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Background Hemostasis is a key factor in cerebrovascular disease, but the association of hemostatic factors with cognitive decline is unclear.Objective To prospectively evaluate associations of 20 hemostatic factor levels with changes in cognition during >= 8 years of follow-up in the Cardiovascular Health Study (CHS) of older adults.Methods We included participants of an existing CHS cross-sectional substudy (n = 400) with hemostatic factors measured in 1989-1990. Between 1989-1990 and 1998-1999, cognitive function was measured using the Modified Mini-Mental State Examination (3MSE) and Digit Symbol Substitution Tests. Mixed-effects linear regression models estimated change in cognitive function over time, adjusting for sociodemographic and clinical factors and APOE genotype, using Bonferroni adjustment. We also derived principal components to account for the interrelationship among factors.Results Of 20 factors evaluated individually, only higher levels of plasmin-alpha(2)-antiplasmin complex (PAP), tissue factor pathway inhibitor (TFPI), and lower factor X (FXc) levels were associated with faster cognitive decline, estimated by annual change in 3MSE points (1 standard deviation PAP beta = -0.65, 95% confidence interval [CI]: -1.08 to -0.21; TFPI beta = -0.55, 95% CI: -0.90 to -0.19; FXc beta = 0.52, 95% CI: 0.21-0.84). One of four principal components, loading positively on D-dimer, prothrombin fragment 1.2 (F1.2), and PAP was significantly associated with change in 3MSE.Conclusions Levels of PAP, TPFI, and FXc and a combination of factors driven by PAP, D-dimer, and F1.2 were associated with cognitive decline. Whether these findings can be used to improve dementia prevention or prediction requires further study.

Context: Mechanisms explaining documented associations of 25-hydroxyvitamin D [25(OH)D] deficiency with increased risks of cardiovascular disease (CVD) and venous thromboembolism may relate to adverse hemostatic and inflammatory responses. Objective: To evaluate whether 25(OH)D deficiency is associated with a prothrombotic and proinflammatory biological profile. Design: Cross-sectional analyses. Setting: The Multi-Ethnic Study of Atherosclerosis, a multicenter prospective cohort of American adults. Participants: Up to 6554 adults free of CVD. Main Outcome Measures: Ten hemostatic biomarkers (D-dimer, fibrinogen, factor VIII, plasmin-antiplasmin, and homocysteine [n = 6443]; von Willebrand factor, soluble tissue factor, plasminogen activator inhibitor-1 (PAI-1), total tissue factor pathway inhibitor (TFPI), and soluble thrombomodulin [n = 814]), and three inflammatory biomarkers (IL-6, C-reactive protein [n = 6443], and TNF-α soluble receptor [n = 3802]). Results: Among 6443 subjects (46.6% men; mean age, 62.1 years; mean body mass index, 28.3 kg/m2) of White (37.8%), Black (27.2%), Chinese (12.2%), and Hispanic (21.8%) race/ethnicity, mean 25(OH)D was 25.3 ng/mL. After multiple adjustment, 25(OH)D concentrations were associated with concentrations of IL-6 and homocysteine and also with concentrations of PAI-1 and TFPI: per 10 ng/mL decrement in 25(OH)D, 5.1% higher IL-6 (95% confidence interval [CI], 3.4-6.9; P < .001); 3.7% higher homocysteine (95% CI, 3.0-4.3; P < .001); 7.0% higher PAI-1 (95% CI, 0.9-13.6; P = .025); and 2.1% higher TFPI (95% CI, 0.0-4.2; P = .047), without racial/ethnic heterogeneity. No significant associations were observed for other hemostatic and inflammatory biomarkers. Conclusions: Increased inflammation as reflected by higher circulating IL-6 and increased homocysteine concentrations may represent mechanisms linking 25(OH)D deficiency to greater risks of CVD and perhaps venous thromboembolism. Low concentrations of 25(OH)D were also associated with PAI-1 and TFPI concentrations, but not with other hemostatic biomarkers.

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.

