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The recently published SPACE-2 trial (Stent-Supported Percutaneous Angioplasty of the Carotid Artery Versus Endarterectomy-2) compared 3 treatments to prevent stroke in patients with asymptomatic carotid stenosis ≥70%: (1) carotid endarterectomy plus best medical treatment (BMT), (2) transfemoral carotid artery stenting plus BMT, or (3) BMT alone. Because of low enrollment, the findings of similar safety and efficacy for carotid endarterectomy, carotid artery stenting, or BMT alone were inconclusive. Publication of the CREST (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial)-2 results should provide level A evidence that has been lacking for 2 to 3 decades, to guide treatment of asymptomatic patients with severe carotid stenosis. For symptomatic patients with ≥70% stenosis, no trials are underway to update the degree of benefit reported for carotid endarterectomy by NASCET (North American Carotid Endarterectomy Trial) and ECST (European Carotid Surgery Trial), published in 1991. Subsequently, the use of cigarettes has plummeted, and major improvements in medical treatments and in carotid revascularization have emerged. These advances have coincided with abrupt decline in the clinical end points necessary for treatment comparisons in procedural trials. One of the advances in the invasive management of carotid disease has been transcarotid artery revascularization, already with limited approval by the US Food and Drug Administration. Establishing safety and efficacy of transcarotid artery revascularization compared with carotid endarterectomy, carotid artery stenting, or BMT alone may be challenging because of enrollment, regulatory, and funding barriers to design and complete an adequately powered randomized trial.

Background and ObjectivesReports assessing the association of stroke risk factors with incident stroke have generally assumed a uniform magnitude of associations across the age spectrum, an assumption we assess in this report.MethodsParticipants enrolled 2003–2007 in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study who were stroke free at baseline were followed for incident stroke. Associations of traditional stroke risk factors with incident stroke were assessed using (1) proportional hazards analysis based on the baseline age of the participant and (2) Poisson regression analysis assessing associations based on the changing age of the participant during their follow-up (age at exposure). In each analysis, age strata were selected to have a similar number of strokes in each stratum, specifically 45–64, 65–73, and 74+ years for the proportional hazards analysis and 45–69, 70–79, and 80+ years for Poisson regression.ResultsA total of 1,405 ischemic stroke events occurred among 28,235 participants over a median follow-up of 11.3 years, with a total of 276,074 person-years exposure. For both analytic approaches, the magnitude of the association with stroke was significantly less at older ages for diabetes (hazard or relative risk decreasing from ≈2.0 in younger strata to ≈1.3 in older strata), heart disease (from ≈2.0 to ≈1.3), and hypertension defined at a threshold of 140/90 mm Hg (from ≈1.80 to ≈1.50); however, there was no age-related difference in the magnitude of the association for smoking, atrial fibrillation, or left ventricular hypertrophy.DiscussionHypertension and diabetes are 2 of the more important risk factors for stroke; however, their association with stroke risk appears substantially less at older ages. That the magnitude of the association for smoking, atrial fibrillation, and left ventricular hypertrophy does not decrease with age suggests their relative importance in determining stroke risk likely increases with age.

The work environment can contribute to the risk of cardiovascular diseases (CVD) including stroke. Our objective was to identify occupations with elevated risk of stroke within the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort.We analyzed incident stroke outcomes (ischemic and hemorrhagic strokes) from 2003 to 2020 and employment characteristics of 13,659 adults aged ≥45 years enrolled in a national population-based cohort study. Using a modified Poisson regression approach, we estimated the relative risks (RRs) and the associated 95% confidence intervals (CI) of stroke in relation to years of employment within each occupation coded using the US Census two-digit Standard Occupation Code. Models were adjusted for Framingham Stroke Risk Score, region, race, age, and body mass index. We conducted stratified analysis by sex, employment time period (pre-1975 vs. post-1975), and region.Workers in the following occupations had a greater risk of stroke with longer duration of employment (per decade): protective service (RR: 2.35, 95% CI: 1.11, 4.97), food preparation and service (RR: 1.51, 95% CI: 1.05, 2.19), and transportation and material moving (RR: 1.30, 95% CI: 1.00, 1.69). The stroke risk in these occupations was disproportionately elevated in men, and differed by region and employment time period.Longer employment in protective service, food preparation and serving, and transportation and materials moving occupations may increase the risk of stroke. Surveillance may uncover specific work-related risk factors in these occupations, leading to interventions to reduce the burden of stroke among US workers.

