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Background and Purpose: Studies of carotid artery disease have suggested that high-grade stenosis can affect cognition, even without stroke. The presence and degree of cognitive impairment in such patients have not been reported and compared with a demographically matched population-based cohort. Methods: We studied cognition in 1000 consecutive CREST-2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) patients, a treatment trial for asymptomatic carotid disease. Cognitive assessment was after randomization but before assigned treatment. The cognitive battery was developed in the general population REGARDS Study (Reasons for Geographic and Racial Differences in Stroke), involving Word List Learning Sum, Word List Recall, and Word List fluency for animal names and the letter F. The carotid stenosis patients were >45 years old with ≥70% asymptomatic carotid stenosis and no history of prevalent stroke. The distribution of cognitive performance for the patients was standardized, accounting for age, race, and education using performance from REGARDS, and after further adjustment for hypertension, diabetes, dyslipidemia, and smoking. Using the Wald Test, we tabulated the proportion of Z scores less than the anticipated deviate for the population-based cohort for representative percentiles. Results: There were 786 baseline assessments. Mean age was 70 years, 58% men, and 52% right-sided stenosis. The overall Z score for patients was significantly below expected for higher percentiles ( P P =0.015). Lower performance was attributed largely to Word List Recall ( P P ≤0.01). The scores for left versus right carotid disease were similar. Conclusions: Baseline cognition of patients with severe carotid stenosis showed below normal cognition compared to the population-based cohort, controlling for demographic and cardiovascular risk factors. This cohort represents the largest group to date to demonstrate that poorer cognition, especially memory, in this disease. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02089217.

Background and ObjectivesWomen have been underrepresented in cardiovascular disease clinical trials but there is less certainty over the level of disparity specifically in stroke. We examined the participation of women in trials according to stroke prevalence in the population.MethodsPublished randomized controlled trials with ≥100 participants enrolled between 1990 and 2020 were identified from ClinicalTrials.gov. To quantify sex disparities in enrollment, we calculated the participation to prevalence ratio (PPR), defined as the percentage of women participating in a trial vs the prevalence of women in the disease population.ResultsThere were 281 stroke trials eligible for analyses with a total of 588,887 participants, of whom 37.4% were women. Overall, women were represented at a lower proportion relative to their prevalence in the underlying population (mean PPR 0.84; 95% confidence interval [CI] 0.81–0.87). The greatest differences were observed in trials of intracerebral hemorrhage (PPR 0.73; 95% CI 0.71–0.74), trials with a mean age of participants p for trend = 0.201).DiscussionWomen are disproportionately underrepresented in stroke trials relative to the burden of disease in the population. Clear guidance and effective implementation strategies are required to improve the inclusion of women and thus broader knowledge of the impact of interventions in clinical trials.

INTRODUCTION Television (TV) viewing may be associated with increased venous thromboembolism (VTE) risk independent of VTE risk factors including physical activity. This association was assessed in a large biracial US cohort of Black and White adults. METHODS Between 2003 and 2007 The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study recruited 30,239 participants aged ≥45 years, who were surveyed for baseline TV viewing and followed for VTE events. TV viewing was categorized as

ObjectiveTo investigate sex and race differences in the association between fasting blood glucose (FBG) and risk of ischemic stroke (IS).MethodsThis prospective longitudinal cohort study included adults age ≥45 years at baseline in the Reasons for Geographic And Racial Differences in Stroke Study, followed for a median of 11.4 years. The exposure was baseline FBG (mg/dL); suspected IS events were ascertained by phone every 6 months and were physician-adjudicated. Cox proportional hazards were used to assess the adjusted sex/race-specific associations between FBG (by category and as a restricted cubic spline) and incident IS.ResultsOf 20,338 participants, mean age was 64.5 (SD 9.3) years, 38.7% were Black, 55.4% were women, 16.2% were using diabetes medications, and 954 IS events occurred. Compared to FBG pFBG×race/sex = 0.004). Analyses using FBG splines suggest that sex was the major contributor to differences by race/sex subgroups.ConclusionsSex differences in the strength and shape of the association between FBG and IS are likely driving the significant differences in the association between FBG and IS across race/sex subgroups. These findings should be explored further and may inform tailored stroke prevention guidelines.

ObjectiveTo test the hypothesis that silent myocardial infarction (MI) is a risk factor for ischemic stroke, we evaluated the association between silent MI and subsequent ischemic stroke in the Cardiovascular Health Study.MethodsThe Cardiovascular Health Study prospectively enrolled community-dwelling individuals ≥65 years of age. We included participants without prevalent stroke or baseline evidence of MI. Our exposures were silent and clinically apparent, overt MI. Silent MI was defined as new evidence of Q-wave MI, without clinical symptoms of MI, on ECGs performed during annual study visits from 1989 to 1999. The primary outcome was incident ischemic stroke. Secondary outcomes were ischemic stroke subtypes: nonlacunar, lacunar, and other/unknown. Cox proportional hazards analysis was used to model the association between time-varying MI status (silent, overt, or no MI) and stroke after adjustment for baseline demographics and vascular risk factors.ResultsAmong 4,224 participants, 362 (8.6%) had an incident silent MI, 421 (10.0%) an incident overt MI, and 377 (8.9%) an incident ischemic stroke during a median follow-up of 9.8 years. After adjustment for demographics and comorbidities, silent MI was independently associated with subsequent ischemic stroke (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.03–2.21). Overt MI was associated with ischemic stroke both in the short term (HR, 80; 95% CI, 53–119) and long term (HR, 1.60; 95% CI, 1.04–2.44). In secondary analyses, the association between silent MI and stroke was limited to nonlacunar ischemic stroke (HR, 2.40; 95% CI, 1.36–4.22).ConclusionIn a community-based sample, we found an association between silent MI and ischemic stroke.

Background and Purpose: CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial) reported a higher periprocedural risk for any stroke, death, or myocardial infarction for women randomized to carotid artery stenting (CAS) compared with women randomized to carotid endarterectomy (CEA). No difference in risk by treatment was detected for women relative to men in the 4-year primary outcome. We aimed to conduct a pooled analysis among symptomatic patients in large randomized trials to provide more precise estimates of sex differences in the CAS-to-CEA risk for any stroke or death during the 120-day periprocedural period and ipsilateral stroke thereafter. Methods: Data from the Carotid Stenosis Trialists’ Collaboration included outcomes from symptomatic patients in EVA-3S (Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis), SPACE (Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients), ICSS (International Carotid Stenting Study), and CREST. The primary outcome was any stroke or death within 120 days after randomization and ipsilateral stroke thereafter. Event rates and relative risks were estimated using Poisson regression; effect modification by sex was assessed with a sex-by-treatment-by-trial interaction term, with significant interaction defined a priori as P ≤0.10. Results: Over a median 2.7 years of follow-up, 433 outcomes occurred in 3317 men and 1437 women. The CAS-to-CEA relative risk of the primary outcome was significantly lower for women compared with men in 1 trial, nominally lower in another, and nominally higher in the other two. The sex-by-treatment-by-trial interaction term was significant ( P =0.065), indicating heterogeneity among trials. Contributors to this heterogeneity are primarily differences in periprocedural period. When the trials are nevertheless pooled, there were no significant sex differences in risk in any follow-up period. Conclusions: There were significant differences between trials in the magnitude of sex differences in treatment effect (CAS-to-CEA relative risk), indicating pooling data from these trials to estimate sex differences might not be valid. Whether sex is acting as an effect modifier of the CAS-to-CEA treatment effect in symptomatic patients remains uncertain. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00190398 (EVA-3S) and NCT00004732 (CREST). URL: https://www.isrctn.com ; Unique identifier: ISRCTN57874028 (SPACE) and ISRCTN25337470 (ICSS).

The tridecapeptide neurotensin has been implicated in the pathogenesis of cardiometabolic disease. Its stable precursor, pro-neurotensin/neuromedin N (pro-NT/NMN), has been associated with composite cardiovascular outcomes including coronary heart disease (CHD) and stroke. The exclusive association of pro-NT/NMN with ischemic stroke has not been evaluated. We conducted a prospective case-cohort study in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. From 2003 to 2007, REGARDS enrolled 30,239 white or black adults aged ⩾ 45 years. Baseline fasting pro-NT/NMN was measured by immunoassay in the analytic sample including 448 incident ischemic stroke cases and 818 random cohort sample participants. A total of 464 ischemic strokes occurred. Risk of stroke was assessed with a Cox proportional-hazards model incorporating demographic covariates and a second adding stroke risk factors. Increased pro-NT/NMN was associated with ischemic stroke in the demographic model overall (hazard ratio (HR) per standard deviation (SD) pro-NT/NMN 1.16, 95% confidence interval (CI) 1.01–1.33) and in men (HR per SD pro-NT/NMN 1.25, 95% CI 1.04–1.50); HRs were attenuated in the risk factor model. Pre-existing diabetes mellitus and CHD were the largest confounders of ischemic stroke risk, each accounting for an estimated 19% of the association of pro-NT/NMN with ischemic stroke observed in the demographic model. There were no significant interactions of race or sex with pro-NT/NMN. Further research on associations of pro-NT/NMN with stroke risk factors such as diabetes mellitus is indicated.

