Cytokines, C-Reactive Protein, and Risk of Incident Hypertension in the REGARDS Study.

BACKGROUND: Hypertension is a highly prevalent cardiovascular disease risk factor that may be related to inflammation. Whether adverse levels of specific inflammatory cytokines relate to hypertension is unknown. The present study sought to determine whether higher levels of IL (interleukin)-1ß, IL-6, TNF (tumor necrosis factor)-α, IFN (interferon)-γ, IL-17A, and CRP (C-reactive protein) are associated with a greater risk of incident hypertension. METHODS: The REGARDS study (Reasons for Geographic and Racial Difference in Stroke) is a prospective cohort study that recruited 30 239 community-dwelling Black and White adults from the contiguous United States in 2003 to 2007 (visit 1), with follow-up 9 years later in 2013 to 2016 (visit 2). We included participants without prevalent hypertension who attended follow-up 9 years later and had available laboratory measures and covariates of interest. Poisson regression estimated the risk ratio of incident hypertension by level of inflammatory biomarkers. RESULTS: Among 1866 included participants (mean [SD] aged of 62 [8] years, 25% Black participants, 55% women), 36% developed hypertension. In fully adjusted models comparing the third to first tertile of each biomarker, there was a greater risk of incident hypertension for higher IL-1ß among White (1.24 [95% CI, 1.01-1.53]) but not Black participants (1.01 [95% CI, 0.83-1.23]) and higher TNF-α (1.20 [95% CI, 1.02-1.41]) and IFN-γ (1.22 [95% CI, 1.04-1.42]) among all participants. There was no increased risk with IL-6, IL-17A, or CRP. CONCLUSIONS: Higher levels of IL-1ß, TNF-α, and IFN-γ, representing distinct inflammatory pathways, are elevated in advance of hypertension development. Whether modifying these cytokines will reduce incident hypertension is unknown.

Interleukin-6, Diabetes, and Metabolic Syndrome in a Biracial Cohort: The Reasons for Geographic and Racial Differences in Stroke Cohort.

OBJECTIVE: Black Americans have a greater risk of type 2 diabetes than White Americans. The proinflammatory cytokine interleukin-6 (IL-6) is implicated in diabetes pathogenesis, and IL-6 levels are higher in Black individuals. This study investigated associations of IL-6 with incident diabetes and metabolic syndrome in a biracial cohort. RESEARCH DESIGN AND METHODS: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study enrolled 30,239 Black and White adults age ≥45 years in 2003-2007, with a follow-up ∼9.5 years later. Baseline plasma IL-6 was measured in 3,399 participants at risk of incident diabetes and 1,871 at risk of metabolic syndrome. Relative risk (RR) by IL-6 was estimated with modified Poisson regression for both groups. RESULTS: Incident diabetes occurred in 14% and metabolic syndrome in 20%; both rates rose across IL-6 quartiles. There was a three-way interaction of IL-6, race, and central adiposity for incident diabetes (P = 8 × 10-5). In Black participants with and without central adiposity, RRs were 2.02 (95% CI 1.00-4.07) and 1.66 (1.00-2.75) for the fourth compared with first IL-6 quartile, respectively. The corresponding RRs were 1.73 (0.92-3.26) and 2.34 (1.17-4.66) in White participants. The pattern was similar for IL-6 and metabolic syndrome. CONCLUSIONS: Although IL-6 was higher in Black than in White participants and those with central adiposity, the association of IL-6 with diabetes risk was statistically significant only among White participants without central adiposity. The association with metabolic syndrome risk was similarly stronger in low-risk groups. The results support the concept of interventions to lower inflammation in diabetes prevention, but to reduce race disparities, better biomarkers are needed.

Urban-rural differences in hypertension prevalence, blood pressure control, and systolic blood pressure levels.

Higher rates of cardiovascular events have been observed among rural residents compared with urban. Hypertension and lack of blood pressure (BP) control are risk factors for cardiovascular events. We compared the prevalence of hypertension and controlled BP, and the distribution of systolic blood pressure (SBP), by urban-rural residence. Participants from the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study, a prospective cohort of Black and White adults aged ≥45 years, were categorized as either urban, large rural, or small-isolated rural, by using the Rural-Urban Commuting Area (RUCA) categorization B system. Oucomes were hypertension prevalence (BP ≥ 140/90 mmHg or antihypertensive use), BP control (BP < 140/90 among participants on antihypertensive medication), and the distribution of SBP. Counfounders were age, race, sex, antihypertensive medication use, and US Census Bureau division. The analysis included 26,133 participants (80.3% urban, 11.6% large-rural, 8.2% small-isolated rural). The unadjusted prevalence of hypertension was not different between groups. However, after adjustment, the odds of hypertension was higher among participants in the large rural group (odds ratio [OR] 1.17; 95% confidence interval [CI], 1.08-1.27) and small-isolated rural group (OR 1.19; 95% CI, 1.08-1.30), compared with the urban group. There was no evidence of an adjusted difference in BP control for those taking antihypertensive medications. Adjusted differences in SBP were greater for both rural groups, compared with urban, at the higher percentiles of SBP. Rural residence was associated with a higher adjusted odds of hypertension and higher SBP.