Individual inflammation biomarkers are associated with incident coronary heart disease (CHD) events. However, there is limited research on whether the risk for incident CHD is progressively higher with a higher number of inflammation biomarkers in abnormal levels.We used data from 15,758 Reasons for Geographic and Racial Differences in Stroke (REGARDS) study participants aged ≥45 years without a history of CHD at baseline in 2003-2007. Abnormal levels of baseline high-sensitivity C-reactive protein, leukocyte count and serum albumin were defined as ≥3.8 mg/L (3rd tertile), ≥6.3 x 10Overall, 38.9% (n = 6,123) had 0, 36.6% (n = 5,774) had 1, 19.8% (n = 3,113) had 2 and 4.7% (n = 748) had 3 biomarkers of inflammation in abnormal levels. Over a median follow-up of 11.4 years, 954 (6.1%) participants had incident CHD. The rate of incident CHD per 1000 person-years for individuals with 0, 1, 2, and 3 biomarkers of inflammation in abnormal levels was 4.4 (95% confidence interval [CI]: 3.9-5.0), 6.3 (95% CI: 5.6-6.9), 8.8 (95% CI: 7.8-9.9), and 10.6 (95% CI: 8.1-13.1), respectively. Multi-variable adjusted hazard ratios for incident CHD associated with 1, 2 and 3 versus no inflammation biomarker in abnormal levels were 1.26 (95% CI: 1.07-1.49), 1.72 (95% CI: 1.43-2.07), and 1.84 (95% CI: 1.37-2.47), respectively (P-trend.001).The number of inflammation markers in abnormal levels was associated with increased risk of incident CHD after multi-variable adjustment.

Identifying individuals at elevated risk for mortality, especially from cardiovascular disease, may help guide testing and treatment. Risk factors for mortality differ by sex and race. We investigated the association of growth hormone (GH) with all-cause and cardiovascular mortality in a racially diverse cohort in the United States.Among an age, sex and race stratified subgroup of 1046 Black and White participants from the REasons for Geographic And Racial Disparities in Stroke (REGARDS) study, 881 had GH available; values were logThe mean age was 67.4 years, 51.1% were women, and 50.2% were Black participants. The median GH was 280 (interquartile range 79-838) ng/L. There were 237 deaths and 74 cardiovascular deaths over a mean of 8.0 years. In multivariable Cox analysis, GH was associated with higher risk of all-cause mortality per doubling (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.09-1.25) and cardiovascular mortality (HR 1.21, 95% CI 1.06-1.37). The association did not differ by sex or race (interaction p 0.05). The addition of GH to a model of clinical variables significantly improved the C-index compared to clinical model alone for all-cause and cardiovascular death.Higher fasting GH was associated with higher risk of all-cause and cardiovascular mortality and improved risk prediction, regardless of sex or race.

