Incident Ischemic Stroke Cases Research Articles

Increased risk of ischemic stroke associated with elevated gamma-glutamyl transferase level in adult cancer survivors: a population-based cohort study

Adult cancer survivors may have an increased risk of developing ischemic stroke, potentially influenced by cancer treatment-related factors and shared risk factors with stroke. However, the association between gamma-glutamyl transferase (GGT) levels and the risk of ischemic stroke in this population remains understudied. Therefore, our study aimed to examine the relationship between GGT levels and the risk of ischemic stroke using a population-based cohort of adult cancer survivors. A population-based cohort of adult cancer survivors was derived from the National Health Insurance Service-Health Screening Cohort between 2003 and 2005 who survived after diagnosis of primary cancer and participated in the biennial national health screening program between 2009 and 2010. Cox proportional hazards model adjusted for sociodemographic factors, health status and behavior, and clinical characteristics was used to investigate the association between GGT level and ischemic stroke in adult cancer survivors. Among 3095 adult cancer survivors, 80 (2.58%) incident cases of ischemic stroke occurred over a mean follow-up of 8.2 years. Compared to the lowest GGT quartile, the hazard ratios (HRs) for ischemic stroke were 1.56 (95% CI 0.75–3.26), 2.36 (95% CI 1.12–4.99), and 2.40 (95% CI 1.05–5.46) for the second, third, and fourth sex-specific quartiles, respectively (Ptrend = 0.013). No significant effect modification was observed by sex, insurance premium, and alcohol consumption. High GGT level is associated with an increased risk of ischemic stroke in adult cancer survivors independent of sex, insurance premium, and alcohol consumption.

Blood Levels of Organochlorine Contaminants Mixtures and Cardiovascular Disease

Cardiovascular toxic effects derived from high exposures to individual organochlorine compounds are well documented. However, there is no evidence on low but continuous exposure to combined organochlorine compounds in the general population. To evaluate the association of combined exposure to several organochlorine compounds, including organochlorine pesticides and polychlorinated biphenyls, with incident cardiovascular disease (CVD) in the general population. This prospective nested case-control study included data from 2 cohorts: the Swedish Mammography Cohort-Clinical (SMC-C) and the Cohort of 60-Year-Olds (60YO), with matched case-control pairs based on age, sex, and sample date. Baseline blood sampling occurred from November 2003 to September 2009 (SMC-C) and from August 1997 to March 1999 (60YO), with follow-up through December 2017 (SMC-C) and December 2014 (60YO). Participants with myocardial infarction or ischemic stroke were matched with controls for composite CVD evaluation. Data were analyzed from September 2020 to May 2023. A total of 25 organochlorine compounds were measured in blood at baseline by gas chromatography-triple quadrupole mass spectrometry. For 7 compounds, more than 75% of the samples were lower than the limit of detection and not included. Incident cases of primary myocardial infarction and ischemic stroke were ascertained via linkage to the National Patient Register (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes I21 and I63). The quantile-based g-computation method was used to estimate the association between the combined exposure to several organochlorine compounds and composite CVD. Of 1528 included participants, 1024 (67.0%) were female, and the mean (SD) age was 72 (7.0) years in the SMC-C and 61 (0.1) years in the 60YO. The odds ratio of composite CVD was 1.71 (95% CI, 1.11-2.64) per 1-quartile increment of total organochlorine compounds mixture. Organochlorinated pesticides were the largest contributors, and β-hexachlorocyclohexane and transnonachlor had the highest impact. Most of the outcome was not explained by disturbances in the main cardiometabolic risk factors, ie, high body mass index, hypertension, lipid alteration, or diabetes. In this prospective nested case-control study, participants with higher exposures to organochlorines had an increased probability of experiencing a cardiovascular event, the major cause of death worldwide. Measures may be required to reduce these exposures.

Risk of Ischemic Stroke Associated with Calcium Supplements and Interaction with Oral Bisphosphonates: A Nested Case-Control Study.

Conflicting results about the association of calcium supplements (CS) with ischemic stroke (IS) have been reported. We tested this hypothesis by differentiating between CS alone (CaM) and CS with vitamin D (CaD) and between cardioembolic and non-cardioembolic IS. We examined the potential interaction with oral bisphosphonates (oBs). A nested case-control study was carried out. We identified incident IS cases aged 40-90 and randomly sampled five controls per case matched by age, sex, and index date. Current users were compared to non-users. An adjusted odds ratios (AOR) and 95% CI were computed through conditional logistic regression. Only new users were considered. We included 13,267 cases (4400 cardioembolic, 8867 non-cardioembolic) and 61,378 controls (20,147 and 41,231, respectively). CaM use was associated with an increased risk of cardioembolic IS (AOR = 1.88; 95% CI: 1.21-2.90) in a duration-dependent manner, while it showed no association with non-cardioembolic IS (AOR = 1.05; 95% CI: 0.74-1.50); its combination with oBs increased the risk of cardioembolic IS considerably (AOR = 2.54; 95% CI: 1.28-5.04), showing no effect on non-cardioembolic. CaD use was not associated with either cardioembolic (AOR = 1.08; 95% CI: 0.88-1.31) or non-cardioembolic IS (AOR = 0.98; 95% CI: 0.84-1.13) but showed a small association with cardioembolic IS when combined with oBs (AOR = 1.35; 95% CI: 1.03-1.76). The results support the hypothesis that CS increases the risk of cardioembolic IS, primarily when used concomitantly with oBs.

