Investigating peripheral blood monocyte and T-cell subsets as non-invasive biomarkers for asymptomatic hepatic steatosis: results from the Multi-Ethnic Study of Atherosclerosis.

Background: Circulating immune cells have gained interest as biomarkers of hepatic steatosis. Data on the relationships between immune cell subsets and early-stage steatosis in population-based cohorts are limited. Methods: This study included 1,944 asymptomatic participants of the Multi-Ethnic Study of Atherosclerosis (MESA) with immune cell phenotyping and computed tomography measures of liver fat. Participants with heavy alcohol use were excluded. A liver-to-spleen ratio Hounsfield units (HU) <1.0 and liver attenuation <40 HU were used to diagnose liver fat presence and >30% liver fat content, respectively. Logistic regression estimated cross-sectional associations of immune cell subsets with liver fat parameters adjusted for risk factors. We hypothesized that higher proportions of non-classical monocytes, Th1, Th17, and memory CD4+ T cells, and lower proportions of classical monocytes and naive CD4+ T cells, were associated with liver fat. Exploratory analyses evaluated additional immune cell phenotypes (n = 19). Results: None of the hypothesized cells were associated with presence of liver fat. Higher memory CD4+ T cells were associated with >30% liver fat content, but this was not significant after correction for multiple hypothesis testing (odds ratio (OR): 1.31, 95% confidence interval (CI): 1.03, 1.66). In exploratory analyses unadjusted for multiple testing, higher proportions of CD8+CD57+ T cells were associated with liver fat presence (OR: 1.21, 95% CI: 1.02, 1.44) and >30% liver fat content (OR: 1.34, 95% CI: 1.07, 1.69). Conclusions: Higher circulating memory CD4+ T cells may reflect liver fat severity. CD8+CD57+ cells were associated with liver fat presence and severity, but replication of findings is required.

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.

Levels of procoagulant factors and peak thrombin generation in relation to dementia risk in older adults: The Cardiovascular Health Study.

INTRODUCTION: Markers of hemostasis such as procoagulant factors and peak thrombin generation are associated with cardiovascular outcomes, but their associations with dementia risk are unclear. We aimed to evaluate prospective associations of selected procoagulant factors and peak thrombin generation with dementia risk. METHODS: We measured levels of 7 hemostatic factors (fibrinogen, factor VII coagulant activity [FVIIc], activated factor VII [FVIIa], factor VIIa-antithrombin [FVIIa-AT], factor XI antigen [FXI], peak thrombin generation, and platelet count) among participants in the Cardiovascular Health Study, a cohort of older adults free of dementia in 1992/1993 (n = 3185). Dementia was adjudicated and classified by DSM-IV criteria through 1998/1999. Cox proportional hazards models estimated hazard ratios (HRs) for any dementia associated with 1-standard deviation (SD) differences, adjusting for sociodemographic and clinical factors and APOE genotype. Secondary analyses separately evaluated the risk of vascular dementia, Alzheimer's disease, and mixed dementia. RESULTS: At baseline, participants had a median age of 73 years. Over 5.4 years of follow-up, we identified 448 dementia cases. There was no evidence of linear associations between levels of these hemostatic factors with any dementia risk (HRs per 1-SD difference ranged from 1.0 to 1.1; 95 % confidence intervals included 1.0). Results of secondary analyses by dementia subtype were similar. CONCLUSIONS: In this prospective study, there was no strong evidence of linear associations between levels of fibrinogen, FVIIc, FVIIa, FVIIa-AT, FXI, peak thrombin generation, or platelet count with dementia risk. Despite their associations with cardiovascular disease, higher levels of these biomarkers measured among older adults may not reflect dementia risk.

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.

Association of Immune Cell Subsets with Incident Hip Fracture: The Cardiovascular Health Study.