Background: Contemporary data on stroke epidemiology and the availability of national stroke clinical registries are important for providing evidence to improve practice and support policy decisions. Aims: To update the most current incidence, case-fatality, and mortality rates on stroke and identify national stroke clinical registries worldwide. Methods: We searched multiple databases (based on our existing search strategy) to identify new original papers, published between 1 November 2018 and 15 December 2021, that met ideal criteria for data on stroke incidence and case-fatality, and added these to the studies reported in our last review. To identify national stroke clinical registries, we updated our last search, using PubMed, from 6 February 2015 until 6 January 2022. We also screened reference lists of review papers, citation history of papers, and the gray literature. Mortality codes for International Classification of Diseases (ICD)-9 and ICD-10 were extracted from the World Health Organization (WHO) for each country providing these data. Population denominators were obtained from the United Nations (UN) or WHO (when data were unavailable in the UN database). Crude and adjusted stroke mortality rates were calculated using country-specific population denominators, and the most recent years of mortality data available for each country. Results: Since our last report in 2020, there were two countries (Chile and France) with new incidence studies meeting criteria for ideal population-based studies. New data on case-fatality were found for Chile and Kenya. The most current mortality data were available for the year 2014 (1 country), 2015 (2 countries), 2016 (11 countries), 2017 (10 countries), 2018 (19 countries), 2019 (36 countries), and 2020 (29 countries). Four countries (Libya, Solomon Islands, United Arab Emirates, and Lebanon) reported mortality data for the first time. Since our last report on registries in 2017, we identified seven more national stroke clinical registries, predominantly in high-income countries. These newly identified registries yielded limited information. Conclusions: Up-to-date data on stroke incidence, case-fatality, and mortality continue to provide evidence of disparities and the scale of burden in low- and middle-income countries. Although more national stroke clinical registries were identified, information from these newly identified registries was limited. Highlighting data scarcity or even where a country is ranked might help facilitate more research or greater policy attention in this field.

Background We examined whether the risk of incident atrial fibrillation (AF) in a large, biracial, prospective cohort is lower in participants who adhere to heart-healthy dietary patterns and higher in participants who adhere to less heart-healthy diets. Methods Between 2003 and 2007, the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort study enrolled 30,239 Black and White Americans aged 45 years or older. Dietary patterns (convenience, plant-based, sweets, Southern, and alcohol and salads) and the Mediterranean diet score (MDS) were derived based on food frequency questionnaire data. The primary outcome was incident AF at the follow-up visit 2013–2016, defined by either electrocardiogram or self-reported medical history of a physician diagnosis. Results This study included 8977 participants (mean age 63 ± 8.3 years; 56% women; 30% Black) free of AF at baseline who completed the follow-up exam an average of 9.4 years later. A total of 782 incident AF cases were detected. In multivariable logistic regression analyses, neither the MDS score (odds ratio (OR) per SD increment = 1.03; 95% confidence interval (CI) 0.95–1.11) or the plant-based dietary pattern (OR per SD increment = 1.03; 95% CI 0.94–1.12) were associated with AF risk. Additionally, an increased AF risk was not associated with any of the less-healthy dietary patterns. Conclusions While specific dietary patterns have been associated with AF risk factors, our findings fail to show an association between diet patterns and AF development.

IntroductionPeople with African ancestry have greater stroke risk and greater heritability of stroke risk than people of other ancestries. Given the importance of nitric oxide (NO) in stroke, and recent evidence that alpha globin restricts nitric oxide release from vascular endothelial cells, we hypothesized that alpha globin gene (HBA)deletion would be associated with reduced risk of incident ischemic stroke.MethodsWe evaluated 8,947 participants self-reporting African ancestry in the national, prospective Reasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. Incident ischemic stroke was defined as non-hemorrhagic stroke with focal neurological deficit lasting ≥ 24 hours confirmed by the medical record or focal or non-focal neurological deficit with positive imaging confirmed with medical records. Genomic DNA was analyzed using droplet digital PCR to determineHBAcopy number. Multivariable Cox proportional hazards regression was used to estimate the hazard ratio (HR) ofHBAcopy number on time to first ischemic stroke.ResultsFour-hundred seventy-nine (5.3%) participants had an incident ischemic stroke over a median (IQR) of 11.0 (5.7, 14.0) years’ follow-up.HBAcopy number ranged from 2 to 6: 368 (4%) -α/-α, 2,480 (28%) -α/αα, 6,014 (67%) αα/αα, 83 (1%) ααα/αα and 2 (HBAcopy number was 1.04; 95%CI 0.89, 1.21; p = 0.66.ConclusionsAlthough a reduction inHBAcopy number is expected to increase endothelial nitric oxide signaling in the human vascular endothelium,HBAcopy number was not associated with incident ischemic stroke in this large cohort of Black Americans.