Background: Hypertension awareness, treatment, and control programs were initiated in the United States during the 1960s and 1970s. Whereas blood pressure (BP) control in the population and subsequent reduced hypertension-related disease risks have improved since the implementation of these interventions, it is unclear whether these BP changes can be generalized to diverse and high-risk populations. This report describes the 4-decade change in BP levels for the population in a high disease risk southeastern region of the United States. The objective is to determine the magnitude of the shift in systolic BP (SBP) among Blacks and Whites from the Southeast between 1960 and 2005 with the assessment of the unique population cohorts. Methods: A multicohort study design compared BPs from the CHS (Charleston Heart Study) and ECHS (Evans County Heart Study) in 1960 and the REGARDS study (Reasons for Geographic and Racial Differences in Stroke) 4 decades later. The analyses included participants ≥45 years of age from CHS (n=1323), ECHS (n=1842), and REGARDS (n=6294) with the main outcome of SBP distribution. Results: Among Whites 45 to 54 years of age, the median SBP was 18 mm Hg (95% CI, 16–21 mm Hg) lower in 2005 than 1960. The median shift was a 45 mm Hg (95% CI, 37–51 mm Hg) decline for those ≥75 years of age. The shift was larger for Blacks, with median declines of 38 mm Hg (95% CI, 32–40 mm Hg) at 45 to 54 years of age and 50 mm Hg (95% CI, 33–60 mm Hg) for ages ≥75 years. The 95th percentile of SBP decreased 60 mm Hg for Whites and 70 mm Hg for Blacks. Conclusions: The results of the current analyses of the unique cohorts in the Southeast confirm the improvements in population SBP levels since 1960. This assessment provides new evidence of improvement in SBP, suggesting that strategies and programs implemented to improve hypertension treatment and control have been extraordinarily successful for both Blacks and Whites residing in a high-risk region of the United States. Severe BP elevations commonly observed in the 1960s have been nearly eliminated, with the current 75th percentile of BP generally less than the 25th percentile of BP in 1960.

Background The neuropeptide neurotensin (NT) has been linked to cardiometabolic disease. Cardiovascular risk factors are being recognized as risk factors for cognitive impairment. Objective To examine the association of the stable precursor of NT, pro-neurotensin/neuromedin N (pro-NT/NMN), with incident cognitive impairment (ICI). Methods We conducted a prospective nested case-control study in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. In 2003-2007, REGARDS enrolled 30,239 Black and White adults aged ≥45 years. ICI was identified using a 3-test cognitive battery administered biannually. Baseline pro-NT/NMN was measured by immunoassay in 393 cases of ICI and 490 controls after 3.4 years follow up. Multivariable logistic regression was used to calculate odds ratios (OR) of ICI by pro-NT/NMN quartiles. Race, age, and sex differences were studied with stratified models and interaction testing. Results Pro-NT/NMN was higher in Black participants and those with hypertension and diabetes. Women with a 4th versus 1st-quartile pro-NT/NMN had 2.28-fold increased odds of ICI (95% CI 1.08-4.78) after adjusting for risk factors and incident stroke. There was no association of higher pro-NT/NMN quartiles with ICI in the overall group or men. There were no race or age differences in associations. Conclusion In this biracial population-based study, elevated systemic pro-NT/NMN was associated with more than doubled risk of ICI in women but not men. Others reported sex-specific associations in women for cardiovascular mortality and diabetes with higher pro-NT/NMN, supporting a role for future research on sex differences in the neurotensinergic system.

Objective:The current study aims to describe the Mediterranean diet (MD) adherence across the US regions, and explore the predictive factors of MD adherence among US adults.Design:Cross-sectional secondary data analysis. MD adherence score (0–9) was calculated using the Block 98 FFQ. Hot spot analysis was conducted to describe the geospatial distribution of MD adherence across the US regions. Logistic regression explored predictors of MD adherence.Setting:Nationwide community-dwelling residency in the USA.Participants:Adults aged ≥45 years (n20 897) who participated in the REasons for Geographic and Racial Differences in Stroke study and completed baseline assessment during January 2003 and October 2007.Results:The mean of MD adherence score was 4·36 (sd1·70), and 46·5 % of the sample had high MD adherence (score 5–9). Higher MD adherence clusters were primarily located in the western and northeastern coastal areas of the USA, whereas lower MD adherence clusters were majorly observed in south and east-north-central regions. Being older, black, not a current smoker, having a college degree or above, an annual household income ≥ $US 75K, exercising ≥4 times/week and watching TV/video Conclusions:There were significant geospatial and population disparities in MD adherence across the US regions. Future studies are needed to explore the causes of MD adherence disparities and develop effective interventions for MD promotion in the USA.

Background and Purpose: Social determinants of health (SDOH) have been previously associated with incident stroke. Although SDOH often cluster within individuals, few studies have examined associations between incident stroke and multiple SDOH within the same individual. The objective was to determine the individual and cumulative effects of SDOH on incident stroke. Methods: This study included 27 813 participants from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study, a national, representative, prospective cohort of black and white adults aged ≥45 years. SDOH was the primary exposure. The main outcome was expert adjudicated incident stroke. Cox proportional hazards models examined associations between incident stroke and SDOH, individually and as a count of SDOH, adjusting for potential confounders. Results: The mean age was 64.7 years (SD 9.4) at baseline; 55.4% were women and 40.4% were blacks. Over a median follow-up of 9.5 years (IQR, 6.0–11.5), we observed 1470 incident stroke events. Of 10 candidate SDOH, 7 were associated with stroke ( P Conclusions: Incremental increases in the number of SDOH were independently associated with higher incident stroke risk in adults aged

Background N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), a commonly used clinical marker of cardiac function, is associated with the presence of stroke symptoms and is a strong risk factor for future atrial fibrillation, stroke, and all‐cause mortality. Few data are available on the association between NT‐proBNP levels and stroke recurrence. Objective We studied the relationship between NT‐proBNP and risk of future ischemic stroke across the continuum of preexisting cerebrovascular conditions: asymptomatic, prior stroke symptoms, prior transient ischemic attack (TIA), and prior stroke. Methods The Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort enrolled 30,239 black and white Americans aged 45 years and older from 2003 to 2007. With 5.4 years follow‐up, baseline NT‐proBNP was measured in 892 participants who developed ischemic stroke and a 4328‐person cohort random sample. Hazard ratios of stroke by baseline NT‐proBNP were calculated in groups based on the presence of prebaseline cerebrovascular conditions. Results In the fully adjusted model, elevated NT‐proBNP was associated with stroke risk in participants without a preexisting cerebrovascular condition (hazard ratio [HR], 2.32; 95% confidence interval [CI], 1.84‐2.94) and in participants with a history of stroke symptoms (HR, 1.67; 95% CI, 1.01‐2.78) or transient ischemic attack (HR, 2.66; 95% CI, 1.00‐7.04) but not among those with prior stroke (HR, 1.26; 95% CI, 0.71‐2.21). Conclusions These findings support the potential for NT‐proBNP testing to identify people who are at highest risk for future stroke.

Patients with hypertension who develop atrial premature complexes (APCs) are at a particularly high risk for atrial fibrillation (AF). We sought to identify medications and modifiable risk factors that could reduce the risk of AF imposed by presence of APCs in such a high risk group. This analysis included 4,331 participants with treated hypertension from the Reasons for Geographic and Racial Differences in Stroke study who were free of AF and cardiovascular disease at the time of enrollment (2003-2007). APCs were detected in 8.2% (n = 356) of the participants at baseline. During a median follow-up of 9.4 years, 9.9% (n = 429) of the participants developed AF. Participants with APCs, compared with those without, were more than twice as likely to develop AF (Odds ratio [95% confidence interval]: 2.36[1.75, 3.19]). This association was significantly weaker in statin users than nonusers (Odds ratio [95% confidence interval]:1.42[0.81,2.48] vs 3.01[2.11,4.32], respectively; interaction p-value = 0.02), and in angiotensin-II receptor blocker users than nonusers (Odds ratio [95% confidence interval]:1.31[0.66,2.61] vs 2.78[1.99,3.89], respectively; interaction p-value = 0.05). Borderline weaker associations between APCs and AF were also observed in alpha-blocker users than nonusers, nondiabetics than diabetics, and in those with systolic blood pressure level 130 to 139 mm Hg compared with those with other systolic blood pressure levels. No significant effect modifications were observed by use of other medications or by presence of other cardiovascular risk factors. In conclusion, the significant AF risk associated with APCs in patients with hypertension could potentially be reduced by treatment with angiotensin-II receptor blockers and statins along with lowering blood pressure and management of diabetes.