In this study, we aimed to evaluate the association of innate and adaptive immune cell subsets in peripheral blood mononuclear cells (PBMCs) with hip fracture. To conduct this study, we used data from the Cardiovascular Health Study (CHS), a U.S. multicenter observational cohort of community-dwelling men and women aged ≥ 65 years. Twenty-five immune cell phenotypes were measured by flow cytometry from cryopreserved PBMCs of CHS participants collected in 1998-1999. The natural killer (NK), γδ T, T helper 17 (Th17), and differentiated/senescent CD4+CD28- T cell subsets were pre-specified as primary subsets of interest. Hip fracture incidence was assessed prospectively by review of hospitalization records. Multivariable Cox hazard models evaluated associations of immune cell phenotypes with incident hip fracture in sex-stratified and combined analyses. Among 1928 persons, 259 hip fractures occurred over a median 9.7 years of follow-up. In women, NK cells were inversely associated with hip fracture [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.60-0.99 per one standard deviation higher value] and Th17 cells were positively associated with hip fracture [HR 1.18, 95% CI 1.01-1.39]. In men, γδ T cells were inversely associated with hip fracture [HR 0.60, 95% CI 0.37-0.98]. None of the measured immune cell phenotypes were significantly associated with hip fracture incidence in combined analyses. In this large prospective cohort of older adults, potentially important sex differences in the associations of immune cell phenotypes and hip fracture were identified. However, immune cell phenotypes had no association with hip fracture in analyses combining men and women.

Gene Expression and Splicing QTL Analysis of Blood Cells in African American Participants from the Jackson Heart Study.

Most gene expression and alternative splicing quantitative trait loci (eQTL/sQTL) studies have been biased toward European ancestry individuals. Here, we performed eQTL and sQTL analysis using TOPMed whole genome sequencing-derived genotype data and RNA sequencing data from stored peripheral blood mononuclear cells in 1,012 African American participants from the Jackson Heart Study (JHS). At a false discovery rate (FDR) of 5%, we identified 4,798,604 significant eQTL-gene pairs, covering 16,538 unique genes; and 5,921,368 sQTL-gene-cluster pairs, covering 9,605 unique genes. About 31% of detected eQTL and sQTL variants with a minor allele frequency (MAF) > 1% in JHS were rare (MAF < 0.1%), and therefore unlikely to be detected, in European ancestry individuals. We also generated 17,630 eQTL credible sets and 24,525 sQTL credible sets for genes (gene-clusters) with lead QTL p < 5e-8. Finally, we created an open database, which is freely available online, allowing fast query and bulk download of our QTL results.

Circulating differentiated and senescent lymphocyte subsets and incident diabetes risk in older adults: The Cardiovascular Health Study.

INTRODUCTION: Cellular senescence is a feature of aging implicated in the pathophysiology of diabetes mellitus (DM). Whether senescent lymphocytes are associated with the future occurrence of DM is uncertain. METHODS: We used cryopreserved peripheral blood mononuclear cells collected from 1860 Cardiovascular Health Study participants (average age 80.2 years) and flow cytometry immunophenotyping to evaluate the longitudinal relationships of naive (CD45RA+ ), memory (CD45RO+ ), senescent (CD28- ), and T effector memory RA+ (TEMRA) (CD28- CD57+ CD45RA+ ) CD4+ and CD8+ T cells, and memory B cells (CD19+ CD27+ ), with the risk of incident DM. In exploratory analyses we evaluated the relationships of 13 additional innate lymphocyte and CD4+ and CD8+ subsets with incident DM risk. RESULTS: Over a median follow-up time of 8.9 years, 155 cases of incident DM occurred. In Cox models adjusted for demographic variables (age, sex, race, study site and flow cytometry analytical batch) or diabetes risk factors (demographic variables plus education, body mass index, smoking status, alcohol use, systolic blood pressure, hypertension medication use and physical activity), no significant associations were observed for any CD4+ , CD8+ or CD19+ cell phenotypes with incident DM. CONCLUSIONS: These results suggest the frequencies of naive, memory and senescent T cells and memory B cells are not strongly associated with incident DM risk in older adults.

Circulating Soluble CD163, Associations With Cardiovascular Outcomes and Mortality, and Identification of Genetic Variants in Older Individuals: The Cardiovascular Health Study.