Objectives:Higher inflammation has been linked to poor physical and mental health outcomes, and mortality, but few studies have rigorously examined whether changes in perceived stress and depressive symptoms are associated with increased inflammation within family caregivers and non-caregivers in a longitudinal design.Design:Longitudinal Study.Setting:REasons for Geographic And Racial Differences in Stroke cohort study.Participants:Participants included 239 individuals who were not caregivers at baseline but transitioned to providing substantial and sustained caregiving over time. They were initially matched to 241 non-caregiver comparisons on age, sex, race, education, marital status, self-rated health, and history of cardiovascular disease. Blood was drawn at baseline and approximately 9.3 years at follow-up for both groups.Measurements:Perceived Stress Scale, Center for Epidemiological Studies-Depression, inflammatory biomarkers, including high-sensitivity C-reactive protein, D dimer, tumor necrosis factor alpha receptor 1, interleukin (IL)-2, IL-6, and IL-10 taken at baseline and follow-up.Results:Although at follow-up, caregivers showed significantly greater worsening in perceived stress and depressive symptoms compared to non-caregivers, there were few significant associations between depressive symptoms or perceived stress on inflammation for either group. Inflammation, however, was associated with multiple demographic and health variables, including age, race, obesity, and use of medications for hypertension and diabetes for caregivers and non-caregivers.Conclusions:These findings illustrate the complexity of studying the associations between stress, depressive symptoms, and inflammation in older adults, where these associations may depend on demographic, disease, and medication effects. Future studies should examine whether resilience factors may prevent increased inflammation in older caregivers.

The stress of family caregiving may affect many health-related variables, including sleep. We evaluated differences in self-reported sleep quality between incident caregivers and matched non-caregiving controls from a national population-based study. Caregivers and controls were identified in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study and matched on seven different demographic and health history factors. Caregivers reported significantly longer sleep onset latency than controls, before and after adjusting for covariates (ps < .05). No differences were found on measures of total sleep time or sleep efficiency. Among caregivers only, employed persons reported less total sleep time and number of care hours was a significant predictor of total sleep time. Dementia caregivers did not differ from other caregivers. This is one of the few population-based studies of sleep quality in family caregivers. Additional research is needed to examine whether sleep disturbance contributes to greater health problems among caregivers.

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults at risk for coronavirus disease 2019 (COVID-19) comprising 14 established United States (US) prospective cohort studies. For decades, C4R cohorts have collected extensive data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R will link this pre-COVID phenotyping to information on SARS-CoV-2 infection and acute and post-acute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and broadly reflects the racial, ethnic, socioeconomic, and geographic diversity of the US. C4R is ascertaining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations, and high-quality events surveillance. Extensive pre-pandemic data minimize referral, survival, and recall bias. Data are being harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these will be pooled and shared widely to expedite collaboration and scientific findings. This unique resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including post-acute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term trajectories of health and aging.

Baseline depressive symptoms are associated with subsequent adverse cardiovascular (CV) events in subjects with and without diabetes but the impact of persistent symptoms vs. improvement remains controversial.Examine long-term changes in depressive symptoms in individuals with and without diabetes and the associated risk for adverse CV events.REGARDS is a prospective cohort study of CV risk factors in 30,000 participants aged 45 years and older.N = 16,368 (16.5% with diabetes mellitus) who remained in the cohort an average of 11.1 years later and who had complete data.Depressive symptoms were measured using the 4-item Centers for Epidemiologic Study of Depression (CES-D) questionnaire at baseline and again at a mean follow-up of 5.07 (SD = 1.66) years. Adjudicated incident stroke, coronary heart disease (CHD), CV mortality, and a composite outcome were assessed in a subsequent follow-up period of 6.1 (SD = 2.6) years.The association of changes in depressive symptoms (CES-D scores) across 5 years with incident CV events was assessed using Cox proportional hazards modeling.Compared to participants with no depressive symptoms at either time point, participants without diabetes but with persistently elevated depressive symptoms at both baseline and follow-up demonstrated a significantly increased risk of incident stroke (HR (95% CI) = 1.84 (1.03, 3.30)), a pattern which was substantially more prevalent in blacks (HR (95% CI) = 2.64 (1.48, 4.72)) compared to whites (HR (95% CI) = 1.06 (0.50, 2.25)) and in those not taking anti-depressants (HR (95% CI) = 2.01 (1.21, 3.35)) in fully adjusted models.The persistence of depressive symptoms across 5 years of follow-up in participants without diabetes identifies individuals at increased risk for incident stroke. This was particularly evident in black participants and among those not taking anti-depressants.