Background and Purpose— In previous studies, isolated nonspecific ST-segment and T-wave abnormalities (NSSTTAs), a common finding on ECGs, were associated with greater risk for incident coronary artery disease. Their association with incident stroke remains unclear. Methods— The REGARDS (Reasons for Geographic and Racial Differences in Stroke) study is a population-based, longitudinal study of 30 239 white and black adults enrolled from 2003 to 2007 in the United States. NSSTTAs were defined from baseline ECG using the standards of Minnesota ECG Classification (Minnesota codes 4-3, 4-4, 5-3, or 5-4). Participants with prior stroke, coronary heart disease, and major and minor ECG abnormalities other than NSSTTAs were excluded from analysis. Multivariable Cox proportional hazards regression was used to examine calculate hazard ratios of incident ischemic stroke by presence of baseline NSSTTAs. Results— Among 14 077 participants, 3111 (22.1%) had NSSTTAs at baseline. With a median of 9.6 years follow-up, 106 (3.4%) with NSSTTAs had ischemic stroke compared with 258 (2.4%) without NSSTTAs. The age-adjusted incidence rates (per 1000 person-years) of stroke were 2.93 in those with NSSTTAs and 2.19 in those without them. Adjusting for baseline age, sex, race, geographic location, and education level, isolated NSSTTAs were associated with a 32% higher risk of ischemic stroke (hazard ratio, 1.32 [95% CI, 1.05–1.67]). With additional adjustment for stroke risk factors, the risk of stroke was increased 27% (hazard ratio, 1.27 [95% CI, 1.00–1.62]) and did not differ by age, race, or sex. Conclusions— Presence of NSSTTAs in persons with an otherwise normal ECG was associated with a 27% increased risk of future ischemic stroke.

Background Data on stroke epidemiology and availability of hospital-based stroke services around the world are important for guiding policy decisions and healthcare planning. Aims To provide the most current incidence, mortality and case–fatality data on stroke and describe current availability of stroke units around the world by country. Methods We searched multiple databases (based on our existing search strategy) to identify new original manuscripts and review articles published between 1 June 2016 and 31 October 2018 that met the ideal criteria for data on stroke incidence and case–fatality. For data on the availability of hospital-based stroke services, we searched PubMed for all literature published up until 31 June 2018. We further screened reference lists, citation history of manuscripts and gray literature for this information. Mortality codes for International Classification of Diseases-9 and International Classification of Diseases-10 were extracted from the World Health Organization mortality database for each country providing these data. Population denominators were obtained from the World Health Organization, and when these were unavailable within a two-year period of mortality data, population denominators within a two-year period were obtained from the United Nations. Using country-specific population denominators and the most recent years of mortality data available for each country, we calculated both the crude mortality from stroke and mortality adjusted to the World Health Organization world population. Results Since our last report in 2017, there were two countries with new incidence studies, China ( n = 1) and India ( n = 2) that met the ideal criteria. New data on case–fatality were found for Estonia and India. The most current mortality data were available for the year 2015 (39 countries), 2016 (43 countries), and 2017 (7 countries). No new data on mortality were available for six countries. Availability of stroke units was noted for 63 countries, and the proportion of patients treated in stroke units was reported for 35/63 countries. Conclusion Up-to-date data on stroke incidence, case–fatality, and mortality statistics provide evidence of variation among countries and changing magnitudes of burden among high and low–middle income countries. Reporting of hospital-based stroke units remains limited and should be encouraged.

Background and Purpose: When reporting primary results from randomized controlled trials, recommendations include reporting results by sex. We reviewed the reporting of results by sex in contemporary acute stroke randomized controlled trials. Methods: We searched MEDLINE for articles reporting the primary results of phase 2 or 3 stroke randomized controlled trials published between 2010 and June 2020 in one of nine major clinical journals. Eligible trials were restricted to those with a therapeutic intervention initiated within one month of stroke onset. Of primary interest was the reporting of results by sex for the primary outcome. We performed bivariate analyses using Fisher exact tests to identify study-level factors associated with reporting by sex and investigated temporal trends using an exact test for trend. Results: Of the 115 studies identified, primary results were reported by sex in 37% (n=42). Reporting varied significantly by journal, with the New England Journal of Medicine (61%) and Lancet journals (40%) having the highest rates ( P =0.03). Reporting also differed significantly by geographic region (21% Europe versus 48% Americas, P =0.03), trial phase (13% phase 2 versus 40% phase 3, P =0.05), and sample size (24% 750 participants, P P =0.11), there was a temporal trend in favor of greater reporting among later publications (25% 2010–2012 versus 48% 2019–2020). Conclusions: Although reporting of primary trial results by sex improved from 2010 to 2020, the prevalence of reporting in major journals is still low. Further efforts are required to encourage journals and authors to comply with current reporting recommendations.

ObjectiveThe purpose of this study was to examine depressive symptoms as a risk factor for incident stroke and determine whether depressive symptomatology was differentially predictive of stroke among Black and White participants.MethodsThe study comprised 9,529 Black and 14,516 White stroke-free participants, aged 45 and older, enrolled in the REasons for Geographic and Racial Differences in Stroke (2003–2007). Incident stroke was the first occurrence of stroke. Association between baseline depressive symptoms (assessed via the 4-item Center for Epidemiologic Studies Depression Scale [CES-D-4]: 0, 1–3, or ≥4) and incident stroke was analyzed with Cox proportional hazards models adjusted for demographics, stroke risk factors, and social factors.ResultsThere were 1,262 strokes over an average follow-up of 9.21 (SD 4.0) years. Compared to participants with no depressive symptoms, after demographic adjustment, participants with CES-D-4 scores of 1–3 had 39% increased stroke risk (hazard ratio [HR] = 1.39, 95% confidence interval [CI] = 1.23–1.57), with slight attenuation after full adjustment (HR = 1.27, 95% CI = 1.11–1.43). Participants with CES-D-4 scores of ≥4 experienced 54% higher risk of stroke after demographic adjustment (HR = 1.54, 95% CI = 1.27–1.85), with risk attenuated in the full model similar to risk with 1–3 symptoms (HR = 1.25, 95% CI = 1.03–1.51). There was no evidence of a differential effect by race (p = 0.53).ConclusionsThe association of depressive symptoms with increased stroke risk was similar among a national sample of Black and White participants. These findings suggest that assessment of depressive symptoms should be considered in primary stroke prevention for both Black and White participants.

Background Atrial fibrillation is associated with increased stroke risk; available risk prediction tools have modest accuracy. We hypothesized that circulating stroke risk biomarkers may improve stroke risk prediction in atrial fibrillation. Methods and Results The REGARDS (Reasons for Geographic and Racial Differences in Stroke) study is a prospective cohort study of 30 239 Black and White adults age ≥45 years. A nested study of stroke cases and a random sample of the cohort included 175 participants (63% women, 37% Black adults) with baseline atrial fibrillation and available blood biomarker data. There were 81 ischemic strokes over 5.2 years in these participants. Adjusted for demographics, stroke risk factors, and warfarin use, the following biomarkers were associated with stroke risk (hazard ratio [HR]; 95% CI for upper versus lower tertile): cystatin C (3.16; 1.04–9.58), factor VIII antigen (2.77; 1.03–7.48), interleukin‐6 (9.35; 1.95–44.78), and NT‐proBNP (N‐terminal B‐type natriuretic peptide) (4.21; 1.24–14.29). A multimarker risk score based on the number of blood biomarkers in the highest tertile was developed; adjusted HRs of stroke for 1, 2, and 3+ elevated blood biomarkers, compared with none, were 1.75 (0.57–5.40), 4.97 (1.20–20.5), and 9.51 (2.22–40.8), respectively. Incorporating the multimarker risk score to the CHA 2 DS 2 VASc score resulted in a net reclassification improvement of 0.34 (95% CI, 0.04–0.65). Conclusions Findings in this biracial cohort suggested the possibility of substantial improvement in stroke risk prediction in atrial fibrillation using blood biomarkers or a multimarker risk score.

BACKGROUND AND AIM: Providing care to an older adult with a disability has been associated with increased risk to the caregiver’s health, but most previous studies of caregiving and health compare persons who are already caregivers with poorly matched non-caregiving controls and are often based on convenience samples. In this report, we describe the enrollment of persons who transitioned into a family caregiving role while participating in a national epidemiological study. METHODS: Participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study were asked on two occasions 9-14 years apart if they were providing care on an ongoing basis to a family member with a chronic illness or disability. Those who answered “no” and “yes,” respectively, to this caregiving question and reported sufficient caregiving responsibilities after their transitions were enrolled in the present study as incident caregivers (N = 251). Participants matched on multiple demographic and health history variables and who reported no history of caregiving were enrolled as non-caregiving controls (N = 251). RESULTS: Among eligible participants, 84% agreed to participate, and 47% of caregivers reported caring for a person with dementia. Descriptive analyses confirmed the success of the matching procedures for balancing the groups on multiple demographic and pre-caregiving health variables. Depressive symptoms and perceived stress increased significantly after the transition to caregiving. CONCLUSION: Comparable, population-based samples of incident caregivers and matched non-caregivers have been enrolled. Future analyses will examine within-person changes in health and circulating biomarkers as a function of the transition to caregiving.

Little is known about whether the relationship between hypertension and ischemic stroke differs by sex. We examined sex differences in the association between hypertension severity and treatment and ischemic stroke risk. We used a longitudinal cohort study in the continental United States, with oversampling of black individuals and those living in the stroke belt. We included 26 461 participants recruited from 2003 to 2007 without prevalent stroke at baseline. The main outcome was incident ischemic stroke ascertained by telephone surveillance (with physician adjudication for suspected events). Proportional hazards regression was used to assess the sex-specific association between systolic blood pressure and stroke and between classes of antihypertensive medications and stroke after adjustment for age, race, sex, and age-by-race and sex-by-treatment interaction terms. A priori, P 140 mm Hg) was higher in women (hazard ratio, 1.25; 95% CI, 1.16–1.34) than men (hazard ratio, 1.14; 95% CI, 1.05–1.23; sex–systolic blood pressure interaction term, P =0.09). Compared with no medications, with each additional class of medications, stroke risk increased by 23% (hazard ratio, 1.23; 95% CI, 1.14–1.33) for women and 21% (hazard ratio, 1.21; 95% CI, 1.12–1.31) for men ( P =0.79). Further work on the biological mechanisms for sex differences in stroke risk associated with hypertension severity and a need for sex-specific clinical guidelines may be warranted.