Background Monocytes/macrophages participate in cardiovascular disease. CD163 (cluster of differentiation 163) is a monocyte/macrophage receptor, and the shed sCD163 (soluble CD163) reflects monocyte/macrophage activation. We examined the association of sCD163 with incident cardiovascular disease events and performed a genome-wide association study to identify sCD163-associated variants. Methods and Results We measured plasma sCD163 in 5214 adults (aged ≥65 years, 58.7% women, 16.2% Black) of the CHS (Cardiovascular Health Study). We used Cox regression models (associations of sCD163 with incident events and mortality); median follow-up was 26 years. Genome-wide association study analyses were stratified on race. Adjusted for age, sex, and race and ethnicity, sCD163 levels were associated with all-cause mortality (hazard ratio [HR], 1.08 [95% CI, 1.04-1.12] per SD increase), cardiovascular disease mortality (HR, 1.15 [95% CI, 1.09-1.21]), incident coronary heart disease (HR, 1.10 [95% CI, 1.04-1.16]), and incident heart failure (HR, 1.18 [95% CI, 1.12-1.25]). When further adjusted (eg, cardiovascular disease risk factors), only incident coronary heart disease lost significance. In European American individuals, genome-wide association studies identified 38 variants on chromosome 2 near MGAT5 (top result rs62165726, P=3.3×10-18),19 variants near chromosome 17 gene ASGR1 (rs55714927, P=1.5×10-14), and 18 variants near chromosome 11 gene ST3GAL4. These regions replicated in the European ancestry ADDITION-PRO cohort, a longitudinal cohort study nested in the Danish arm of the Anglo-Danish-Dutch study of Intensive Treatment Intensive Treatment In peOple with screeNdetcted Diabetes in Primary Care. In Black individuals, we identified 9 variants on chromosome 6 (rs3129781 P=7.1×10-9) in the HLA region, and 3 variants (rs115391969 P=4.3×10-8) near the chromosome 16 gene MYLK3. Conclusions Monocyte function, as measured by sCD163, may be predictive of overall and cardiovascular-specific mortality and incident heart failure.

Association of immune cell subsets with incident heart failure in two population-based cohorts.

AIMS: Circulating inflammatory markers are associated with incident heart failure (HF), but prospective data on associations of immune cell subsets with incident HF are lacking. We determined the associations of immune cell subsets with incident HF as well as HF subtypes [with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF)]. METHODS AND RESULTS: Peripheral blood immune cell subsets were measured in adults from the Multi-Ethnic Study of Atherosclerosis (MESA) and Cardiovascular Health Study (CHS). Cox proportional hazard models adjusted for demographics, HF risk factors, and cytomegalovirus serostatus were used to evaluate the association of the immune cell subsets with incident HF. The average age of the MESA cohort at the time of immune cell measurements was 63.0 ± 10.4 years with 51% women, and in the CHS cohort, it was 79.6 ± 4.4 years with 62% women. In the meta-analysis of CHS and MESA, a higher proportion of CD4+ T helper (Th) 1 cells (per one standard deviation) was associated with a lower risk of incident HF [hazard ratio (HR) 0.91, (95% CI 0.83-0.99), P = 0.03]. Specifically, higher proportion of CD4+ Th1 cells was significantly associated with a lower risk of HFrEF [HR 0.73, (95% CI 0.62-0.85), <0.001] after correction for multiple testing. No association was observed with HFpEF. No other cell subsets were associated with incident HF. CONCLUSIONS: We observed that higher proportions of CD4+ Th1 cells were associated with a lower risk of incident HFrEF in two distinct population-based cohorts, with similar effect sizes in both cohorts demonstrating replicability. Although unexpected, the consistency of this finding across cohorts merits further investigation.

Monocyte subsets, T cell activation profiles, and stroke in men and women: The Multi-Ethnic Study of Atherosclerosis and Cardiovascular Health Study.

BACKGROUND AND AIMS: Despite mechanistic data implicating unresolving inflammation in stroke pathogenesis, data regarding circulating immune cell phenotypes - key determinants of inflammation propagation versus resolution - and incident stroke are lacking. Therefore, we aimed to comprehensively define associations of circulating immune phenotypes and activation profiles with incident stroke. METHODS: We investigated circulating leukocyte phenotypes and activation profiles with incident adjudicated stroke in 2104 diverse adults from the Multi-Ethnic Study of Atherosclerosis (MESA) followed over a median of 16.6 years. Cryopreserved cells from the MESA baseline examination were thawed and myeloid and lymphoid lineage cell subsets were measured using polychromatic flow cytometry and intracellular cytokine activation staining. We analyzed multivariable-adjusted associations of cell phenotypes, as a proportion of parent cell subsets, with incident stroke (overall) and ischemic stroke using Cox regression models. RESULTS: We observed associations of intermediate monocytes, early-activated CD4+ T cells, and both CD4+ and CD8+ T cells producing interleukin-4 after cytokine stimulation (Th2 and Tc2, respectively) with higher risk for incident stroke; effect sizes ranged from 35% to 62% relative increases in risk for stroke. Meanwhile, differentiated and memory T cell phenotypes were associated with lower risk for incident stroke. In sex-stratified analyses, positive and negative associations were especially strong among men but null among women. CONCLUSIONS: Circulating IL-4 producing T cells and intermediate monocytes were significantly associated with incident stroke over nearly two decades of follow-up. These associations were stronger among men and not among women. Further translational studies are warranted to define more precise targets for prognosis and intervention.

