Evidence for the association between environmental exposures and ischemic stroke (IS) is limited and inconsistent. We aimed to assess the relationship between exposure to air pollutants, residential surrounding greenness, and incident IS, and to identify population subgroups particularly sensitive to these exposures. We used data from administrative health registries of the public healthcare system in Catalonia, Spain to construct a cohort of individuals aged 18 years and older without a previous stroke diagnosis at 1st January 2016 (n = 3 521 274). We collected data on sociodemographic characteristics and cerebrovascular risk factors, and derived exposure at the participant's residence to ambient levels of fine particulate matter (PM_2.5), black carbon (BC), nitrogen dioxide (NO₂), and Normalized Difference Vegetation Index (NDVI) in a 300 m buffer as an indicator of greenness. The primary outcome was IS diagnosis at any point during the follow-up. We used Cox proportional hazards models to estimate associations between environmental exposures and incident IS and stratified analyses to investigate effect modification. Between 1st January 2016 and 31st December 2017, 10 865 individuals were admitted to public hospitals with an IS diagnosis. Median exposure levels were: 17 µg/m³ PM_2.5, 35 µg/m³ NO₂, 2.28 µg/m³ BC and 0.27 NDVI. Individuals with higher residential exposure to air pollution were at greater risk of IS: HR 1·04 (95% CI:0·99-1·10) per 5 µg/m³ of PM_2.5; HR 1.05 (95% CI:1·00-1·10) per 1 µg/m³ of BC; HR 1·04 (95% CI:1·03-1·06) per 10 µg/m³ of NO₂. Conversely, individuals with higher residential surrounding green space, had lower risk of IS (HR 0·84; CI 95%:0·7-1.0). There was no evidence of effect modification by individual characteristics. Higher incidence of IS was observed in relation to long-term exposures to air pollution, particularly NO₂, in a region that meets European health-based air quality standards. Residential surrounding greenness was associated with lower incidence of IS.

Rationale. DNA methylation is dynamic, varies throughout the life course, and its levels are influenced by lifestyle and environmental factors, as well as by genetic variation. The leading genetic variants at stroke risk loci identified to date explain roughly 1–2% of stroke heritability. Most of these single nucleotide polymorphisms are situated within a regulatory sequence marked by DNase I hypersensitivity sites, which would indicate involvement of an epigenetic mechanism. Objective. To detect epigenetic variants associated to stroke occurrence and stroke subtypes. Methods and Results. A two-stage case-control epigenome-wide association study was designed. The discovery sample with 401 samples included 218 ischemic stroke (IS) patients, assessed at Hospital del Mar (Barcelona, Spain) and 183 controls from the REGICOR cohort. In two independent samples (N=226 and N=166), we replicated 22 CpG sites differentially methylated in IS in 21 loci, including 2 CpGs in locus ZFHX3, which includes known genetic variants associated with stroke. The pathways associated to these loci are inflammation and angiogenesis. The meta-analysis identified 384 differentially methylated CpGs, including loci of known stroke and vascular risk genetic variants, enriched by loci involved in lipid metabolism, adipogenesis, circadian clock, and glycolysis pathways. Conclusions. We identified a set of 22 CpGs in 21 loci associated with IS. Our analysis suggests that DNA methylation changes may contribute to orchestrating gene expression that contributes to IS.

The association between long-term exposure to ambient air pollutants and severe COVID-19 is uncertain. We followed 4,660,502 adults from the general population in 2020 in Catalonia, Spain. Cox proportional models were fit to evaluate the association between annual averages of PM_2.5, NO₂, BC, and O₃ at each participant’s residential address and severe COVID-19. Higher exposure to PM_2.5, NO_2, and BC was associated with an increased risk of COVID-19 hospitalization, ICU admission, death, and hospital length of stay. An increase of 3.2 µg/m³ of PM_2.5 was associated with a 19% (95% CI, 16–21) increase in hospitalizations. An increase of 16.1 µg/m³ of NO₂ was associated with a 42% (95% CI, 30–55) increase in ICU admissions. An increase of 0.7 µg/m³ of BC was associated with a 6% (95% CI, 0–13) increase in deaths. O₃ was positively associated with severe outcomes when adjusted by NO₂. Our study contributes robust evidence that long-term exposure to air pollutants is associated with severe COVID-19.