// Tomi Akinyemiju 1 , Justin X. Moore 2 , Daniel Tefera Dibaba 3 , Maria Pisu 4 , Michael Goodman 5 , Virginia J. Howard 6 , Monika Safford 7 , Susan C. Gilchrist 8 , Mary Cushman 9 , LeAnn Long 10 and Suzanne E. Judd 10 1 Department of Population Health Sciences, Duke University School of Medicine, Durham, NC, USA 2 Division of Public Health Sciences and Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA 3 Tennessee Clinical and Translational Science Institute, University of Tennessee Health Science Center, Memphis, TN, USA 4 Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham AL, USA 5 Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA 6 Department of Epidemiology, University of Alabama at Birmingham, Birmingham AL, USA 7 Department of Medicine, Weill Cornell Medical College, New York, NY, USA 8 Department of Clinical Cancer Prevention and Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 9 Department of Medicine and Vermont Cancer Center, Larner College of Medicine at the University of Vermont, Burlington, VT, USA 10 Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA Correspondence to: Tomi Akinyemiju, email: tomi.akinyemiju@duke.edu Keywords: inflammatory biomarkers; racial disparities; cancer mortality; obesity Received: December 12, 2018 Accepted: June 29, 2019 Published: August 06, 2019 ABSTRACT This study examines the association between inflammatory biomarkers and risk of cancer mortality by race. Data were obtained from 1,856 participants in the prospective REGARDS cohort who were cancer-free at baseline, and analyzed in relation to cancer mortality prospectively. Biomarkers were log-transformed and categorized into tertiles due to non-normal distributions, and Cox proportional hazard regression models were utilized to compute hazard ratios with 95% confidence intervals using robust sandwich methods. Individuals in the highest tertile of IL-6 had over a 12-fold increased risk of cancer mortality (HR: 12.97, 95% CI: 3.46–48.63); those in the highest tertile of IL-8 had over a 2-fold increased risk of cancer mortality (HR: 2.21, 95% CI: 0.86–5.71), while those in the highest tertile of IL-10 had over a 3-fold increased risk of cancer mortality (HR: 3.06, 95% CI: 1.35–6.89). In race-stratified analysis, each unit increase in IL-6 was associated with increased risk of cancer mortality among African-Americans (HR: 3.88, 95% CI: 1.17–12.88) and Whites (5.25, 95% CI: 1.24–22.31). If replicated in larger, racially diverse prospective cohorts, these results suggest that cancer patients may benefit from clinical or lifestyle approaches to regulate systemic inflammation as a cancer prevention strategy.

Background Most carotid revascularization studies define asymptomatic as symptom-free for more than 180 days; however, it is unknown if intervention carries similar risk among those currently asymptomatic but with previous symptoms (PS) vs those who were always asymptomatic (AA). Methods We compared the periprocedural and 4-year risks of PS vs AA patients in the Carotid Revascularization Endarterectomy vs Stenting Trial (CREST) randomized to carotid endarterectomy (CEA) or carotid artery stenting (CAS)/angioplasty. Proportional hazards models adjusting for age, sex, and treatment were used to assess the risk of periprocedural stroke and/or death (S+D; any S+D during periprocedural period), stroke and death at 4 years (any S+D within the periprocedural period and ipsilateral stroke out to 4 years) and the primary end point at 4 years (any stroke, death, and myocardial infarction within the periprocedural period and ipsilateral stroke out to 4 years). Analysis was performed pooling the CEA-treated and CAS-treated patients, and separately for each treatment. Results Of 1181 asymptomatic patients randomized in CREST, 1104 (93%) were AA and 77 (7%) were PS. There was no difference in risk when comparing the AA and PS cohorts in the pooled CAS+CEA population for periprocedural S+D (2.0% vs 1.3%), S+D at 4 years (3.6% vs 3.2%), or the primary end point (5.2% vs 5.8%). There were also no differences among those assigned to CEA (periprocedural S+D, 1.5% vs 0%; S+D at 4 years, 2.7% vs 0%; or primary end point, 5.1% vs 2.4%) or CAS (periprocedural S+D, 2.5% vs 2.8%; S+D at 4 years, 4.4% vs 6.9%; or primary end point, 5.3% vs 9.8%) when analyzed separately. Conclusions In CREST, only a small minority of asymptomatic patients had previous ipsilateral symptoms. The outcomes of periprocedural S+D, periprocedural S+D, and ipsilateral stroke up to 4 years, and the primary end point did not differ for AA patients compared with PS patients.

Background Retrospective studies have reported an association between cancer and arterial thromboembolic event (ATE) risk. Objectives We sought to confirm this in a prospective cohort with adjudicated outcomes. Methods We evaluated participants enrolled in the REGARDS (REasons for Geographic and Racial Differences in Stroke) study with Medicare coverage for 365 days before their baseline visit (2003-2007). Medicare claims were used to identify new cancer diagnoses during follow-up. Using incidence-density sampling, participants who developed cancer were matched by age, sex, race, and education 1:4 to control participants who had not developed cancer. Participants were prospectively followed through 2015 for an expert-adjudicated ATE, defined as acute myocardial infarction or ischemic stroke. Cox regression was performed to evaluate the association between incident cancer and subsequent ATE. Results In this analysis, 836 REGARDS participants with incident cancer were matched to 3339 control participants without cancer. In the 30 days after cancer diagnosis, 0.60% (n = 5) of the participants had an ATE; most of these events occurred near the time of cancer diagnosis. After adjustment for demographics, geographic region, and cardiovascular risk factors, compared to the noncancer controls, participants with incident cancer had an increased risk of ATE in the first 30 days after diagnosis (hazard ratio, 5.8; 95% confidence interval, 2.1-15.9). There was no association between cancer diagnosis and ATE beyond 30 days. Cancers with known metastases and types considered high risk for venous thromboembolism had the strongest associations with ATE. Conclusions Incident cancer is associated with an increased short-term risk of ATE independent of vascular risk factors.

Objective: To describe the relationship between metabolic health parameters and depressive symptoms and perceived stress, and whether the co-occurrence of these two psychological stressors has an additive influence on metabolic dysregulation in adults at different levels of body mass index (BMI) without diabetes. Methods: Participants without diabetes (N=20,312) from the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) study (recruited between 2003–2007) who had a body mass index (BMI) ≥18.5 kg/m2 were included in this cross-sectional analysis. Mean age of sample was 64.4 years, with 36% African American, and 56% women. Depressive symptoms and perceived stress were measured using brief versions of the Center for Epidemiologic Studies Depression (CES-D-4 item) questionnaire and Cohen Perceived Stress Scale (PSS), respectively. Metabolic health parameters included waist circumference, blood pressure (systolic and diastolic), low- and high-density lipoprotein (LDL, HDL) cholesterol, triglycerides, fasting glucose, and high sensitivity C-reactive protein (hs-CRP). Sequentially adjusted General Linear Regression Models (GLM) for each metabolic parameter were used to assess the association between having both elevated depressive symptoms and stress, either of these psychological risk factors, or none with all analyses stratified by BMI category (i.e., normal, overweight, and obesity). Results: The presence of elevated depressive symptoms and/or perceived stress was generally associated with increased waist circumference, higher CRP, and lower HDL. The combination of depressive symptoms and perceived stress, compared to either alone, was typically associated with poorer metabolic health outcomes. However, sociodemographic and lifestyle factors generally attenuated the associations between psychological factors and metabolic parameters. Conclusions: Elevated depressive symptoms in conjunction with high levels of perceived stress were more strongly associated with several parameters of metabolic health than only one of these psychological constructs in a large, diverse cohort of adults. Findings suggest that healthy lifestyle factors may attenuate the association between psychological distress and metabolic health impairment.

Background: Hypertension is a leading cause of disability-adjusted life years lost in the United States. Adiponectin is a cytokine secreted by adipocytes that increases insulin sensitivity, maintains vascular homeostasis, and is inversely associated with adiposity. We sought to determine the risk of incident hypertension by level of adiponectin at baseline. Methods: The REasons for Geographic and Racial Differences in Stroke (REGARDS) study enrolled 30,239 Black and White US adults in 2003-2006, with a second visit ~9 years later. Adiponectin was measured at the baseline visit among a random sample of 4,400 participants who attended the second visit. Modified Poisson regression estimated the relative risk (RR) for incident hypertension by each 1 SD higher of log-transformed adiponectin level adjusting for age, race, and sex in a minimally adjusted model. The fully adjusted model added Southern Diet pattern, dietary ratio of sodium to potassium, BMI, waist circumference, and systolic blood pressure. Restricted cubic splines visualized RR of hypertension by level of adiponectin, relative to the median. Results: After excluding those with prevalent hypertension (threshold 140/90 mm Hg or blood pressure medication use; n=2477) and missing adiponectin (n =129), 1,877 participants remained (mean age 62 years, 49% male, 36% Black, with lower adiponectin in Black participants pFigure ). Conclusions: In a cohort of Black and White US adults without hypertension, level of adiponectin did not associate with risk of incident hypertension 9 years later after adjusting for other hypertension risk factors.