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.

Soluble Urokinase Plasminogen Activator Receptor: Genetic Variation and Cardiovascular Disease Risk in Black Adults.

BACKGROUND: suPAR (Soluble urokinase plasminogen activator receptor) has emerged as an important biomarker of coagulation, inflammation, and cardiovascular disease (CVD) risk. The contribution of suPAR to CVD risk and its genetic influence in Black populations have not been evaluated. METHODS: We measured suPAR in 3492 Black adults from the prospective, community-based JHS (Jackson Heart Study). Cross-sectional associations of suPAR with lifestyle and CVD risk factors were assessed, whole-genome sequence data were used to evaluate genetic associations of suPAR, and relationships of suPAR with incident CVD outcomes and overall mortality were estimated over follow-up. RESULTS: In Cox models adjusted for traditional CVD risk factors, estimated glomerular filtration rate, and CRP (C-reactive protein), each 1-SD higher suPAR was associated with a 21% to 31% increased risk of incident coronary heart disease, heart failure, stroke, and mortality. In the genome-wide association study, 2 missense (rs399145 encoding p.Thr86Ala, rs4760 encoding p.Phe272Leu) and 2 noncoding regulatory variants (rs73935023 within an enhancer element and rs4251805 within the promoter) of PLAUR on chromosome 19 were each independently associated with suPAR and together explained 14% of suPAR phenotypic variation. The allele frequencies of each of the four suPAR-associated genetic variants differ considerably across African and European populations. We further show that PLAUR rs73935023 can alter transcriptional activity in vitro. We did not find any association between genetically determined suPAR and CVD in JHS or a larger electronic medical record-based analyses of Blacks or Whites. CONCLUSIONS: Our results demonstrate the importance of ancestry-differentiated genetic variation on suPAR levels and indicate suPAR is a CVD biomarker in Black adults.

Association of immune cell subsets with cardiac mechanics in the Multi-Ethnic Study of Atherosclerosis.

BackgroundImmunomodulatory therapy may help prevent heart failure (HF). Data on immune cells and myocardial remodeling in older adults with cardiovascular risk factors are limited.MethodsIn the Multi-Ethnic Study of Atherosclerosis cohort, 869 adults had 19 peripheral immune cell subsets measured and underwent cardiac MRI during the baseline exam, of which 321 had assessment of left ventricular global circumferential strain (LV-GCS). We used linear regression with adjustment for demographics, cardiovascular risk factors, and cytomegalovirus serostatus to evaluate the cross-sectional association of immune cell subsets with left ventricular mass index (LVMI) and LV-GCS.ResultsThe average age of the cohort was 61.6 ± 10.0 years and 53% were women. Higher proportions of γ/δ T cells were associated with lower absolute (worse) LV-GCS (-0.105% [95% CI -0.164%, -0.046%] per 1 SD higher proportion of γ/δ T cells, P = 0.0006). This association remained significant after Bonferroni's correction. Higher proportions of classical monocytes were associated with worse absolute LV-GCS (-0.04% [95% CI -0.07%, 0.00%] per 1 SD higher proportion of classical monocytes, P = 0.04). This did not meet significance after Bonferroni's correction. There were no other significant associations with LV-GCS or LVMI.ConclusionPathways associated with γ/δ T cells may be potential targets for immunomodulatory therapy targeted at HF prevention in populations at risk.FundingContracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 and grant R01 HL98077 from the National Heart, Lung, and Blood Institute/NIH and grants KL2TR001424, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences/NIH.

Impact of an institutional grant award on early career investigator applicants and peer reviewers.