Association of oral bisphosphonates with cardioembolic ischemic stroke: a nested case-control study.

Background: Bisphosphonates have been reported to increase the risk of atrial fibrillation. Therefore, it is conceivable that they may increase the risk of cardioembolic ischemic stroke (IS). However, most epidemiological studies carried out thus far have not shown an increased risk of IS, though none separated by the main pathophysiologic IS subtype (cardioembolic and non-cardioembolic) which may be crucial. In this study, we tested the hypothesis that the use of oral bisphosphonates increases specifically the risk of cardioembolic IS, and explored the effect of treatment duration, as well as the potential interaction between oral bisphosphonates and calcium supplements and anticoagulants. Methods: We performed a case-control study nested in a cohort of patients aged 40-99years, using the Spanish primary healthcare database BIFAP, over the period 2002-2015. Incident cases of IS were identified and classified as cardioembolic or non-cardioembolic. Five controls per case were randomly selected, matched for age, sex, and index date (first recording of IS) using an incidence-density sampling. The association of IS (overall and by subtype) with the use of oral bisphosphonates within the last year before index date was assessed by computing the adjusted odds ratios (AOR) and their 95% CI using a conditional logistic regression. Only initiators of oral bisphosphonates were considered. Results: A total of 13,781 incident cases of IS and 65,909 controls were included. The mean age was 74.5 (SD ± 12.4) years and 51.6% were male. Among cases, 3.15% were current users of oral bisphosphonates, while among controls they were 2.62%, yielding an AOR of 1.15 (95% CI:1.01-1.30). Of all cases, 4,568 (33.1%) were classified as cardioembolic IS (matched with 21,697 controls) and 9,213 (66.9%) as non-cardioembolic IS (matched with 44,212 controls) yielding an AOR of 1.35 (95% CI:1.10-1.66) and 1.03 (95% CI: 0.88-1.21), respectively. The association with cardioembolic IS was clearly duration-dependent (AOR≤1year = 1.10; 95% CI:0.82-1.49; AOR>1-3years = 1.41; 95% CI:1.01-1.97; AOR>3years = 1.81; 95% CI:1.25-2.62; p for trend = 0.001) and completely blunted by anticoagulants, even in long-term users (AOR>1year = 0.59; 0.30-1.16). An interaction between oral bisphosphonates and calcium supplements was suggested. Conclusion: The use of oral bisphosphonates increases specifically the odds of cardioembolic IS, in a duration-dependent manner, while leaves materially unaffected the odds of non-cardioembolic IS.

Association of Circulating Metabolites With Racial Disparities in Hypertension and Stroke in the REGARDS Study.

In the United States, the risk of stroke is greater among Black compared with that among White individuals. However, the reasons for the difference in stroke incidence are not fully elucidated. We aimed to identify metabolites that account for higher prevalent hypertension and incident ischemic stroke among Black adults. We used a stroke case cohort nested within the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Targeted metabolomic profiling of 162 plasma metabolites was performed by liquid chromatography-tandem mass spectrometry. We identified metabolites that were associated with prevalent hypertension and incident ischemic stroke and mediated the relationship between hypertension and ischemic stroke by weighted logistic regression, Cox proportional hazard model, and inverse odds ratio weighting mediation analysis. Incident ischemic stroke cases adjudicated through April 1, 2019 (n = 1,075) were included in the study. The random cohort sample was derived from the full cohort using stratified sampling (n = 968). Among 162 metabolites, gluconic acid was associated with prevalent hypertension in Black adults (odds ratio [OR] 1.86, 95% CI 1.39-2.47, p = 2.58 × 10-5) but not in White adults (OR 1.00, 95% CI 0.80-1.24, p = 0.97; p for interaction = 4.57 × 10-4). Gluconic acid also demonstrated an association with incident ischemic stroke among Black participants (hazard ratio [HR] 1.53, 95% CI 1.28-1.81, p = 1.76 × 10-6) but not White participants (HR 1.16, 95% CI 1.00-1.34, p = 0.057; p for interaction = 0.019). In mediation analysis, gluconic acid mediated 25.4% (95% CI 4.1%-46.8%, p = 0.02) of the association between prevalent hypertension and incident ischemic stroke among Black individuals. Specific socioeconomic factors were linked to elevated gluconic acid level among Black adults in multivariable analysis, including a Southern dietary pattern (β = 0.18, 95% CI 0.08-0.28, p < 0.001), lower educational attainment (β = 0.45, 95% CI 0.19-0.72, p = 0.001), and a lack of exercise (β = 0.26, 95% CI 0.01-0.51, p = 0.045). Gluconic acid is associated with prevalent hypertension and incident ischemic stroke and mediates the relationship between hypertension and ischemic stroke in Black but not White adults. Gluconic acid is a biomarker that is associated with social determinants of health including a Southern diet, low educational attainment, and low physical activity.