Our knowledge of the association between abdominal obesity (AO) and the risk of atrial fibrillation (AF) after adjusting for body mass index (BMI) is limited. We included 11,617 Black and White participants (mean age 63.0 ± 8.4 years) from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) national cohort study who were free of AF at baseline. A multivariable logistic regression model was used to estimate the odds ratio (OR) with 95% confidence interval (CI) of incident AF associated with AO. We also evaluated the association between waist circumference (WC) and incident AF. Over a median follow-up of 9.4 years, 999 participants developed AF. AO was associated with an increased risk of AF in a multivariable model adjusted for sociodemographic, lifestyle, and cardiovascular risk factors (OR 1.43, 95% CI 1.24 to 1.65, p0.001). The association was attenuated after adjusting for BMI (OR 1.13, 95% CI 0.95 to 1.35, p = 0.16). There was no evidence of interaction between AO and incident AF by age category (age65 vs age ≤65), gender, race, obesity, or BMI category. Conversely, a 10cm increase in WC was associated with a higher incidence of AF after controlling for BMI (OR 1.18 95% CI 1.09 to 1.29, p0.001), in both nonobese (OR 1.14, 95% CI 1.03 to 1.28, p = 0.02) and obese (OR 1.26, 95% CI 1.11 to 1.42, p0.001) people. In conclusion, there was an association between AO and incident AF, but the association was weakened after adjusting for BMI. There was a significant association between WC and incident AF, after taking other AF risk factors and BMI into account. WC is a potentially modifiable risk factor for AF, and further research is warranted to explore the effect of decreasing WC on the population AF burden.

Background: Adults with cardiovascular co-morbidities and risk factors are at greater risk of severe COVID-19. These same risk factors may also be associated with an attenuated antibody response to COVID-19 vaccines, although studies in diverse, U.S. population-based cohorts have been limited. Methods: The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) conducted a serosurvey for SARS-CoV-2 antibodies via dried blood spot (DBS) in 14 U.S. cohorts. IgG antibodies to SARS-CoV-2 spike subunit 1 (S1) and nucleocapsid (N) were measured from DBS using a semi-quantitative microsphere immunoassay and reported as median fluorescence intensity (MFI). Multivariable adjusted linear models regressed log-transformed anti-S1 MFI on age, sex, race/ethnicity, education attainment, self-reported diabetes, hypertension, cardiovascular disease (CVD), chronic kidney disease, smoking history, body mass index (BMI), asthma, obstructive lung diseases, DBS batch, anti-N MFI, vaccine type, time between vaccine and DBS, and vaccine dose at time of DBS collection. Results are presented as the percent difference in anti-S1 MFI compared with a reference group. Results: There were 6614 vaccinated participants prior to booster regimens and DBS collection (April 2021-July 2022) with 50%, 48%, and 2% of the cohort who received BNT162b2, mRNA-1273, or other vaccines, respectively. The mean (SD) time between vaccination and DBS was 3.8 (1.8) months. Over 10% of the cohort had self-reported a history of diabetes, 55% had hypertension, and 74% had a BMI>25 kg/m 2 . Anti-S1 MFI decreased as the time between vaccine dose and DBS collection increased. Diabetes was associated with a 16.1% lower anti-S1 MFI (95%CI:-22.4,-9.5) whereas neither hypertension (-3.8%;95%CI:-9.3,2.1), nor cardiovascular disease history (-5.3%;95%CI:-16.3,7.4) were associated with anti-S1 MFI. Former and current smoking history were each associated with a lower anti-S1 MFI: (-6.6%;95%CI:-12.1,-0.8) and (-16.1%;95%CI:-24.7,-6.6), respectively. Participants with a BMI 25-29.9 kg/m 2 had a 7.6% higher anti-S1 MFI (95%CI:0.3,15.4) whereas those with a BMI of 30-35 kg/m 2 and >35 kg/m 2 had 6.2% (95%CI:-2.4,15.5) higher and 8.9% lower (95%CI:-17.6,0.7) MFI levels, respectively. Older age and male sex were each associated with a lower anti-S1 MFI and mRNA-1273 vaccine, Asian subgroup, higher anti-N titer, and prior COVID-19 infection were each associated with higher anti-S1 MFI. Chronic kidney disease, education attainment, and lung disease were not associated with anti-S1 MFI. Conclusions: Several traditional cardiovascular disease risk factors were associated with diminished humoral responses to the initial COVID-19 vaccine regimens in a diverse U.S. population-based cohort and may have implications on strategies to improve vaccine responses.