Background: Stroke onset in women occurs later in life compared with men. The underlying mechanisms of these differences have not been established. Epigenetic clocks, based on DNA methylation (DNAm) profiles, are the most accurate biological age estimate. Epigenetic age acceleration (EAA) measures indicate whether an individual is biologically younger or older than expected. Our aim was to analyze whether sexual dichotomy at age of stroke onset is conditioned by EAA. Methods: We used 2 DNAm datasets from whole blood samples of case-control genetic studies of ischemic stroke (IS), a discovery cohort of 374 IS patients (N women=163, N men=211), from GRECOS (Genotyping Recurrence Risk of Stroke) and SEDMAN (Dabigatran Study in the Early Phase of Stroke, New Neuroimaging Markers and Biomarkers) studies and a replication cohort of 981 IS patients (N women=411, N men=570) from BASICMAR register. We compared chronological age, 2 DNAm-based biomarkers of aging and intrinsic and extrinsic epigenetic age acceleration EAA (IEAA and extrinsic EAA, respectively), in IS as well as in individual IS etiologic subtypes. Horvath and Hannum epigenetic clocks were used to assess the aging rate. A proteomic study using the SOMAScan multiplex assay was performed on 26 samples analyzing 1305 proteins. Results: Women present lower Hannum-extrinsic EAA values, whereas men have higher Hannum-extrinsic EAA values (women=−0.64, men=1.24, P =1.34×10 ^-2 ); the same tendency was observed in the second cohort (women=−0.57, men=0.79, P =0.02). These differences seemed to be specific to cardioembolic and undetermined stroke subtypes. Additionally, 42 blood protein levels were associated with Hannum-extrinsic EAA ( P <0.05), belonging to the immune effector process ( P =1.54×10 ^-6 ) and platelet degranulation ( P <8.74×10 ^-6 ) pathways. Conclusions: This study shows that sex-specific underlying biological mechanisms associated with stroke onset could be due to differences in biological age acceleration between men and women.

Background: The aim of the study was to determine the association between previous stroke and mortality after coronavirus disease 2019 (COVID-19) according to sex, age groups, and stroke subtypes. Methods: Prospective population-based cohort study including all COVID-19 positive cases between February 1 and July 31, 2020. Comorbidities and mortality were extracted using linked health administration databases. Previous stroke included transient ischemic attack, ischemic stroke, hemorrhagic stroke, spontaneous subarachnoid hemorrhage, and combined stroke for cases with more than one category. Other comorbidities were obesity, diabetes, hypertension, ischemic heart disease, atrial fibrillation, heart failure, chronic obstructive pulmonary disease, chronic kidney disease, cirrhosis, dementia, individual socioeconomic index, and deprivation index. Cases were followed up until December 31, 2020. Primary outcome was mortality of any cause after COVID-19 positivity. Cox proportional regression analysis adjusted for comorbidities was used. Stratified analyses were performed for sex and age (<60, 60–79, and ≥80 years). Results: There were 91 629 COVID-19 cases. Previous strokes were 5752 (6.27%), of which 3887 (67.57%) were ischemic, 1237 (21.50%) transient ischemic attack, 255 (4.43%) combined, 203 (3.53%) hemorrhagic, and 170 (2.96%) subarachnoid hemorrhage. There were 9512 deaths (10.38%). Mortality was associated with previous stroke (hazard ratio [HR]=1.12 [95% CI, 1.06–1.18]; P <0.001), in both sexes separately (men=1.13 [1.05–1.22]; P =0.001; women=1.09 [1.01–1.18]; P =0.023), in people <60 years (HR=2.97 [1.97–4.48]; P <0.001) and 60 to 79 years (HR=1.32 [1.19–1.48]; P <0.001) but not in people ≥80 years (HR=1.02 [0.96–1.09]; P =0.437). Ischemic (HR=1.11 [1.05–1.18]; P =0.001), hemorrhagic (HR=1.53 [1.20–1.96]; P =0.001) and combined (HR=1.31 [1.05–1.63]; P =0.016) strokes were associated but not transient ischemic attack. Subarachnoid hemorrhage was associated only in people <60 years (HR=5.73 [1.82–18.06]; P =0.003). Conclusions: Previous stroke was associated with a higher mortality in people younger than 80 years. The association occurred for both ischemic and hemorrhagic stroke but not for transient ischemic attack. These data might help healthcare authorities to establish prioritization strategies for COVID-19 vaccination.