Plasma β-Alanine is Positively Associated With Risk of Ischemic Stroke: a Nested Case-Control Study

BackgroundPrevious studies suggested that β-alanine as a neurotransmitter could affect the pathogenesis of ischemic damage. However, the association between circulating β-alanine and risk of ischemic stroke (IS) has not been evaluated in populations. ObjectivesWe aimed to examine the association between β-alanine and IS risk in a nested case-control study. MethodsWe performed a case-control study nested within a prospective community-based cohort (n = 16457; median follow-up time: 5.3 y), which included 321 incident IS cases and 321 controls matched by age and sex. Β-alanine and other metabolites were measured in plasma after overnight fasting by LC-MS/MS. The association of β-alanine with risk of IS was evaluated by conditional logistic regression. BMI, current smoking, educational attainment, physical activity, total energy intake, family history of stroke, hypertension, diabetes, hyperlipidemia, and estimated GFR were adjusted in multivariable models. ResultsThere was a significant Spearman partial correlation between β-alanine and 4-pyridoxic acid (ρ = 0.239; P < 0.001). Participants with elevated β-alanine levels were more likely to develop IS with an adjusted OR of 1.26 (95% CI: 1.06–1.51; P = 0.011) (per standard deviation increment). This association remained significant after excluding the first 2 y of follow-up, and after further adjustment for red meat intake, total protein intake, medication use, or vitamin B6 indicators. ConclusionsOur novel findings revealed that plasma β-alanine at baseline were positively associated with risk of IS and may function as an early biomarker of IS risk.

Abstract 83: Racial Disparities In Gluconic Acid, A Lifestyle-related Biomarker Associated With Stroke In REGARDS

Introduction: In the United States, the risk of stroke is greater among Black compared to White adults. Furthermore, hypertension has a greater impact on stroke risk among Black adults. We hypothesized that race-specific metabolites may account for some of this observed disparity. Methods: This was a case-cohort study nested in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Incident ischemic stroke cases (n=1,075) were compared with a random cohort sample (n=968). Metabolites were measured by liquid chromatography-tandem mass spectrometry. Weighted logistic regression and Cox proportional hazard model were used to identify race-specific metabolites in association with prevalent hypertension and incident stroke respectively. Candidate metabolites were assessed for mediation between hypertension and incident ischemic stroke. Linear regression was used to explore the association of metabolites with lifestyle factors. Results: A total of 162 plasma metabolites were quantified. Of these, gluconic acid was associated with prevalent hypertension in Black adults (OR=1.86, 95% CI=1.39-2.47, P =2.58x10 -5 ) but not in White adults (OR=1.00, 95% CI=0.80-1.24, P =0.97; P for interaction=4.57x10 -4 ). Gluconic acid was also associated with incident ischemic stroke among Black adults (HR=1.53, 95% CI=1.28-1.81, P =1.76x10 -6 ) but not White adults (HR=1.16, 95% CI=1.00-1.34, P =0.057; P for interaction=0.019). Gluconic acid mediated 25.4% (95% CI=4.1%-46.8%, P =0.02) of the association between hypertension and ischemic stroke among Black adults. Specific lifestyle factors were linked to elevated gluconic acid level among Black adults in multivariable analysis, including a Southern diet (β=0.18, 95% CI=0.08-0.28, P &lt;0.001), lower educational attainment (β=0.45, 95% CI=0.19-0.72, P =0.001), and lack of exercise (β=0.26, 95% CI=0.01-0.51, P =0.045). Conclusions: Gluconic acid is a lifestyle-related biomarker that is associated with prevalent hypertension, incident ischemic stroke, and mediates the relationship between hypertension and ischemic stroke in Black adults. Key factors linked to gluconic acid include Southern diet, low educational attainment, and low physical activity.

Influenza Vaccination and Risk of Ischemic Stroke: A Population-Based Case-Control Study.