Importance Intracerebral hemorrhage and arterial ischemic disease share risk factors, to our knowledge, but the association between the 2 conditions remains unknown. Objective To evaluate whether intracerebral hemorrhage was associated with an increased risk of incident ischemic stroke and myocardial infarction. Design, Setting, and Participants An analysis was conducted of pooled longitudinal participant-level data from 4 population-based cohort studies in the United States: the Atherosclerosis Risk in Communities (ARIC) study, the Cardiovascular Health Study (CHS), the Northern Manhattan Study (NOMAS), and the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Patients were enrolled from 1987 to 2007, and the last available follow-up was December 31, 2018. Data were analyzed from September 1, 2019, to March 31, 2020. Exposure Intracerebral hemorrhage, as assessed by an adjudication committee based on predefined clinical and radiologic criteria. Main Outcomes and Measures The primary outcome was an arterial ischemic event, defined as a composite of ischemic stroke or myocardial infarction, centrally adjudicated within each study. Secondary outcomes were ischemic stroke and myocardial infarction. Participants with prevalent intracerebral hemorrhage, ischemic stroke, or myocardial infarction at their baseline study visit were excluded. Cox proportional hazards regression was used to examine the association between intracerebral hemorrhage and subsequent arterial ischemic events after adjustment for baseline age, sex, race/ethnicity, vascular comorbidities, and antithrombotic medications. Results Of 55 131 participants, 47 866 (27 639 women [57.7%]; mean [SD] age, 62.2 [10.2] years) were eligible for analysis. During a median follow-up of 12.7 years (interquartile range, 7.7-19.5 years), there were 318 intracerebral hemorrhages and 7648 arterial ischemic events. The incidence of an arterial ischemic event was 3.6 events per 100 person-years (95% CI, 2.7-5.0 events per 100 person-years) after intracerebral hemorrhage vs 1.1 events per 100 person-years (95% CI, 1.1-1.2 events per 100 person-years) among those without intracerebral hemorrhage. In adjusted models, intracerebral hemorrhage was associated with arterial ischemic events (hazard ratio [HR], 2.3; 95% CI, 1.7-3.1), ischemic stroke (HR, 3.1; 95% CI, 2.1-4.5), and myocardial infarction (HR, 1.9; 95% CI, 1.2-2.9). In sensitivity analyses, intracerebral hemorrhage was associated with arterial ischemic events when updating covariates in a time-varying manner (HR, 2.2; 95% CI, 1.6-3.0); when using incidence density matching (odds ratio, 2.3; 95% CI, 1.3-4.2); when including participants with prevalent intracerebral hemorrhage, ischemic stroke, or myocardial infarction (HR, 2.2; 95% CI, 1.6-2.9); and when using death as a competing risk (subdistribution HR, 1.6; 95% CI, 1.1-2.1). Conclusions and Relevance This study found that intracerebral hemorrhage was associated with an increased risk of ischemic stroke and myocardial infarction. These findings suggest that intracerebral hemorrhage may be a novel risk marker for arterial ischemic events.

The underenrollment of women in randomized clinical trials represents a threat to the validity of the evidence supporting clinical guidelines and potential disparities in access to novel treatments.To determine whether women were underenrolled in contemporary randomized clinical trials of acute stroke therapies published in 9 major journals after accounting for their representation in underlying stroke populations.MEDLINE was searched for acute stroke therapeutic trials published between January 1, 2010, and June 11, 2020.Eligible articles reported the results of a phase 2 or 3 randomized clinical trial that enrolled patients with stroke and/or transient ischemic attack and examined a therapeutic intervention initiated within 1 month of onset.Data extraction was performed by 2 independent authors in duplicate. Individual trials were matched to estimates of the proportion of women in underlying stroke populations using the Global Burden of Disease database.The primary outcome was the enrollment disparity difference (EDD), the absolute difference between the proportion of trial participants who were women and the proportion of strokes in the underlying disease populations that occurred in women. Random-effects meta-analyses of the EDD were performed, and multivariable metaregression was used to explore the associations of trial eligibility criteria with disparity estimates.The search returned 1529 results, and 115 trials (7.5%) met inclusion criteria. Of 121 105 randomized patients for whom sex was reported, 52 522 (43.4%) were women. The random-effects summary EDD was -0.053 (95% CI, -0.065 to -0.040), indicating that women were underenrolled by 5.3 percentage points. This disparity persisted across virtually all geographic regions, intervention types, and stroke types, apart from subarachnoid hemorrhage (0.117 [95% CI, 0.084 to 0.150]). When subarachnoid hemorrhage trials were excluded, the summary EDD was -0.067 (95% CI, -0.078 to -0.057). In the multivariable metaregression analysis, an upper age limit of 80 years as an eligibility criterion was associated with a 6-percentage point decrease in the enrollment of women.Further research is needed to understand the causes of the underenrollment of women in acute stroke trials. However, to maximize representation, investigators should avoid imposing age limits on enrollment.

Four seminal randomized controlled trials (RCTs) have investigated aspirin, aspirin plus extended-release dipyridamole, and clopidogrel for the prevention of recurrent vascular events. Despite studying over 32,000 patients with stroke in these trials, the decision on which antiplatelet agent to select for secondary stroke prevention remains controversial. Attempts to translate the results of these RCTs into clinical practice are complicated by each trial's selection of participants and choice of primary outcome. Herein, we argue that by examining RCT results with participant selection limited to patients with ischemic stroke or TIA and by focusing on recurrent stroke as our outcome, we can use the standard epidemiology 2 × 2 table to assist in selecting an antiplatelet agent for secondary stroke prevention.

ObjectiveNo systematic review of the literature has dedicated itself to looking at the management of symptomatic carotid stenosis in female patients. In this scoping review, we aimed to identify all randomised controlled trials (RCTs) that reported sex-specific outcomes for patients who underwent carotid revascularisation, and determine whether sufficient information is reported within these studies to assess short-term and long-term outcomes in female patients.Design, setting and participantsWe systematically searched Medline, Embase, Pubmed and Cochrane libraries for RCTs published between 1991 and 2020 that included female patients and compared either endarterectomy with stenting, or any revascularisation (endarterectomy or stenting) with medical therapy in patients with symptomatic high-grade (>50%) carotid stenosis.ResultsFrom 1537 references examined, 27 eligible studies were identified. Sex-specific outcomes were reported in 13 studies. Baseline patient characteristics of enrolled female patients were reported in 2 of those 13 studies. Common outcomes reported included stroke and death, however, there was significant heterogeneity in the reporting of both periprocedural and long-term outcomes. Sex-specific differences relating to the degree of stenosis and time from index event to treatment are largely limited to studies comparing endarterectomy to medical therapy. Adverse events were not reported by sex.ConclusionsOnly half of the previously published RCTs and systematic reviews report sex-specific outcomes. Detailed analyses on the results of carotid artery intervention for female patients with symptomatic stenosis are limited.

Background and Purpose: No systematic review of the literature has dedicated itself to looking at the management of symptomatic carotid stenosis in women. In this scoping review, we aimed to identify all randomized controlled trials (RCTs) that reported sex-specific outcomes for patients who underwent carotid revascularization, and determine whether sufficient information is reported within these studies to assess women’s short and long-term outcomes. Methods: We systematically searched Medline, Embase, Pubmed, and Cochrane libraries for RCTs published between 1991 and 2020 that included women and compared either endarterectomy with stenting, or any revascularization (endarterectomy or stenting) with medical therapy in patients with symptomatic high grade (greater than 50%) carotid stenosis. Results: From 1,537 references examined, 27 eligible studies were identified. Sex-specific outcomes were reported in 13 studies. Baseline patient characteristics of enrolled women were reported in 2 of those 13 studies. Common outcomes reported included stroke and death, however there was significant heterogeneity in the reporting of both periprocedural and long-term outcomes. Sex-specific differences relating to the degree of stenosis and time from index event to treatment were limited to studies comparing endarterectomy to medical therapy. Adverse events were not reported by sex. Conclusions: Half of the previously published RCTs and systematic reviews report sex-specific outcomes. Detailed analysis on the benefits of carotid artery intervention for women with symptomatic stenosis is limited . Further analysis with individual patient data and a network meta-analysis is the necessary next step to better assess the treatment effects of carotid management in women.

Introduction: When reporting primary results, it is recommended that RCTs report sex-specific outcomes. We reviewed the reporting of sex-specific outcomes in contemporary acute stroke RCTs. Methods: We searched MEDLINE for manuscripts published between 2010 and June 2020 in one of nine major clinical journals reporting the primary results of phase 2 or 3 stroke RCTs. Eligible trials tested a therapeutic intervention initiated within one month of stroke onset. Reporting of sex-specific primary results was the outcome of interest. We also investigated whether the trial formally tested for an interaction between sex and treatment and if that interaction test was statistically significant. We performed bivariate analyses using Fisher’s exact tests to identify study-level factors associated with sex-specific reporting including journal, geographic region, trial phase, sample size, stroke type, trial type (e.g. thrombolytic, EVT, secondary prevention), and industry funding. Temporal trends using two-year time periods were also explored. Results: Of the 115 studies identified, sex-specific primary outcome data were reported in 37% (n=42). Reporting varied significantly by journal, with NEJM (61%) and Lancet journals (40%) having the highest rates (p=0.03) (Table). Reporting also differed by geographic region (p=0.03), trial phase (p=0.05), and sample size (p Conclusions: Although reporting of sex-specific outcomes improved from 2010 to 2020, the prevalence of reporting in major journals is still low. Further efforts are required to ensure that journals and authors comply with reporting guidelines.