Rationale: The impact of the COVID-19 pandemic on tobacco use patterns remains incompletely understood. We aimed to examine changes in cigarette smoking patterns over the first 2 years of the COVID-19 pandemic (2020-22) in a large, multiethnic, US community-based sample. Methods: The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) ascertained the impact of the COVID-19 pandemic on participants from 14 longitudinal NIH-funded cohorts via 2 waves of standardized questionnaires conducted 2020-22. The C4R questionnaire collected data on cigarette use patterns for the current and immediate pre-pandemic periods (January-March 2020). These data were used to define pandemic-era smoking initiation, smoking cessation, and changes in smoking intensity. Multivariable logistic regression models were adjusted for centrally harmonized pre-pandemic data on sociodemographic characteristics, remote smoking history, and co-morbidities and pandemic-era psychological health, insomnia, and SARS-CoV-2 infection history ascertained through C4R questionnaires. Multiple imputation by chained equations was used to account for missing covariate data. Results: Of 17179 participants completing C4R questions on pandemic-era smoking behaviors, 1899 (11%) participants reported current smoking in the immediate pre-pandemic period (mean age 70 years, 59% women, 31% African American, 2% Hispanic, 1% Asian, 22% American Indian/Alaskan Native [AIAN]). Of these 181 (10%) self-reported quitting during the pandemic. Among 1718 (90%) who continued smoking, smoking intensity increased in 17% and decreased in 26%. Among 15093 participants who were not smoking prior to March 2020, 135 (0.9%) initiated smoking during the pandemic period, including 120 (89%) with a remote history of smoking and 15 (11%) with no history of smoking. Pandemic-era smoking cessation was associated with older age(80+ years vs Conclusion: Greater odds of smoking initiation and/or increased smoking intensity were observed in minoritized groups and participants reporting depressive symptoms. Majority of those who initiated smoking during pandemic-era were relapsers. Smoking cessation programs remain important to improving public health and reducing health disparities.

Introduction: Black adults experience the highest hypertension burden of any American group. Evidence indicates social factors adversely affecting Black people explain some of the excess hypertension burden. It’s unclear whether residential segregation, a key cause of health inequities, has a differential impact on Black and White people. Hypothesis: The magnitude of the association of residential segregation and risk of incident hypertension will be greater in Black than White people. Methods: Our sample included 6,143 Black and White REasons for Geographic And Racial Differences in Stroke (REGARDS) study participants without prevalent hypertension (2003-7), and with a follow-up visit 9.3 years later. Baseline county-level segregation was measured with the (1) dissimilarity index (DI, the difference in race distribution of census tracts relative to their county), (2) isolation index (ISI, the degree to which Black people are exposed only to one another in a county), and (3) interaction index (ITI, the degree to which Black people are exposed to White people in a county). Modified Poisson regression estimated the risk ratios (RR) of incident hypertension per SD increment of baseline residential segregation. Results: The mean (SD) age was 61(8) years for Black people and 62(8) years for White people. Hypertension incidence was 46% for Black people and 33% for White people. There was no association of any of the three measures of residential segregation (DI, ISI and ITI) with incident hypertension, with RRs all around 1.0 ( Figure ). Conclusions: Three measures of residential segregation were not associated with incident hypertension risk in Black and White participants of the REGARDS cohort. Findings differ from a previous study that reported that a measure of racial clustering was associated with higher risk of hypertension in Black people. Taken together, findings suggest that, in Black people, different domains of residential segregation capture factors related differently to hypertension development.