BACKGROUND: Obtaining research funding support is integral to a successful career in science. Training and practice in grant writing, as well as engagement in peer review of grant applications may help lead to successful research funding. However, there is little evidence on the impact of institutional programs on the career development of early career investigators (ECIs). OBJECTIVES: Understand the impact of participation in an institutional research award program on the career development of ECIs. METHODS: The Cardiovascular Research Institute of Vermont established an Early Career Research (ECR) award program in 2018. ECIs who participated as applicants or reviewers in the first 3 years of the program (2018-2020) were surveyed to understand the impact of the ECR award program on their grant writing and professional development. RESULTS: Ninety-four percent of 17 applicants and 90% of 19 reviewers completed the survey. Ninety-two percent of funded and 75% of unfunded applicants, and 87% of reviewers reported that the program was beneficial to their professional development. Similarly, 85% of funded applicants, 75% of unfunded applicants, and 80% of reviewers reported improvement in their grant-writing skills. All respondents reported they would recommend the ECR award program to their peers. CONCLUSIONS: This single-institution ECR award program had a positive impact on ECI's professional development and grant-writing skills and may lead to further extramural funding opportunities.

Soluble CD14 Levels in the Jackson Heart Study: Associations With Cardiovascular Disease Risk and Genetic Variants.

[Figure: see text].

Nonclassical Monocytes (CD14dimCD16+) Are Associated With Carotid Intima-Media Thickness Progression for Men but Not Women: The Multi-Ethnic Study of Atherosclerosis-Brief Report.

[Figure: see text].

Natural killer cells, gamma delta T cells and classical monocytes are associated with systolic blood pressure in the multi-ethnic study of atherosclerosis (MESA).

BACKGROUND: Hypertension is a major source of cardiovascular morbidity and mortality. Recent evidence from mouse models, genetic, and cross-sectional human studies suggest increased proportions of selected immune cell subsets may be associated with levels of systolic blood pressure (SBP). METHODS: We assayed immune cells from cryopreserved samples collected at the baseline examination (2000-2002) from 1195 participants from the multi-ethnic study of atherosclerosis (MESA). We used linear mixed models, with adjustment for age, sex, race/ethnicity, smoking, exercise, body mass index, education, diabetes, and cytomegalovirus titers, to estimate the associations between 30 immune cell subsets (4 of which were a priori hypotheses) and repeated measures of SBP (baseline and up to four follow-up measures) over 10 years. The analysis provides estimates of the association with blood pressure level. RESULTS: The mean age of the MESA participants at baseline was 64 ± 10 years and 53% were male. A one standard deviation (1-SD) increment in the proportion of γδ T cells was associated with 2.40 mmHg [95% confidence interval (CI) 1.34-3.42] higher average systolic blood pressure; and for natural killer cells, a 1-SD increment was associated with 1.88 mmHg (95% CI 0.82-2.94) higher average level of systolic blood pressure. A 1-SD increment in classical monocytes (CD14++CD16-) was associated with 2.01 mmHG (95% CI 0.79-3.24) lower average systolic blood pressure. There were no associations of CD4+ T helper cell subsets with average systolic blood pressure. CONCLUSION: These findings suggest that the innate immune system plays a role in levels of SBP whereas there were no associations with adaptive immune cells.

Soluble CD14, Ischemic Stroke, and Coronary Heart Disease Risk in a Prospective Study: The REGARDS Cohort.

Background Soluble CD14 (sCD14), a circulating pattern recognition receptor, has been suggested as a cardiovascular disease risk factor. Prospective studies evaluating sCD14 with incident cardiovascular disease events are limited, particularly among racially diverse populations. Methods and Results Between 2003 and 2007, the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study recruited 30 239 black and white participants across the United States. In a nested case-cohort study, sCD14 was measured in baseline serum from 548 cases of incident ischemic stroke, 612 cases of incident coronary heart disease (CHD), and a cohort random sample (n=1039). Cox models estimated hazards ratios (HR) of incident ischemic stroke or CHD per 1 SD higher sCD14, adjusting for cardiovascular disease risk factors. There was a differential association of sCD14 with ischemic stroke and CHD risk by race. Among blacks, the adjusted HR of stroke per SD increment of sCD14 was 1.42 (95% CI: 1.12, 1.80), with no association among whites (HR 1.02 [95% CI: 0.82, 1.27]). Higher sCD14 was associated with increased CHD risk in blacks but not whites, and relationships between sCD14 and CHD were stronger at younger ages. Adjusted for risk factors, the HR of CHD per SD higher sCD14 among blacks at age 45 years was 2.30 (95% CI: 1.45, 3.65) compared with 1.56 (95% CI: 0.94, 2.57) among whites. At age 65 years, the CHD HR was 1.51 (95% CI: 1.20, 1.91) among blacks and 1.02 (95% CI: 0.80, 1.31) among whites. Conclusions sCD14 may be a race-specific stroke and CHD risk marker.