Associations of Telomere Length and Change With Cognitive Decline Were Modified by Sex and Race: The REGARDS Study.

INTRODUCTION: We examined the associations of baseline telomere length (TL) and TL change with cognitive function over time in older US adults, as well as differences by sex and race. METHODS: A total of 1820 cognitively healthy individuals (median baseline age: 63 years) were included. Telomere length was measured using qPCR-based method at baseline and among 614 participants in the follow-up examination 10 years later. Cognitive function was assessed by a four-test battery every 2 years. RESULTS: In multivariable-adjusted linear mixed models, longer baseline TL and smaller attrition/lengthening of TL over time were associated with better Animal Fluency Test score. Longer baseline TL was also linearly associated with better Letter Fluency Test score. The observed associations were consistently more pronounced in women than men and in Black compared to White participants. DISCUSSION: Telomere length may be a biomarker that predicts long-term verbal fluency and executive function, particularly in women and Black Americans.

D-dimer and the risk of hypertension: The REasons for Geographic And Racial Differences in Stroke Cohort Study.

Background: Reasons for increased risk of hypertension in Black compared with White people are only partly understood. D-dimer, a thrombo-inflammatory marker higher in Black individuals, is also higher in people with hypertension. However, the impact of D-dimer on racial disparities in risk of incident hypertension has not been studied. Objectives: To assess whether D-dimer is associated with the risk of incident hypertension, whether the association between D-dimer and the risk of incident hypertension differs by race, and whether the biology reflected by D-dimer explains racial disparities in the risk of incident hypertension. Methods: This study included 1867 participants in the REasons for Geographic And Racial Differences in Stroke cohort study without baseline hypertension and with a second visit 9.4 years after baseline. Risk ratios of incident hypertension by baseline D-dimer level were estimated, a D-dimer-by-race interaction was tested, and the mediating effect of D-dimer (which represents underlying biological processes) on the association of race and hypertension risk was assessed. Results: The risk of incident hypertension was 47% higher in persons in the top quartile than in those in the bottom quartile of D-dimer (risk ratio [RR]: 1.47; 95% CI: 1.23-1.76). The association was partly attenuated after adjusting for sociodemographic and adiposity-related risk factors (RR: 1.22; 95% CI: 1.02-1.47). The association of D-dimer and hypertension did not differ by race, and D-dimer did not attenuate the racial difference in the risk of incident hypertension. Conclusion: D-dimer concentration reflects pathophysiology related to the development of hypertension. Specific mechanisms require further study and may involve adiposity.

Telomere shortening and the transition to family caregiving in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study.

Telomere length (TL) is widely studied as a possible biomarker for stress-related cellular aging and decreased longevity. There have been conflicting findings about the relationship between family caregiving stress and TL. Several initial cross-sectional studies have found associations between longer duration of caregiving or perceived stressfulness of caregiving and shortened TL, suggesting that caregiving poses grave risks to health. Previous reviews have suggested the need for longitudinal methods to investigate this topic. This study examined the association between the transition to family caregiving and change in TL across ~9 years. Data was utilized from the Caregiving Transitions Study, an ancillary study to the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. TL was assayed using qPCR and analyzed as the telomere-to-single copy gene ratio for each participant at baseline and follow-up. General linear models examined the association between caregiving status and the change in TL for 208 incident caregivers and 205 controls, as well as associations between perceived stress and TL among caregivers. No association was found between TL change and caregiving (p = 0.494), and fully adjusted models controlling for health and socioeconomic factors did not change the null relationship (p = 0.305). Among caregivers, no association was found between perceived caregiving stress and change in TL (p = 0.336). In contrast to earlier cross-sectional studies, this longitudinal, population-based study did not detect a significant relationship between the transition into a family caregiving role and changes in TL over time. Given the widespread citation of previous findings suggesting that caregiving shortens telomeres and places caregivers at risk of early mortality, these results demonstrate the potential need of a more balanced narrative about caregiving.

Rural/urban differences in the prevalence of stroke risk factors: A cross-sectional analysis from the REGARDS study.

PURPOSE: We previously described the magnitude of rural-urban differences in the prevalence of stroke risk factors and stroke mortality. In this report, we sought to extend the understanding of rural-urban differences in the prevalence of stroke risk factors by using an enhanced definition of rural-urban status and assessing the impact of neighborhood socioeconomic status (nSES) on risk factor differences. METHODS: This analysis included 28,242 participants without a history of stroke from the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. Participants were categorized into the 6-level ordinal National Center for Health Statistics Urban-Rural Classification Scheme. The prevalence of stroke risk factors (hypertension, diabetes, smoking, atrial fibrillation, left ventricular hypertrophy, and heart disease) was assessed across the rural-urban scale with adjustment for demographic characteristics and further adjustment for nSES score. FINDINGS: Hypertension, diabetes, and heart disease were more prevalent in rural than urban regions. Higher odds were observed for these risk factors in the most rural compared to the most urban areas (odds ratios [95% CI]: 1.25 [1.11-1.42] for hypertension, 1.15 [0.99-1.33] for diabetes, and 1.19 [1.02-1.39] for heart disease). Adjustment for nSES score partially attenuated the odds of hypertension and heart disease with rurality, completely attenuated the odds of diabetes, and unmasked an association of current smoking. CONCLUSIONS: Some of the higher stroke mortality in rural areas may be due to the higher burden of stroke risk factors in rural areas. Lower nSES contributed most notably to rural-urban differences for diabetes and smoking.