To assess the relationship between influenza vaccination in the general population and risk of a first ischemic stroke (IS) during pre-epidemic, epidemic, and postepidemic periods. A nested case-control study was conducted in a Spanish primary care database over 2001-2015. Individuals aged 40-99 years with at least 1 year registry and no history of stroke or cancer were selected to conform the source cohort, from which incident IS cases were identified and classified as cardioembolic or noncardioembolic. Five controls per case were randomly selected, individually matched with cases for exact age, sex, and date of stroke diagnosis (index date). A patient was considered vaccinated when he/she had a recorded influenza vaccination at least 14 days before the index date within the same season. Adjusted odds ratios (aORs) and their respective 95% CIs were computed through a conditional logistic regression. Pneumococcal vaccination was used as a negative control. From a cohort of 3,757,621 patients, we selected 14,322 incident IS cases (9,542 noncardioembolic and 4,780 cardioembolic) and 71,610 matched controls. Of them, 41.4% and 40.5%, respectively, were vaccinated yielding a crude OR of 1.05 (95% CI 1.01-1.10). Vaccinated patients presented a higher prevalence of vascular risk factors, diseases, and comedication than those nonvaccinated, and after full adjustment, the association of influenza vaccination with IS yielded an aOR of 0.88 (95% CI 0.84-0.92), appearing early (aOR15-30 days 0.79; 95% CI 0.69-0.92) and slightly declining over time (aOR>150 days 0.92; 95% CI 0.87-0.98). A reduced risk of similar magnitude was observed with both types of IS, in the 3 epidemic periods, and in all subgroups analyzed (men, women, individuals younger and older than 65 years of age, and those with intermediate and high vascular risk). By contrast, pneumococcal vaccination was not associated with a reduced risk of IS (aOR 1.08; 95% CI 1.04-1.13). Results are compatible with a moderate protective effect of influenza vaccine on IS appearing early after vaccination. The finding that a reduced risk was also observed in pre-epidemic periods suggests that either the "protection" is not totally linked to prevention of influenza infection or it may be partly explained by unmeasured confounding factors.

Associations of plasma carnitine, lysine, trimethyllysine and glycine with incident ischemic stroke: Findings from a nested case-control study

Carnitine biosynthesis has been related to fatty acid oxidation, a process probably exerting neuroprotective effects. However, the role of carnitine biosynthesis in the development of ischemic stroke (IS) remains unclear. We aimed to examine the associations between plasma markers of carnitine biosynthesis and the IS risk. We performed a case-control study nested in a community-based cohort (2013-2018, n=16457). The study included 321 incident cases of IS and 321 controls matched by age and gender. Carnitine, lysine, trimethyllysine (TML), glycine, and their ratios were measured/calculated in the baseline plasma samples using ultra-high performance liquid chromatography-tandem mass-spectrometry (UHPLC-MS/MS). Conditional logistic regression analyses were used to calculate odds ratios (ORs) and their 95% confidence intervals (CIs). Plasma carnitine, lysine, TML, and glycine were not significantly associated with the IS risk, although a gradually reduced risk was observed across the increasing tertiles of glycine. Notably, the ratios of glycine/carnitine, glycine/lysine, and glycine/TML were all inversely associated with the IS risk. Compared to the lowest tertiles, the corresponding odds ratios for the highest tertiles were 0.60 (95% CI: 0.40-0.91), 0.63 (95% CI: 0.42-0.94), and 0.63 (95% CI: 0.42-0.95), respectively, after adjustment for body mass index, smoking, hypertension, family history of stroke, estimated glomerular filtration rate and total cholesterol. Repeating the analyses by excluding the first two years of follow-up did not materially alter the risk associations for the ratios of glycine/lysine and glycine/carnitine. Increased ratios of plasma glycine to carnitine, lysine, and TML were associated with a lower risk of incident IS. Our observational findings suggest that the homeostasis of circulating carnitine, lysine, TML, and glycine may involve in the pathogenesis of IS.

Association Between Change in Leisure-Time Physical Activity During the Postretirement Period and Incident Stroke.

To investigate the association of change in leisure-time physical activity (LTPA) occurring during the postretirement period with incident stroke. The current study enrolled 12,644 retired workers from the Dongfeng-Tongji cohort from April to October 2013. The change in LTPA was categorized as follows, according to whether the LTPA time met the WHO recommended minimum (at least 150 minutes per week): (1) stayed inactive at both surveys; (2) stayed inactive at the 2008 survey but became active at the 2013 survey; (3) stayed active at the 2008 survey but became inactive at the 2013 survey; (4) stayed active at both surveys. We used multivariable-adjusted Cox proportional hazards regression models to examine the association between change in LTPA and the risk of incident stroke. During 70,437 person-years of follow-up, we documented 549 incident stroke cases, including 434 incident ischemic stroke cases and 115 incident hemorrhagic stroke (HS) cases. Compared with participants who stayed active at both the 2008 and 2013 surveys, those who were active at the 2008 survey but became inactive at the 2013 survey had significantly higher risks of incident total stroke (hazard ratio [HR] 1.30, 95% CI 1.03, 1.65) and HS (HR 2.34, 95% CI 1.51, 3.63). When stratified by body mass index (BMI) categories, a significant elevated risk of total stroke was seen among overweight participants who stayed active at the 2008 survey but became inactive at the 2013 survey (HR 1.65, 95% CI 1.20, 2.27). The risk of incident stroke decreased with increasing LTPA levels between the 2 surveys (HR of per 150 min/wk increase of LTPA: HR 0.97, 95% CI 0.94, 1.00). In addition, we found that compared with participants who maintained their BMI and stayed active at both the 2008 and 2013 surveys, those who were inactive at both points or who became inactive had higher risks of stroke (HR 2.13, 95% CI 1.09, 4.15; HR 1.50, 95% CI 1.07, 2.08, respectively). Among Chinese older adults, increasing LTPA levels during the postretirement period was associated with a lower risk of incident stroke. Retired individuals should be encouraged to participate in LTPA more frequently to lessen future risk of incident stroke.