Background Multiple prospective studies have established an association between inflammation and higher risk of atrial fibrillation (AF), but the association between lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity and incident AF has not been extensively evaluated. Methods Using data from 10,794 Atherosclerosis Risk In Communities (ARIC) study participants aged 53-75 years, 5,181 Cardiovascular Health Study (CHS) participants aged 65 to 100 years, and 5,425 Multi-Ethnic Study of Atherosclerosis (MESA) participants aged 45-84 years, we investigated the association between baseline Lp-PLA2 levels and the risk of developing AF. Incident AF was identified in each cohort by follow-up visit electrocardiograms, hospital discharge coding of AF, or Medicare claims data. Results Over a mean of 13.1, 11.5, and 10.0 years of follow-up, 1,439 (13%), 2,084 (40%), and 615 (11%) incident AF events occurred in ARIC, CHS, and MESA, respectively. In adjusted analyses, each SD increment in Lp-PLA2 activity was associated with incident AF in both ARIC (hazard ratio [HR] 1.13, 95% CI 1.06-1.20) and MESA (HR 1.24, 95% CI 1.05-1.46). Each SD increment in Lp-PLA2 mass was also associated with incident AF in MESA (HR 1.25, 95% CI 1.11-1.41). No significant associations were observed among CHS participants. Conclusions Although higher Lp-PLA2 mass and activity were associated with development of AF in ARIC and MESA, this relationship was not observed in CHS, a cohort of older individuals.

Objective— Plasma levels of the fibrinogen degradation product D-dimer are higher among African Americans (AAs) compared with those of European ancestry and higher among women compared with men. Among AAs, little is known of the genetic architecture of D-dimer or the relationship of D-dimer to incident cardiovascular disease. Approach and Results— We measured baseline D-dimer in 4163 AAs aged 21 to 93 years from the prospective JHS (Jackson Heart Study) cohort and assessed association with incident cardiovascular disease events. In participants with whole genome sequencing data (n=2980), we evaluated common and rare genetic variants for association with D-dimer. Each standard deviation higher baseline D-dimer was associated with a 20% to 30% increased hazard for incident coronary heart disease, stroke, and all-cause mortality. Genetic variation near F3 was associated with higher D-dimer (rs2022030, β=0.284, P =3.24×10 –11 ). The rs2022030 effect size was nearly 3× larger among women (β=0.373, P =9.06×10 –13 ) than among men (β=0.135, P =0.06; P interaction =0.009). The sex by rs2022030 interaction was replicated in an independent sample of 10 808 multiethnic men and women ( P interaction =0.001). Finally, the African ancestral sickle cell variant ( HBB rs334) was significantly associated with higher D-dimer in JHS (β=0.507, P =1.41×10 –14 ), and this association was successfully replicated in 1933 AAs ( P =2.3×10 –5 ). Conclusions— These results highlight D-dimer as an important predictor of cardiovascular disease risk in AAs and suggest that sex-specific and African ancestral genetic effects of the F3 and HBB loci contribute to the higher levels of D-dimer among women and AAs.

T-helper type 1 (Th1) cells are pro-inflammatory and provide signals to immune cells. Animal models and in vitro human cell culture experiments have indicated that long chain n-3 polyunsaturated fatty acids (LCn3PUFAs) reduce Th1 cell levels; however, the association is unknown in healthy humans. We hypothesized that circulating levels and dietary intake of LCn3PUFAs have an inverse association with circulating levels of Th1 cells and studied 895 participants in the Multi-Ethnic Study of Atherosclerosis (age 61 ± 10 years at exam 1, 52% women, 44% white, 21% African-American, 24% Hispanic-American, 11% Chinese-American). Phospholipid LCn3PUFAs (% of total fatty acids), measured by gas chromatography, and intake of LCn3PUFAs, evaluated by food frequency questionnaire, were evaluated at exam 1 (2000-02) and defined as the sum of eicosapentaenoic and docosahexaenoic acids. Th1 cells were measured by flow cytometry at exam 4 (2005-07), expressed as a percentage of CD4+ lymphocytes that were interferon-γ+ (%Th1: CD4+IFN-γ+). Median (interquartile range) plasma LCn3PUFA, dietary LCn3PUFA, and %Th1 levels were 4.31% (3.40–5.82%), 0.09 (0.05–0.16) g/day, and 14.4% (9.8–20.0%), respectively. When the association of LCn3PUFA-quartiles with %Th1 was analyzed using general linear models, neither plasma nor dietary LCn3PUFAs were significantly associated with %Th1 (P-trend = 0.58 and 0.80, respectively), which remained even after adjusting for demographics, lifestyle factors, lipids, season, and cytomegalovirus titers. In this multi-ethnic U.S. population, circulating levels and dietary intake of LCn3PUFAs were not significantly associated with Th1 cell levels. Further research is needed to assess potential benefits of supplementation and much higher dietary consumption of LCn3PUFAs on Th1 cells.