Background: Data from the CDC show that approximately one-quarter of adults have elevated triglyceride (TG) levels. Recent trials have demonstrated that pharmacologic treatment of high TG levels, in patients already on statin therapy, reduces the rate of major vascular events such as myocardial infarction and stroke (REDUCE-IT trial). We sought to assess how often patients with asymptomatic carotid stenosis (CS) have elevated TG levels and factors associated with high TG values. Methods: Patients enrolled in the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST 2) were analyzed. Baseline lipid profiles were evaluated to determine high TG treatment eligibility as per the REDUCE-IT trial. We also evaluated baseline use of pharmacologic treatment for high TG levels. Demographic factors and baseline medical conditions were studied in relation to high (>150 mg/dl) TG values. Chi square and t tests were used to assess baseline factors and abnormal TG values. Results: As of August 10, 2020, 1655 of 1689 randomized patients (mean age 69.7 years, 61% men) had baseline lipid profiles suitable for analysis. Treatment eligibility according to REDUCE-IT (LDL 41-100 mg/dl, TG>150 mg/dl) was present in 21% (345) of subjects. In these patients, the median TG value was 205 (IQR 93) mg/dl. Fibrate medications were used at baseline in 4.5% of patients. Analysis of demographic and medical history factors and TG values greater than 150 mg/dl is found in the Table. There was significant positive correlation between baseline hemoglobin A1C and triglyceride values (p Conclusions: One in five patients in CREST 2 has TG values that potentially justify pharmacologic treatment. Elevated TG levels are most correlated with diabetes, hypertension, obesity, decreased physical activity, and heart disease. Clinicians should investigate treatment of elevated TG levels as a component of intensive medical therapy for stroke prevention.

Introduction: The inadequate enrollment of women in RCTs represents a threat to trial generalizability and potential inequities in access to novel treatments. We sought to determine whether women were under-enrolled in contemporary acute stroke trials. Methods: We searched MEDLINE for completed RCTs published in one of nine major journals between 2010 and 2020. Eligible studies were phase 2 or 3 trials undertaken to test therapeutic interventions within one month of stroke onset. For each trial we calculated the proportion of trial participants that were women (PPW). We used Global Burden of Disease (GBD) data to estimate the expected proportion of strokes occurring in women in the underlying stroke populations (PSW). We matched individual estimates from the GBD data to each trial based on geographic location, year, and stroke type. To quantify disparities, we calculated the enrollment disparity difference (EDD), defined as EDD = PSW - PPW. A positive EDD indicates that women were under-represented in the trial. We used random effects meta-analysis to pool individual EDDs and conducted subgroup analyses. Results: We identified 115 trials that met eligibility criteria. The random effects summary EDD was 0.053 (95% CI = 0.040, 0.053), indicating that women were under-enrolled in acute stroke trials by 5% relative to their representation in the underlying stroke population. However, there was substantial between-trial variability in the EDD (I 2 =84.4%). In subgroup analyses, the EDD was similar across subgroups except for stroke type (figure); trials that only included subarachnoid hemorrhages enrolled women in excess of their representation in the underlying population (summary EDD = -0.117 [95% CI = -0.150, -0.084]). Conclusions: Overall, women were modestly under-represented in contemporary acute stroke trials compared to their representation among all strokes. Further study is needed to elucidate factors driving sex differences in enrollment between RCTs.

Background Epidemiological studies utilize residential histories to assess environmental exposure risk. The validity from using commercially-sourced residential histories within national longitudinal studies remains unclear. Our study assessed predictors of non-agreement between baseline addresses from the commercially-sourced LexisNexis database and participants in the national longitudinal study, REasons for Geographic and Racial Differences in Stroke (REGARDS). Additionally, we assessed differences in stroke risk by neighborhood socioeconomic score (nSES) based on participant reported address compared to nSES from LexisNexis/REGARDS matched baseline address. Methods From January 2003–October 2007, REGARDS enrolled 30,239 black and white adults aged 45 and older within the continental United States and collected their baseline address. ArcGIS Desktop 10.5.1 with ESRI 2016 Business Analyst Data was used to geocode baseline addresses from LexisNexis and REGARDS. Logistic regression was used to estimate the likelihood that LexisNexis address matched REGARDS baseline address for each participant. Survival analysis was used to estimate association between nSES and incident stroke. Results Approximately 91% of REGARDS participants had a LexisNexis address. Of these geocoded addresses, 93% of REGARDS baseline addresses matched LexisNexis addresses. Odds of agreement between LexisNexis and REGARDS was higher for older-aged participants (OR = 1.02 per year, 95% CI: 1.01, 1.02), blacks compared to whites (OR = 1.16, 95% CI: 1.05, 1.29), females compared to males (OR = 1.15, 95% CI: 1.04, 1.26), participants with an income of $34k-74k compared to an income less than $20k (OR = 1.62, 95% CI: 1.39, 1.89). Odds of agreement were lower for residents in Midwest compared to residents in the south (OR = 0.82, 95% CI: 0.73, 0.94). No significant differences in nSES-stroke associations were observed between REGARDS only and LexisNexis/REGARDS matched addresses; however, differences in interactions were observed. Conclusion Agreement between LexisNexis and REGARDS addresses varied by sociodemographic groups, potentially introducing bias in studies reliant on LexisNexis alone for residential address data., Highlights • Approximately 9% of REGARDS participants did not have a LexisNexis address history available. • Of participants with both REGARDS and LexisNexis addresses available, 93% of these addresses matched. • Agreement between REGARDS and LexisNexis address varied by socio-demographics—potentially biasing environmental exposures. • Compared to LexisNexis, REGARDS addresses may be valuable in detecting interactions contributing to stroke disparities.

Background: High awareness that cardiovascular disease is the leading cause of death (LCOD) among women is critical to prevention. This study evaluated longitudinal trends in this awareness among women. Methods and Results: Online surveys of US women (≥25 years of age) were conducted in January 2009 and January 2019. Data were weighted to the US population distribution of sociodemographic characteristics. Multivariable logistic regression was used to evaluate knowledge of the LCOD. In 2009, awareness of heart disease as the LCOD was 65%, decreasing to 44% in 2019. In 2019, awareness was greater with older age and increasing education and lower among non-White women and women with hypertension. The 10-year awareness decline was observed in all races/ethnicities and ages except women ≥65 years of age. The greatest declines were among Hispanic women (odds ratio of awareness comparing 2019 to 2009, 0.14 [95% CI, 0.07–0.28]), non-Hispanic Black women (odds ratio, 0.31 [95% CI, 0.19–0.49]), and 25- to 34-year-olds (odds ratio, 0.19 [95% CI, 0.10–0.34]). In 2019, women were more likely than in 2009 to incorrectly identify breast cancer as the LCOD (odds ratio, 2.59 [95% CI, 1.86–3.67]), an association that was greater in younger women. Awareness of heart attack symptoms also declined. Conclusions: Awareness that heart disease is the LCOD among women declined from 2009 to 2019, particularly among Hispanic and non-Hispanic Black women and in younger women (in whom primordial/primary prevention may be most effective). An urgent redoubling of efforts by organizations interested in women’s health is required to reverse these trends.

Background and Purpose: Life’s Simple 7 (LS7) is a metric for cardiovascular health based on the 7 domains of smoking, diet, physical activity, body mass index, blood pressure, total cholesterol, and fasting glucose. Because they may be targeted for secondary prevention purposes, we hypothesized that stroke survivors would experience improvement in LS7 score over time compared with people who did not experience a stroke. We addressed this hypothesis in the REGARDS study (Reasons for Geographic and Racial Differences in Stroke) cohort of Black and White adults enrolled between 2003 and 2007. Methods: Participants who had LS7 data at baseline, were stroke-free at baseline, had a 10-year follow-up visit, and either did not have a stroke or had an ischemic stroke >1 year before follow-up were included (N=7569). Among these participants, 149 (2.0%) had an adjudicated ischemic stroke between the LS7 assessments. LS7 scores were classified as 0 to 2 points for each domain for a maximum score of 14, with higher scores representing better health. Multivariable linear regression was used to test the association of ischemic stroke with change in LS7 score. Covariates included baseline LS7 score, age, race, sex, education, and geographic region. Results: The 149 stroke survivors had an average of 4.9 years (SD=2.5) of follow-up from the stroke event to the second LS7 assessment. After adjusting for covariates, participants who experienced an ischemic stroke showed 0.28 points more decline in total LS7 score ( P =0.03) than those who did not experience a stroke. Conclusions: Stroke survivors did not experience improvements in cardiovascular health due to secondary prevention after ischemic stroke. On the contrary, they experienced significantly greater decline, indicating the need for greater efforts in secondary prevention after a stroke.