Per- and Polyfluoroalkyl Substances and Risk of Myocardial Infarction and Stroke: A Nested Case-Control Study in Sweden.

Background:Per- and polyfluoroalkyl substances (PFAS) are widespread and persistent pollutants that have been associated with elevated cholesterol levels. However, data on incident cardiovascular disease (CVD) is lacking.Objectives:We investigated the association of exposure to PFAS with risk of myocardial infarction and stroke and, subsidiary, with baseline blood lipids.Methods:This population-based nested case–control study included first incident myocardial infarction and stroke cases with matched controls from two Swedish cohorts: the Swedish Mammography Cohort-Clinical (SMC-C) and the Cohort of 60-year-olds (60YO). Baseline blood sampling occurred during 2003–2009 and 1997–1999 with follow-up through 2017 and 2014 for the SMC-C and the 60YO, respectively. Eight plasma PFAS concentrations were measured using targeted liquid chromatography–triple quadrupole mass spectrometry. Five of these were quantifiable in both cohorts; individual values and their standardized sum were categorized into tertiles based on the controls. First incident myocardial infarction () and ischemic stroke () cases were ascertained via linkage to the National Inpatient Register and the Cause of Death Register. Controls were randomly selected from each cohort after matching for age, sex, and sample date. Baseline blood lipids were measured in plasma or serum after overnight fasting.Results:Among the 1,528 case–control subjects, the mean (standard deviation) age was 66 (7.7) y and 67% of them were women. In multivariable-adjusted analyses, the third tertile of the standardized sum of five PFAS associated with higher cholesterol and lower triglyceride levels among controls at baseline (). The corresponding results were [95% confidence interval (CI): 0.53, 0.93] for CVD, 0.60 (95% CI: 0.39, 0.92) for myocardial infarction, and 0.83 (95% CI: 0.46, 1.50) for stroke.Discussion:This study indicated that exposure to PFAS, although associated with increased cholesterol levels, did not associate with an increased risk of myocardial infarction, stroke, or their composite end point. The findings improve our knowledge on potential health effects of environmental contaminants in the CVD context. https://doi.org/10.1289/EHP9791

Risk of ischaemic stroke among new users of glucosamine and chondroitin sulphate: a nested case-control study.

Background:Several studies have reported that the use of chondroitin sulphate (CS) and glucosamine may reduce the risk of acute myocardial infarction. Although it is thought that this potential benefit could be extended to ischaemic stroke (IS), the evidence is scarce.Objective:To test the hypothesis that the use of prescription glucosamine or CS reduces the risk of IS.Design:Case–control study nested in an open cohort.Methods:Patients aged 40–99 years registered in a Spanish primary healthcare database (BIFAP) during the 2002–2015 study period. From this cohort, we identified incident cases of IS, applying a case-finding algorithm and specific validation procedures, and randomly sampled five controls per case, individually matched with cases by exact age, gender and index date. Adjusted odds ratios (AORs) and 95% confidence interval (CI) were computed through a conditional logistic regression. Only new users of glucosamine or CS were considered.Results:A total of 13,952 incident cases of IS and 69,199 controls were included. Of them, 106 cases (0.76%) and 803 controls (1.16%) were current users of glucosamine or CS at index date, yielding an AOR of 0.66 (95% CI: 0.54–0.82) (for glucosamine, AOR: 0.55; 95% CI: 0.39–0.77; and for CS, AOR: 0.77; 95% CI: 0.60–0.99). The reduced risk among current users was observed in both sexes (men, AOR: 0.69; 95% CI: 0.49–0.98; women, AOR: 0.65; 95% CI: 0.50–0.85), in individuals above and below 70 years of age (AOR: 0.69; 95% CI: 0.53–0.89 and AOR: 0.59; 95% CI: 0.41–0.85, respectively), in individuals with vascular risk factors (AOR: 0.53; 95% CI: 0.39–0.74) and among current/recent users of nonsteroidal anti-inflammatory drugs (NSAIDs) (AOR: 0.71; 95% CI: 0.55–0.92). Regarding duration, the reduced risk was observed in short-term users (<365 days, AOR: 0.61; 95% CI: 0.48–0.78) while faded and became nonsignificant in long-term users (>364 days AOR: 0.86; 95% CI: 0.57–1.31).Conclusions:Our results support a protective effect of prescription CS and glucosamine in IS, which was observed even in patients at vascular risk.Mini abstractOur aim was to analyse whether the use of glucosamine or chondroitin sulphate (CS) reduces the risk of ischaemic stroke (IS). We detected a significant decrease.

Serum Zinc Levels and Incidence of Ischemic Stroke: The Reasons for Geographic and Racial Differences in Stroke Study.