Background During atrial fibrillation (AF), a high rate of myocyte activation causes cellular stress and initiates the process of atrial remodeling, which further promotes persistence of AF. Although heat shock proteins (HSPs) have been shown to prevent atrial remodeling and suppress the occurrence of AF in cellular and animal experimental models, increased levels of HSP-60 have been observed in patients with postoperative AF, likely reflecting a response to cellular stress. To better understand the role of HSP-60 in relation to AF, we examined the association of HSP-60 levels in relation to the future development of AF in the Multi-Ethnic Study of Atherosclerosis (MESA). Methods MESA is a cohort study that recruited 6,814 participants aged 45-84 years and free of known cardiovascular disease at baseline (2000-2002) from six field centers. We investigated 983 participants, selected at random from the total cohort, who had HSP-60 measured and were free of AF at baseline. We tested the association of HSP-60 levels with the incidence of AF using multivariate Cox models after adjustment for demographics, clinical characteristics, and biomarkers. Results During an average of 10.6 years of follow-up, 77 participants developed AF. We did not observe a significant association between the log-transformed HSP-60 levels and development of AF on either unadjusted or multivariate analysis (adjusted hazard ratio: 1.02 per unit difference on natural log scale, 95% confidence interval: 0.77-1.34 ln (ng/mL). Conclusion Contrary to the findings from the preclinical studies, which demonstrated an important role of HSP-60 in the pathogenesis of AF, we did not observe a significant association between HSP-60 and occurrence of AF.

BACKGROUND: C-reactive protein (CRP) is an inflammatory biomarker used in vascular risk prediction, though with less data in non-white populations. Blacks have higher stroke incidence and also higher CRP than whites. We studied the association of CRP on ischemic stroke risk in blacks and whites. METHODS: REGARDS, an observational cohort study, recruited and followed 30,239 black and white Americans aged 45 and older for ischemic stroke. We calculated hazard ratios (HR) and 95% confidence intervals of ischemic stroke by CRP category (10 mg/L, while in blacks an association was only seen for CRP >10 mg/L. Considered as a continuous variable, the the risk factor-adjusted HRs per SD higher lnCRP were 1.18 (95% CI 1.09 - 1.28) overall, 1.14 (95% CI 1.00 - 1.29) in blacks and 1.22 (95% CI 1.10 - 1.35) in whites. Spline regression analysis visually confirmed the race difference in the association. CONCLUSIONS: CRP may not be equally useful in stroke risk assessment in blacks and whites. Confirmation, similar study for coronary heart disease, and identification of reasons for these racial differences require further study.

Background and aims Previous research has implicated dysregulation of phosphate metabolism and calcium-phosphate solubilization in cardiovascular calcification, but epidemiologic studies evaluating longitudinal associations with valvular or annular calcification by computed tomography (CT), a highly sensitive imaging modality, are lacking. Our primary aim was to investigate the associations of mineral biomarkers with incidence and progression of aortic valve calcification (AVC) and mitral annular calcification (MAC). Methods We evaluated the associations of serum FGF-23 (n = 6547 participants), phosphate (n = 6547), and fetuin-A (n = 2550) measured at baseline in the community-based Multi-Ethnic Study of Atherosclerosis with AVC and MAC on CT performed at baseline and at a median of 2.4 (1.6, 3.1) years later. We used linear mixed-effects models to account simultaneously for prevalence, incidence and progression of AVC and MAC. Results After adjustment for demographic and clinical characteristics, a significant association was documented for FGF-23 with accelerated annual progression of MAC (2.83 Agatston units (AU), 95% CI = 0.49, 5.17 AU, per standard deviation (18.46 pg/mL) of FGF-23), but this was not seen for phosphate or fetuin-A. None of these biomarkers was associated with accelerated annual progression of AVC. Conclusions This study provides evidence relating serum FGF-23 to accelerated annual MAC progression. Whether this mineral regulator is a risk marker or is involved in pathogenesis merits further investigation.

