exposures to ozone have been associated with poorer cognition13 particularly among people with ≥1 copies of the APOE4 (apolipoprotein E) allele14; however, mechanisms have not been widely studied.

    We found that higher levels of ambient ozone below the levels set for national air quality standards are associated with an elevated risk of lobar ICH and CAA. Our study has limitations, including lack of information on precise timing of outcomes, which could lead to underestimation of associations, and the use of stationary monitoring, which may reduce precision and concerns about generalizability to other populations. However, information about modifiable short-term risk factors for ICH related to CAA remains limited. As ozone levels are projected to rise in many urban areas and there remains limited knowledge about acute, modifiable risk factors that lead CAA patients to develop ICH, the effects of ozone on the brain and its impact on ICH will need to be confirmed and validated in future larger studies.

    Footnotes

    Guest Editor for this article was Emmanuel Touzé, PhD.

    Correspondence to Elissa H. Wilker, ScD, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02461. Email

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