Despite zinc's role as an antioxidant and anti-inflammatory agent, prospective studies relating zinc levels to ischemic stroke risk are lacking. To examine the association between serum zinc levels and incidence of ischemic stroke in a US population. Using a case-cohort study nested within the Reasons for Geographic and Racial Differences in Stroke cohort, participants were randomly selected from the Reasons for Geographic and Racial Differences in Stroke cohort to generate a sub-cohort (n=2346). All incident ischemic stroke cases as of September 2012 (n=660) were included, with 62 incident cases overlapping in the sub-cohort. Serum zinc levels were measured at baseline. Barlow-weighted Cox's proportional hazards regression models were used to calculate multivariable-adjusted hazard ratios and the corresponding 95% CI of ischemic stroke by serum zinc levels. The median zinc level for the sub-cohort was 121.19 µg/dL (interquartile range, 104.86-140.39 µg/dL). Serum zinc levels were inversely associated with incidence of ischemic stroke after adjustment for potential confounders (quartile 4 versus quartile 1: hazard ratio, 0.78 [95% CI, 0.61-0.98], P=0.03 for trend). When stratified by prespecified factors (sex, race, region), only sex showed a significant modification (P=0.03 for interaction). The inverse association was more pronounced among females (quartile 4 versus quartile 1: hazard ratio, 0.58 [95% CI, 0.41-0.84], P<0.01 for trend) than males (quartile 4 versus quartile 1: hazard ratio, 1.08 [95% CI, 0.78-1.51], P=0.92 for trend). Serum zinc concentration was inversely associated with incidence of ischemic stroke, especially among women, indicating that low zinc levels may be a risk factor for ischemic stroke.

Metabolomic Profiles Associated With Incident Ischemic Stroke.

Women have higher lifetime risk of stroke than men, and metabolic factors seem more strongly associated with stroke for women than men. However, few studies in either men or women have evaluated metabolomic profiles and incident stroke. We applied liquid chromatography-tandem mass spectrometry to measure 519 plasma metabolites in a discovery set of women in the Nurses' Health Study (NHS; 454 incident ischemic stroke cases, 454 controls) with validation in 2 independent, prospective cohorts: Prevención con Dieta Mediterránea (PREDIMED; 118 stroke cases, 791 controls) and Nurses' Health Study 2 (NHS2; 49 ischemic stroke cases, 49 controls). We applied logistic regression models with stroke as the outcome to adjust for multiple risk factors; the false discovery rate was controlled through the q value method. Twenty-three metabolites were significantly associated with incident stroke in NHS after adjustment for traditional risk factors (q < 0.05). Of these, 14 metabolites were available in PREDIMED and 3 were significantly associated with incident stroke: methionine sulfoxide, N6-acetyllysine, and sucrose (q < 0.05). In NHS2, one of the 23 metabolites (glucuronate) was significantly associated with incident stroke (q < 0.05). For all 4 metabolites, higher levels were associated with increased risk. These 4 metabolites were used to create a stroke metabolite score (SMS) in the NHS and tested in PREDIMED. Per unit of standard deviation of SMS, the odds ratio for incident stroke was 4.12 (95% confidence interval [CI] 2.26-7.51) in PREDIMED, after adjustment for risk factors. In PREDIMED, the area under the receiver operating characteristic curve (AUC) for the model including SMS and traditional risk factors was 0.70 (95% CI 0.75-0.79) vs the AUC for the model including the traditional risk factors only of 0.65 (95% CI 0.70-0.75), corresponding to a 5% improvement in risk prediction with SMS (p < 0.005). Metabolites associated with stroke included 2 amino acids, a carboxylic acid, and sucrose. A composite SMS including these metabolites was associated with ischemic stroke and showed improvement in risk prediction beyond traditional risk factors. This study provides Class II evidence that a SMS accurately predicts incident ischemic stroke risk.

Interaction between walkability and fine particulate matter on risk of ischemic stroke: A prospective cohort study in China

Living in walkable neighborhoods has been reported to be associated with a lower risk of cardiovascular disease. Features of walkable neighborhoods, however, may be related to particulate matter with an aerodynamic diameter ≤2.5 μm (PM2.5), which could increase risk of cardiovascular disease. The interaction effect between walkability and PM2.5 on risk of ischemic stroke remains to be elucidated. In this study, we recruited a total of 27,375 participants aged ≥40 years from Yinzhou District, Ningbo, Zhejiang Province, China to investigate the associations of walkability and PM2.5 with risk of ischemic stroke. We used amenity categories and decay functions to evaluate walkability and high-spatiotemporal-resolution land-use regression models to assess PM2.5 concentrations. We used Cox proportional hazards regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). During a median follow-up of 4.08 years, we identified a total of 637 incident cases of ischemic stroke in the entire cohort. Higher walkability was associated with a lower risk of ischemic stroke (quartile, Q4 vs. Q1 walkability: HR = 0.59, 95% CI: 0.47–0.75), whereas PM2.5 was positively associated with risk of ischemic stroke (Q4 vs. Q1 PM2.5: HR = 1.70, 95% CI: 1.29–2.25). Furthermore, we observed a significant interaction between walkability and PM2.5 on risk of ischemic stroke. Walkability was inversely associated with risk of ischemic stroke at lower PM2.5 concentrations, but this association was attenuated with increasing PM2.5 concentrations. Although walkable neighborhoods appear to decrease the risk of ischemic stroke, benefits may be offset by adverse effects of PM2.5 exposure in the most polluted areas. These findings are meaningful for future neighborhood design, air pollution control, and stroke prevention.