Key Points Question Is sickle cell trait associated with increased risk of myocardial infarction and coronary heart disease among African American individuals? Findings In this cohort study of 23 197 African American individuals in 5 cardiovascular epidemiologic studies, sickle cell trait was not associated with increased risk of myocardial infarction or coronary heart disease among African American individuals. Meaning In this study, sickle cell trait was not associated with increased risk of fatal and nonfatal myocardial infarction or coronary heart disease, suggesting that these disorders may not be associated with sickle cell trait–related sudden death., Importance The incidence of and mortality from coronary heart disease (CHD) are substantially higher among African American individuals compared with non-Hispanic White individuals, even after adjusting for traditional factors associated with CHD. The unexplained excess risk might be due to genetic factors related to African ancestry that are associated with a higher risk of CHD, such as the heterozygous state for the sickle cell variant or sickle cell trait (SCT). Objective To evaluate whether there is an association between SCT and the incidence of myocardial infarction (MI) or composite CHD outcomes in African American individuals. Design, Setting, and Participants This cohort study included 5 large, prospective, population-based cohorts of African American individuals in the Women’s Health Initiative (WHI) study, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, the Multi-Ethnic Study of Atherosclerosis (MESA), the Jackson Heart Study (JHS), and the Atherosclerosis Risk in Communities (ARIC) study. The follow-up periods included in this study were 1993 and 1998 to 2014 for the WHI study, 2003 to 2014 for the REGARDS study, 2002 to 2016 for the MESA, 2002 to 2015 for the JHS, and 1987 to 2016 for the ARIC study. Data analysis began in October 2013 and was completed in October 2020. Exposures Sickle cell trait status was evaluated by either direct genotyping or high-quality imputation of rs334 (the sickle cell variant). Participants with sickle cell disease and those with a history of CHD were excluded from the analyses. Main Outcomes and Measures Incident MI, defined as adjudicated nonfatal or fatal MI, and incident CHD, defined as adjudicated nonfatal MI, fatal MI, coronary revascularization procedures, or death due to CHD. Cox proportional hazards regression models were used to estimate the hazard ratio for incident MI or CHD comparing SCT carriers with noncarriers. Models were adjusted for age, sex (except for the WHI study), study site or region of residence, hypertension status or systolic blood pressure, type 1 or 2 diabetes, serum high-density lipoprotein level, total cholesterol level, and global ancestry (estimated from principal components analysis). Results A total of 23 197 African American men (29.8%) and women (70.2%) were included in the combined sample, of whom 1781 had SCT (7.7% prevalence). Mean (SD) ages at baseline were 61.2 (6.9) years in the WHI study (n = 5904), 64.0 (9.3) years in the REGARDS study (n = 10 714), 62.0 (10.0) years in the MESA (n = 1556), 50.3 (12.0) years in the JHS (n = 2175), and 53.2 (5.8) years in the ARIC study (n = 2848). There were no significant differences in the distribution of traditional factors associated with cardiovascular disease by SCT status within cohorts. A combined total of 1034 participants (76 with SCT) had incident MI, and 1714 (137 with SCT) had the composite CHD outcome. The meta-analyzed crude incidence rate of MI did not differ by SCT status and was 3.8 per 1000 person-years (95% CI, 3.3-4.5 per 1000 person-years) among those with SCT and 3.6 per 1000 person-years (95% CI, 2.7-5.1 per 1000 person-years) among those without SCT. For the composite CHD outcome, these rates were 7.3 per 1000 person-years (95% CI, 5.5-9.7 per 1000 person-years) among those with SCT and 6.0 per 1000 person-years (95% CI, 4.9-7.4 per 1000 person-years) among those without SCT. Meta-analysis of the 5 study results showed that SCT status was not significantly associated with MI (hazard ratio, 1.03; 95% CI, 0.81-1.32) or the composite CHD outcome (hazard ratio, 1.16; 95% CI, 0.92-1.47). Conclusions and Relevance In this cohort study, there was not an association between SCT and increased risk of MI or CHD in African American individuals. These disorders may not be associated with sickle cell trait–related sudden death in this population., This cohort study evaluates whether African American individuals with sickle cell trait have a higher incidence of myocardial infarction or composite coronary heart disease outcomes compared with those without sickle cell trait.

Background and Purpose: We examined differences in the volume and pattern of physical activity (PA) and sedentary behavior between adults with and without stroke. Methods: We studied cohort members with an adjudicated or self-reported stroke (n=401) and age-, sex-, race-, region of residence-, and body mass index-matched participants without a history of stroke (n=1203) from the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). Sedentary behavior (total volume and bouts), light-intensity PA, and moderate-to-vigorous-intensity PA were objectively measured for 7 days via hip-worn accelerometer. Results: Sedentary time (790.5±80.4 versus 752.4±81.9 min/d) and mean sedentary bout duration (15.7±12.6 versus 11.9±8.1 min/d) were higher and PA (light-intensity PA: 160.5±74.6 versus 192.9±73.5 min/d and moderate-to-vigorous-intensity PA: 9.0±11.9 versus 14.7±17.0 min/d) lower for stroke survivors compared with controls ( P P Conclusions: Stroke survivors accrued a lower volume of PA, higher volume of sedentary time, and exhibited accrual patterns of more prolonged sedentary bouts and shorter, lower intensity activity breaks compared with persons without stroke.

Background and Aim: Women have been under-represented in clinical trials areas of cardiovascular disease but there is less certainty over the level of disparity specifically in stroke and whether there is any influence of pathological subtype, age and time. We examined the participation of women in trials according to stroke prevalence in the population. Methods: Randomized controlled trials with ≥100 participants enrolled between 1990 and 2020 identified from ClinicalTrials.gov, using keywords “stroke” and “cerebrovascular accidents”, and subsequently published (identified using PubMed, Google Scholar, and Scopus) were included. To quantify sex disparites in enrolment we calculate the participation to prevalence ratio (PPR), defined as the percentage of women participating in a trial against the prevalence of women in the disease population. Results: There were 281 stroke trials eligible for analyses with a total of 588,887 participants, of whom 37.4 % were women. Overall, women were represented at a lower proportion relative to their prevalence in the underlying population (mean PPR 0.84; 95% confidence interval [CI] (0.81 to 0.87)). The greatest differences were observed in trials of hemorrhagic stroke (PPR 0.73; 95% CI 0.71 to 0.74), trials with a mean age of participants

Mortality, incidence, and prevalence are indices used to describe differences in distribution of a specific disease among selected populations. Each index provides particular information that addresses the burden of disease, but there are marked differences in quantity and quality of the data. The properties of these indices should be considered related to describing the burden of cardiovascular disease (CVD) in African Americans. CVD is usually defined to include all diseases of the circulatory system and referred to as “total cardiovascular diseases.” It includes hypertension, coronary heart disease (CHD), stroke, and heart failure. Throughout this chapter, we will specify CVD, CHD, stroke, or other components of CVD. Most of what we know about CVD epidemiology comes from mortality data because it is mandated that these data be collected. Relative to other race/sex groups, African Americans have the highest rates of CHD mortality, with rates especially high in middle-aged African American men. Overall, stroke mortality among African Americans is about 40% higher than White Americans with the largest disparity at younger ages. Data are somewhat inconsistent in incidence of CHD comparing African Americans with White Americans; this may be due to differences between incident fatal and nonfatal CHD with African Americans having higher rates of incident fatal CHD. The increased risk of incident stroke in African Americans compared to White Americans has been confirmed across many populations. The most critical finding from CVD epidemiology is the substantially higher risk of heart disease and stroke among African Americans and particularly among younger African Americans for stroke.

Objectives: Aging in place (residential stability) is a desirable means of aging where adults remain in their homes, even when facing challenges that impair their capacity for self-care. Residential stability, especially following acute health challenges, depends on individual and community factors, possibly including proximity to medical facilities. Methods: We explored the association between the density of medical facilities around homes with risk of incident myocardial infarction (MI) and with aging in place following incident MI. Results: Densities of neighborhood pharmacies were not associated with aging in place or time to MI. High densities of neighborhood clinical care facilities were significantly associated with decreased residential stability. Discussion: The lack of significant associations between medical facility exposures and MI-related outcomes, coupled with prior findings, casts doubt on their salience and may indicate that other neighborhood features are more strongly associated with these outcomes.

Background: Despite improvements in prognosis following myocardial infarction (MI), racial disparities persist. The objective of this study was to examine disparities between Black and White adults in cardiovascular disease (CVD), coronary heart disease, stroke, heart failure (HF), and mortality after MI and characteristics that may explain the disparities. Methods: This prospective cohort study included 1122 REGARDS (Reasons for Geographic and Racial Differences in Stroke) study participants with incident MI between 2003 and 2016. We followed participants for subsequent CVD events (MI, stroke, HF hospitalization, or death from CVD; n=431), coronary heart disease events (MI or death from coronary heart disease; (n=277), stroke (n=68), HF events (HF hospitalization or death from HF; n=191), and all-cause mortality (n=527; 3-year median follow-up after MI). Results: Among 1122 participants with incident MI, 37.5% were Black participants, 45.4% were women, and mean age was 73.2 (SD, 9.5) years. The unadjusted hazard ratio for CVD events comparing Black to White participants was 1.42 (95% CI, 1.17–1.71). Adjusting for sociodemographic characteristics did not attenuate the association (1.41 [95% CI, 1.14–1.73]), but further adjusting for pre-MI health status (1.25 [95% CI, 1.00–1.56]) and characteristics of the MI (1.01 [95% CI, 0.80–1.27]) resulted in substantial attenuation. Similar patterns were observed for the other outcomes, although the number of strokes was small. Conclusions: Black individuals had a higher risk of CVD events and mortality after MI than White individuals. The disparities were explained by health status before MI and characteristics of the MI. These findings suggest that both primordial prevention of risk factors and improved acute treatment strategies are needed to reduce disparities in post-MI outcomes.