Health care experiences during the COVID-19 pandemic by race and social determinants of health among adults age ≥ 58 years in the REGARDS study.

BACKGROUND: Understanding health care experiences during the COVID-19 pandemic may provide insights into patient needs and inform policy. The objective of this study was to describe health care experiences by race and social determinants of health. METHODS: We conducted a telephone survey (July 6, 2020-September 4, 2021) among 9492 Black and White participants in the longitudinal REasons for Geographic And Racial Differences in Stroke cohort study, age 58-105 years, from the continental United States. Among participants with symptoms of COVID-19, outcomes were: 1. Sought care or advice for the illness; 2. Received a SARS-CoV-2 test for the illness; and 3. Tested positive. Among participants without symptoms of COVID-19, outcomes were: 1. Wanted a test; 2. Wanted and received a test; 3. Did not want but received a test; and 4. Tested positive. We examined these outcomes overall and in subgroups defined by race, household income, marital status, education, area-level poverty, rural residence, Medicaid expansion, public health infrastructure ranking, and residential segregation. RESULTS: The average age of participants was 76.8 years, 36% were Black, and 57% were female. Among participants with COVID-19 symptoms (n = 697), 74% sought care or advice for the illness, 50% received a SARS-CoV-2 test, and 25% had a positive test (50% of those tested). Among participants without potential COVID-19 symptoms (n = 8795), 29% wanted a SARS-CoV-2 test, 22% wanted and received a test, 8% did not want but received a test, and 1% tested positive; a greater percentage of participants who were Black compared to White wanted (38% vs 23%, p < 0.001) and received tests (30% vs 18%, p < 0.001) and tested positive (1.4% vs 0.8%, p = 0.005). CONCLUSIONS: In this national study of older US adults, many participants with potential COVID-19 symptoms and asymptomatic participants who desired testing did not receive COVID-19 testing.

Thrombo-inflammatory biomarkers and D-dimer in a biracial cohort study.

BACKGROUND: Higher D-dimer is a risk factor for cardiovascular diseases and venous thromboembolism. In the general population, D-dimer and other thrombo-inflammatory biomarkers are higher among Black individuals, who also have higher risk of these conditions compared to White people. OBJECTIVE: To assess whether Black individuals have an exaggerated correlation between D-dimer and thrombo-inflammatory biomarkers characteristic of cardiovascular diseases. METHODS: Linear regression was used to assess correlations of 11 thrombo-inflammatory biomarkers with D-dimer in a cross-sectional study of 1068 participants of the biracial Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. RESULTS: Adverse levels of most biomarkers, especially fibrinogen, factor VIII, C-reactive protein, N-terminal pro-B-type natriuretic peptide, and interleukin (IL)-6, were associated with higher D-dimer. Several associations with D-dimer differed significantly by race. For example, the association of factor VIII with D-dimer was more than twice as large in Black compared to White participants. Specifically, D-dimer was 26% higher per standard deviation (SD) higher factor VIII in Black adults and was only 11% higher per SD higher factor VIII in White adults. In Black but not White adults, higher IL-10 and soluble CD14 were associated with higher D-dimer. CONCLUSIONS: Findings suggest that D-dimer might relate to Black/White differences in cardiovascular diseases and venous thromboembolism because it is a marker of amplified thrombo-inflammatory response in Black people. Better understanding of contributors to higher D-dimer in the general population is needed.

Identifying Genetic and Biological Determinants of Race-Ethnic Disparities in Stroke in the United States.

In the United States, causes of racial differences in stroke and its risk factors remain only partly understood, and there is a long-standing disparity in stroke incidence and mortality impacting Black Americans. Only half of the excess risk of stroke in the United States Black population is explained by traditional risk factors, suggesting potential effects of other factors including genetic and biological characteristics. Here, we nonsystematically reviewed candidate laboratory biomarkers for stroke and their relationships to racial disparities in stroke. Current evidence indicates that IL-6 (interleukin-6), a proinflammatory cytokine, mediates racial disparities in stroke through its association with traditional risk factors. Only one reviewed biomarker, Lp(a) (lipoprotein[a]), is a race-specific risk factor for stroke. Lp(a) is highly genetically determined and levels are substantially higher in Black than White people; clinical and pharmaceutical ramifications for stroke prevention remain uncertain. Other studied stroke risk biomarkers did not explain racial differences in stroke. More research on Lp(a) and other biological and genetic risk factors is needed to understand and mitigate racial disparities in stroke.