Perfluoroalkyl substances and risk of myocardial infarction and stroke

BACKGROUND AND AIM: Perfluoroalkyl substances (PFAS) are widespread persistent pollutants and its exposure in humans relates to elevated cholesterol. However, the potential to impact public health globally by increasing risk of cardiovascular disease remains unexplored. Therefore, we investigated associations of PFAS exposure with risk of myocardial infarction and/or stroke and subsidiary, with baseline blood lipids. METHODS: A nested case-control study with first incident myocardial infarction and stroke and matched controls from two Swedish cohorts (Swedish Mammography Cohort-Clinical and Cohort of 60-year-olds) was used. Baseline blood sampling occurred during 2003-2009 and 1997-1999 with follow-up through 2017 and 2014 for the cohorts, respectively. Eight plasma PFAS´ concentrations were measured using targeted liquid chromatography-triple quadrupole mass spectrometry. Individual values and the standardized sum of five quantifiable PFAS were categorized into tertiles based on the controls. First incident myocardial infarction (n=345) and ischemic stroke (n=354) cases were ascertained via linkage to the National Inpatient Register and the Cause of Death Register. Control individuals, matched for age, sex and sample date, were randomly selected from each cohort. Baseline blood lipids were measured after overnight fasting. RESULTS:We investigated 1528 case-control subjects with mean [SD] age of 66 [7.7] years, 67% women and PFAS levels around or slightly below established benchmark doses. In multivariable-adjusted analyses, the third tertile of the standardized sum of five PFAS associated with higher total cholesterol and lower triglyceride levels amongst controls at baseline (n=631), but not with increased risk of cardiovascular disease (OR=0.70, 95% CI=0.53, 0.93), myocardial infarction (OR=0.60, 95% CI=0.39, 0.92) or stroke (OR=0.83, 95% CI=0.46-1.50). CONCLUSIONS:This study indicated that PFAS exposure, although associated with increased cholesterol levels, did not associate with increased risk of myocardial infarction, stroke or their composite endpoint. The findings improve our knowledge on cardiovascular health effects of environmental factors and suggest disturbances in pathways unrelated to cholesterol. KEYWORDS: Cardiovascular diseases, PFAS, Environmental Epidemiology

Habitual flavonoid intake and ischemic stroke incidence in the Danish Diet, Cancer, and Health Cohort

ABSTRACTBackgroundFlavonoid-rich foods have antiinflammatory, antiatherogenic, and antithrombotic properties that may contribute to a lower risk of ischemic stroke.ObjectivesWe aimed to investigate the relationship between habitual flavonoid consumption and incidence of ischemic stroke in participants from the Danish Diet, Cancer and Health Study.DesignIn this prospective cohort study, 55,169 Danish residents without a prior ischemic stroke [median (IQR) age at enrolment of 56 y (52–60)], were followed for 21 y (20–22). We used Phenol-Explorer to estimate flavonoid intake from food frequency questionnaires obtained at study entry. Incident cases of ischemic stroke were identified from Danish nationwide registries and restricted cubic splines in Cox proportional hazards models were used to investigate relationships with flavonoid intake.ResultsDuring follow-up, 4237 individuals experienced an ischemic stroke. Compared with participants in Q1 and after multivariable adjustment for demographics and lifestyle factors, those in Q5—for intake of total flavonoids, flavonols, and flavanol oligo + polymers—had a 12% [HR (95% CI): 0.88 (0.81, 0.96)], 10% [0.90 (0.82, 0.98)], and 18% [0.82 (0.75, 0.89)] lower risk of ischemic stroke incidence, respectively. Multivariable (demographic and lifestyle) adjusted associations for anthocyanins and flavones with risk of ischemic stroke were not linear, with moderate but not higher intakes associated with lower risk [anthocyanins Q3 vs. Q1 HR (95% CI): 0.85 (0.79, 0.93); flavones: 0.90 (0.84, 0.97)]. Following additional adjustment for dietary confounders, similar point estimates were observed; however, significance was only retained for anthocyanins and flavanol oligo + polymers [anthocyanins Q3 vs. Q1 HR (95% CI): 0.86 (0.79, 0.94); flavanol oligo + polymers Q5 vs. Q1 0.86 (0.78, 0.94)].ConclusionsThese findings suggest that moderate habitual consumption of healthy flavonoid-rich foods is associated with a lower risk of ischemic stroke and further investigation is therefore warranted.