Introduction: Long-term neurological consequences (eg, stroke, impaired cognition) have been linked to SARS-CoV-2 infection and severity. There are limited data from studies with racial, ethnic, socioeconomic, and geographic diversity. C4R is a prospective study of adults from 14 cohorts that aims to link pre-COVID phenotyping, including cognition (8 studies), to COVID related illness and sequelae. We aimed to conduct pre-statistical harmonization of cognitive tests administered in English and Spanish from 8 cohorts: ARIC, CARDIA, FHS, HCHS/SOL-INCA, MESA, NOMAS, REGARDS, and SHS (Table). Methods: We conducted extensive item-level review of administration, scoring, and coding procedures and score distributions for 84 tests administered in English (all studies) and Spanish (NOMAS, MESA, HCHS/SOL-INCA). Results: Orientation to time and 3-word registration and recall spanned all studies and both languages. Word list recall and verbal fluency (animal; letter) spanned 7 studies (Table). There was variability in the structure, content, administration, scoring, and data coding procedures for items across cohorts and between Spanish and English. Word lists varied by number of words (9-16) and learning trials (3-5). Animal naming varied by time (30 vs. 60 seconds), animal type (4-legged vs. any animal), and scoring (allowing mythical/imaginary animals). Letter fluency varied by whether both Spanish and English words were permitted. Other tests differed by version, study-specific adaptations, prompts/cues, and specificity of scoring rules across cohorts. Conclusions: Cognitive test harmonization requires detailed review of administration, scoring, coding, translation, and procedural differences. Accounting for this variability is essential to cognitive data interpretation. Our pre-statistical harmonization will inform data augmentation and formal harmonization to yield harmonized measures of cognition to clarify population-level differences in cognitive outcomes linked to SARS-CoV-2 infection.

Background: Black adults have a disproportionate hypertension burden. While some excess risk is mediated by diet and sociodemographics factors (e.g., income, education) much remains unexplained. Pro-thrombotic and pro-inflammatory states are associated with hypertension risk; higher coagulation factor VIII (FVIII) is associated with thrombosis, inflammation, and cardiovascular disease. Black adults have higher FVIII than White adults. We sought to estimate incident hypertension risk among Black and White REGARDS adults by FVIII level, and determine if FVIII mediates some of the excess hypertension burden in Black REGARDS participants. Methods: Hypertension was use of blood pressure (BP)-lowering medications or 140/90 mm Hg BP threshold. We included Black and White participants from REGARDS without Visit 1 (2003-2007) hypertension, and hypertension assessment at visit 2 (2013-2016), and Visit 1 ELISA-measured FVIII. Modified Poisson regression estimated risk ratios (RR) of incident hypertension by FVIII level in models controlling for known confounders, stratified by race given a significant race*FVIII interaction on incident hypertension. Inverse odds ratio weighting estimated % mediation of the Black-White hypertension risk in each model that was due to FVIII. Results: Among the 1,870 included participants, mean (SD) age was 62 (8), 51% were female and 36% were Black participants. Relative to White participants, Black participants had higher mean FVIII level (114% vs. 103%; PFigure ). Factor VIII did not mediate excess burden of hypertension among Black participants in any models. Conclusions: FVIII was not associated with greater hypertension risk and did not mediate any of the excess burden of incident hypertension seen among Black participants.