Markers of systemic inflammation are associated with increased risk of cognitive impairment, but it is unclear if they are associated with a faster rate of cognitive decline and whether this relationship differs by race. Our objective was to examine the association of baseline C-reaction protein (CRP) with cognitive decline among a large racially diverse cohort of older adults. Participants included 21,782 adults aged 45 and older (36% were Black, Mean age at baseline 64) from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. CRP was measured at baseline and used as a continuous variable or a dichotomous grouping based on race-specific 90th percentile cutoffs. Cognitive measures of memory and verbal fluency were administered every 2 years for up to 12 years. Latent growth curve models evaluated the association of CRP on cognitive trajectories, adjusting for relevant demographic and health factors. We found that higher CRP was associated with worse memory (B = -.039, 95% CI [-.065,-.014]) and verbal fluency at baseline (B = -.195, 95% CI [-.219,-.170]), but not with rate of cognitive decline. After covariate adjustment, the association of CRP on memory was attenuated (B = -.005, 95% CI [-.031,-.021]). The association with verbal fluency at baseline, but not over time, remained (B = -.042, 95% CI [-.067,-.017]). Race did not modify the association between CRP and cognition. Findings suggest that levels of CRP at age 45+, are a marker of cognitive impairment but may not be suitable for risk prediction for cognitive decline.

Background The Life’s Simple 7 (LS7) metric incorporates health behaviors (body mass index, diet, smoking, physical activity) and health factors (blood pressure, cholesterol, glucose) to estimate an individual’s level of cardiovascular health. The association between cardiovascular health and incident hypertension is unresolved. Hypertension’s threshold was recently lowered and it is unclear if better cardiovascular health is associated with lower risk of incident hypertension with the updated threshold or in a multirace cohort. We sought to assess the association between better LS7 score and risk of incident hypertension among Black and White adults using a 130/80 mm Hg hypertension threshold. Methods and Results We determined the association between LS7 metric and incident hypertension in the REGARDS (Reasons for Geographic and Racial Disparities in Stroke) study, including participants free of baseline hypertension (2003–2007) who completed a second visit between 2013 and 2016. Hypertension was defined as systolic/diastolic blood pressure ≥130/80 mm Hg or antihypertensive medication use. Each LS7 component was assigned 0 (poor), 1 (intermediate), or 2 (ideal) points. We generated a 14‐point score by summing points. Among 2930 normotensive participants (20% Black, 80% White), the median (25th–75th percentiles) LS7 total score was 9 (8–10) points. Over a median follow‐up of 9 years, 42% developed hypertension. In the fully adjusted model, each 1‐point higher LS7 score had a 6% lower risk of incident hypertension (risk ratio, 0.94 per 1 point; 95% CI, 0.92–0.96). Conclusions Better cardiovascular health was associated with lower risk of incident hypertension using a 130/80 mm Hg hypertension threshold among Black and White adults.

Background Atrial fibrillation ( AF ) is associated with a 5‐fold increased stroke risk. While most patients with AF warrant anticoagulation, optimal treatment remains uncertain for patients with AF without cardiovascular comorbidities because the risk of stroke in this population has not been well‐characterized. Methods and Results Participants (N=28 253; 55% women, mean age 64.6±9.4 years), from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study (2003–present) were classified into 1 of 4 groups based on the presence or absence of AF and the presence or absence of cardiovascular comorbidities. Cox proportional hazards analysis was used to compare the risk of stroke between groups. During 244 560 person‐years of follow‐up (median 8.7 years), 1206 strokes occurred. Compared with patients with neither AF nor cardiovascular comorbidities, we did not find an increased stroke risk (hazard ratio [HR], 1.23; 95% CI , 0.62–2.18 [ P =0.511]) among participants with AF alone. Participants without AF but with cardiovascular comorbidities had both an elevated stroke risk (HR, 1.77; 95% CI , 1.48–2.18 [ P CI , 1.48–3.90 [ P =0.0002]). Conclusions In this large cohort of participants with AF without cardiovascular comorbidities, we found that AF itself, without cardiovascular comorbidities, did not confer increased risk of stroke. Cardiovascular comorbidities, however, were associated with an increased risk of both stroke of any type and cardioembolic stroke, even in the absence of AF .

The association between objectively measured physical activity and atrial fibrillation (AF) has not been examined. Therefore, we examined the association between moderate and vigorous physical activity (MVPA) with incident AF in 5,147 participants who completed accelerometer assessment for 4 to 7 consecutive days in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. MVPA was defined as1,065 counts/minute, and daily mean time spent in MVPA was computed. Incident AF was identified during follow-up by a study-scheduled electrocardiogram and also from self-reported medical history of a physician diagnosis. Logistic regression was used to assess the relation between daily time in MVPA and incident AF. A total of 429 (8.3%) incident AF cases were detected after a median follow-up of 3.5 years following accelerometer assessment. Participants with higher daily time spent in MVPA were less likely to develop AF than those with lower MVPA achievement (Quartile 1 = 12.4%; Quartile 2 = 8.3%; Quartile 3 = 7.1%; Quartile 4 = 5.4%; p-trend0.001). In a multivariable model adjusted for AF risk factors, the risk of AF decreased with higher levels of daily MVPA (Quartile 1: Ref; Quartile 2: hazard ratio [HR] = 0.77, 95% confidence interval [CI] 0.58 to 1.01; Quartile 3: HR = 0.72, 95% CI 0.53 to 0.98; Quartile 4: HR = 0.62, 95% CI 0.44 to 0.87; p-trend = 0.0056). In conclusion, higher levels of objectively measured daily MVPA are protective against the development of AF suggesting that promotion of MVPA should be encouraged to reduce the risk of AF.

Introduction: Whether plasma lipid levels are associated with stroke risk remains controversial, with even less data for American blacks versus whites. Hypothesis: We hypothesized that abnormal lipid levels are not associated with stroke incidence in either blacks or whites. Methods: The REasons for Geographic And Racial Differences in Stroke (REGARDS) study recruited 30,283 black and white individuals aged 45+ from the contiguous U.S. between 2003 to 2007, participants with a history of stroke at baseline were excluded. Participants were followed until 2018 for stroke events following the WHO definition and confirmed by review of medical records. The association of lipid measures with stroke were assessed using Cox regression models adjusted for traditional CVD risk factors and an age-x-race interaction term. Results: With 27,714 participants (mean age 64.85± 9.43, 59.5% white and 55.4% female), over a median of 11 years of follow up, 1,415 stroke events occurred, of which 599 among blacks. After adjusting for traditional stroke risk factors, there were modest associations between higher total cholesterol and higher LDL, but not higher triglycerides, with stroke risk. There was no evidence of a race interaction. Overall, HDL levels were not associated with stroke risk. However, when stratified by race, whites had a reduced risk of stroke with higher HDL-C, whereas no association was seen among blacks (p-interaction 0.09). Conclusion: In REGARDs, there was a modest association of cholesterol measures with stroke risk. The association for HDL with stroke may be influenced by race, with a less strong association among blacks than among whites.

Introduction: The neuropeptide neurotensin (NT) has been linked to cardiovascular and metabolic disease risk. Through measurement of its stable equimolar precursor, pro-neurotensin/neuromedin N (pro-NT/NMN), hyperactivity of NT has been associated with aggregate cardiovascular outcomes that include stroke. However, the exclusive association of pro-NT/NMN with incident ischemic or hemorrhagic stroke has not been studied. Hypothesis: Higher serum pro-NT/NMN is associated with incident ischemic and hemorrhagic stroke. Methods: Prospective case-cohort study in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. From 2003-2007, REGARDS enrolled 30,239 White or Black adults aged ≥45. Pro-NT/NMN was measured by immunoassay in 464 ischemic stroke cases, 49 hemorrhagic stroke cases, and 800 non-cases from a random cohort. Cox proportional-hazards models were used to calculate hazard ratios (HR) of stroke by pro-NT/NMN quartiles and per standard deviation (SD) of log pro-NT/NMN. Model 1 (both stroke types) included demographic factors as covariates, Model 2A (ischemic only) added ischemic stroke risk factors, and Model 2B (hemorrhagic only) added hemorrhagic stroke risk factors. Results: The table shows an increased HR of ischemic stroke for those in the 4th vs 1st-quartile pro-NT/NMN in Model 1 with a trend of increased risk across quartiles; this was attenuated in Model 2A. Prebaseline diabetes and coronary artery disease were the largest confounders of ischemic stroke risk, with each accounting for 19% of the association observed in Model 1. There was no association of pro-NT/NMN with hemorrhagic stroke in either model. There were no interactions of race or sex with log pro-NT/NMN. Conclusions: Higher pro-NT/NMN is associated with increased risk of ischemic stroke after adjusting for demographics, but this was not independent of stroke risk factors. No significant association with hemorrhagic stroke was observed; this analysis was limited by a small number of events.