Mortality of major cardiovascular emergencies among patients admitted to hospitals on weekends as compared with weekdays in Taiwan

BackgroundSeveral studies have found a so-called weekend effect that patients admitted at the weekends had worse clinical outcomes than patients admitted at the weekdays. We performed this retrospective cohort study to explore the weekend effect in four major cardiovascular emergencies in Taiwan.MethodsThe Taiwan National Health Insurance (NHI) claims database between 2005 and 2015 was used. We extracted 3811 incident cases of ruptured aortic aneurysm, 184,769 incident cases of acute myocardial infarction, 492,127 incident cases of ischemic stroke, and 15,033 incident cases of pulmonary embolism from 9,529,049 patients having at least one record of hospitalization in the NHI claims database within 2006 ~ 2014. Patients were classified as weekends or weekdays admission groups. Dates of in-hospital mortality and one-year mortality were obtained from the Taiwan National Death Registry.ResultsWe found no difference in in-hospital mortality between weekend group and weekday group in patients with ruptured aortic aneurysm (45.4% vs 45.3%, adjusted odds ratio [OR] 1.01, 95% confidence interval [CI] 0.87–1.17, p = 0.93), patients with acute myocardial infarction (15.8% vs 16.2%, adjusted OR 0.98, 95% CI 0.95–1.00, p = 0.10), patients with ischemic stroke (4.1% vs 4.2%, adjusted OR 0.99, 95% CI 0.96–1.03, p = 0.71), and patients with pulmonary embolism (14.6% vs 14.6%, adjusted OR 1.02, 95% CI 0.92–1.15, p = 0.66). The results remained for 1 year in all the four major cardiovascular emergencies.ConclusionsWe found no difference in either short-term or long-term mortality between patients admitted on weekends and patients admitted on weekdays in four major cardiovascular emergencies in Taiwan.

Abstract P590: Serum Zinc Levels and Incidence of Ischemic Stroke: The Reasons for Geographic and Racial Differences in Stroke Study

Background and Purpose: Despite zinc’s role as an anti-oxidant and anti-inflammatory agent, prospective studies relating zinc levels to ischemic stroke risk are lacking. We aimed to examine the association between serum zinc levels and incidence of ischemic stroke in a US population. Methods: Using a case-cohort study nested within the REGARDS (REasons for Geographic and Racial Differences in Stroke) cohort, participants were randomly selected from the REGARDS cohort to generate a sub-cohort ( n= 2,346). All incident ischemic stroke cases as of September 2012 ( n =660) were included, with 62 incident cases overlapping in the sub-cohort. Serum zinc levels were measured at baseline. Barlow-weighted Cox’s proportional hazards regression models were used to calculate multivariable-adjusted hazard ratios (HR) and the corresponding 95% confidence intervals (CI) of ischemic stroke by serum zinc levels. Results: The median zinc level for the sub-cohort was 121.19 μg/dL (interquartile range 104.86 to 140.39 μg/dL). Serum zinc levels were inversely associated with incidence of ischemic stroke after adjustment for potential confounders (quartile 4 vs. quartile 1: HR=0.78, 95% CI: 0.61-0.98, p=0.03 for trend). When stratified by pre-specified factors (sex, race, region), only sex showed a significant modification (p=0.03 for interaction). The inverse association was more pronounced among females (quartile 4 vs. quartile 1: HR=0.58, 95% CI: 0.41-0.84, p&lt;0.01 for trend) than males (quartile 4 vs. quartile 1: HR=1.08, 95% CI: 0.78-1.51, p=0.92 for trend). Conclusions: Serum zinc concentration was inversely associated with incidence of ischemic stroke, especially among women, indicating that low zinc levels may be a risk factor for ischemic stroke.

Fetal exposure to the Great Chinese Famine and risk of ischemic stroke in midlife.

Epidemiological studies have reported an association between famine exposure and increased risk of cardiovascular disease. However, it is unclear whether fetal exposure to the Great Chinese Famine of 1959 to 1961 was associated with risk of ischemic stroke in midlife. A total of 17,787 participants of the Kailuan study, who were free of cardiovascular disease and cancer at baseline (2006) were enrolled in the study. All participants were divided into three groups: unexposed (born between 1 October 1962 and 30 September 1964, used as the reference group in current analyses), fetal exposure (born between 1 October 1959 and 30 September 1961), and early childhood exposure (born between 1 October 1956 and 30 September 1958). Incident ischemic stroke cases between 2006 and 2017 were confirmed by review of medical records. Cox proportional hazards regression was applied to analyze the effect of fetal famine exposure on ischemic stroke risk. During the mean (10.4±2.2) years of follow-up, 547 incident ischemic stroke cases were identified. After adjustment for potential confounders, the hazard ratio (HR) for ischemic stroke was 1.45, and the 95% confidence interval (CI) was 1.14, 1.84 for fetal famine-exposed compared with unexposed individuals. Similar associations were observed in men (adjusted HR: 1.40; 95% CI: 1.08, 1.80) and overweight individuals (adjusted HR: 1.56; 95% CI: 1.18, 2.07), but not in their counterparts. The results of the early childhood-exposed group were similar to the above. Our findings support an association between fetal malnutrition and higher risk of ischemic stroke in adulthood.