Background: Limited population-based evidence is available about risk factor management following stroke. We examined age, race, sex, and regional (Stroke Belt vs. other) differences in discharge antihypertensive prescribing and smoking cessation counseling after ischemic stroke using population level data from a national cohort study. Methods: Medical record data was abstracted from 1042 participants enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study who had an adjudicated ischemic stroke between 2003-2016. Participants with a history of prior stroke, in-hospital death, hospice discharge, incomplete records, and non-smokers for smoking cessation analyses were excluded resulting in 798 cases for discharge antihypertensive prescribing and 117 cases for smoking cessation counseling in the final analyses. Differences were assessed using modified Poisson regression adjusting for patient and hospital level factors. Results: Overall, 86% received discharge antihypertensives while 50% of current smokers received counseling at discharge. Participants who were older, female, had a greater number of CV risk factors, and higher BMIs were significantly more likely to receive discharge antihypertensives compared to younger participants, males, those with fewer risk factors and lower BMIs, respectively (age RR 1.05; 95% CI, 1.02-1.09; female sex RR 1.09; 95% CI, 1.03-1.16; total risk factors RR 1.07; 95% CI, 1.04-1.10; BMI RR 1.01; 95% CI, 1.00-1.01). There was an increasing trend in receipt of smoking cessation counseling over time (RR 1.12; 95% CI, 1.04-1.21). Conclusions: Discharge antihypertensive prescribing varies modestly by patient-level variables. There were no differences in smoking cessation counseling by age, sex, race, or study region. Smoking cessation counseling has improved over time, yet only half of smokers received cessation counseling.

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

Background: Leptin is an anorexigenic and sympathoexcitatory adipokine strongly associated with obesity and associated with hypertension in animal models. Whether leptin is associated with hypertension incidence independent of obesity is unclear. Methods: REGARDS recruited 30,239 Black or White adults aged ≥45 years recruited from 48 US contiguous states in 2003-07 with a second visit in 2013-16. Baseline serum leptin was measured by ELISA in a sex- and race-stratified sample of 4,400 REGARDS participants. Modified Poisson regression estimated relative risk (RR) of incident hypertension (140/90 mm Hg threshold or use of antihypertensives) per higher leptin tertile, stratified by a BMI of 30 kg/m 2 , adjusting for known confounders. Results: Among the 1,834 participants without prevalent hypertension (mean [SD] age 62, 56% women, 25% Black adults), median follow-up was 9 years. Incident hypertension developed in 35%. BMI significantly modified the relationship between leptin and incident hypertension (P-interaction 2 ( Figure ). This association was fully attenuated when adjusting for waist circumference and BMI. Conclusions: Leptin is associated with hypertension among normal weight but not obese adults in REGARDS. Adiposity may be on the causal pathway between leptin levels and obesity.

Background: Leptin is a hypertension-related adipokine. We previously found leptin to associate with greater risk of incident hypertension in non-obese adults. Relative to White adults, Black adults have higher circulating leptin concentration. As such, leptin may be a mediator of the excess burden of incident hypertension among Black adults. Methods: REGARDS recruited 30,239 Black or White adults aged ≥45 years from 48 US states. Leptin was measured from baseline samples among 4,400 participants who attended 2 visits 9 years apart. Modified Poisson regression estimated the relative risk (RR) of incident hypertension (≥140/90 mmHg or use of antihypertensives) of Black relative to White adults, adjusting for risk factors. Inverse odds ratio weighting estimated the % mediation by leptin of the excess hypertension RR among Black relative to White participants in 1,000 bootstrapped samples. Results: In 1,834 participants without prevalent hypertension (mean age 62, 56% women, 25% Black adults), incident hypertension developed in 47% of Black & 32% of White participants. The Table presents the RR for incident hypertension among Black relative to White adults. In the crude model, Black adults had a 52% greater risk of incident hypertension and leptin mediated 20% of this disparity. Similar associations were seen when adjusting for demographics, behaviors, and diseases. After adjusting for measures of adiposity, leptin no longer mediated the disparity. Conclusions: Leptin mediated approximately 20% of the Black-White disparity in hypertension incidence in crude and some adjusted models. These data support that this mediation acts through adiposity.