BACKGROUND Circulating levels of endothelin-1 (ET1) are elevated in heart failure and predict poor prognosis. However, it is not clear whether ET1 elevation is an adaptive response, maladaptive response, or an epiphenomenon of heart failure. In this study, we evaluated the relationships between ET1, cardiac morphology, and incident heart failure or cardiovascular death in participants with no evidence of clinical cardiovascular disease at the time ET1 was measured. METHODS AND RESULTS ET1 was measured in 1,361 participants in the Multi-Ethnic Study of Atherosclerosis Angiogenesis Sub-Study. As suggested by linear regression , participants with lower circulating ET1 levels tended to be older, non-white, more likely to have smoked heavily, and less likely to report intentional exercise. Participants with higher ET1 levels had smaller left ventricular end-diastolic volumes (8.9 ml smaller per log increase in ET1, 95% confidence interval 17.1–0.7, p = 0.03) with an increased left ventricular ejection fraction (2.8% per log increase in ET1, 95% confidence interval 0.5%–5.2%, p = 0.02). As suggested by Cox Proportional Hazards estimates, participants with higher ET1 levels had a lower risk for the composite outcome of heart failure or cardiovascular death in models that were unadjusted or had limited adjustment (p = 0.03 and p = 0.05, respectively). Lower risk for heart failure with higher ET1 levels could not be clearly shown in a model including health behaviors. CONCLUSIONS These results suggest, but do not confirm, that elevated levels of circulating ET1 are associated with a more favorable cardiac phenotype. The relationship between ET1 and outcomes was not fully independent of one or more covariates.

Background and objectives Family caregiving stress has been widely reported to have negative effects on circulating biomarkers of immune system function and inflammation. Our goals were to systematically review this literature and conduct a meta-analysis on the extracted effects. Research design and methods A systematic search of published studies comparing caregivers and noncaregivers on biomarkers measured from blood samples was conducted in the PubMed, Embase, and Cochrane databases. This search identified 2,582 articles and abstracts. After removing duplicative papers and studies not meeting inclusion criteria, 30 articles were identified that reported analyses on 86 relevant biomarkers from 1,848 caregivers and 3,640 noncaregivers. Results Random-effects models revealed an overall effect size across all biomarkers of 0.164 SD units (d). A slightly larger overall effect (d = 0.188) was found for dementia caregivers only. Immune system comparisons yielded somewhat larger differences than inflammation comparisons. Most studies used small convenience samples, and effect sizes were larger for studies with moderate or high bias ratings than for studies with low bias ratings. No significant associations were found in studies that used population-based samples. Discussion and implications Caregivers had small but significantly reduced immune system functioning and greater inflammation than noncaregivers, but associations were generally weak and of questionable clinical significance. The absence of clear associations from low bias studies and population-based studies underscores concerns with possible selection biases in many of the convenience samples. Population-based studies that assess biomarkers before and after the onset of caregiving might add much clarity to this literature.

Prospective studies supporting a relationship between elevated lipoprotein-associated phospholipase A2 (Lp-PLA2) and incident peripheral arterial disease (PAD) are limited. We evaluated the association of Lp-PLA2 with incident PAD in a multi-ethnic cohort without clinical cardiovascular disease. A total of 4622 participants with measurement of Lp-PLA2 mass and Lp-PLA2 activity and an ankle–brachial index (ABI) between 0.9 and 1.4 were followed for the development of PAD (median follow-up = 9.3 years), defined as an ABI ⩽0.9 and decline from baseline ⩾0.15. There were 158 incident PAD events during follow-up. In adjusted logistic regression models, each higher standard deviation of both Lp-PLA2 activity and mass did not confer an increased risk of developing PAD [odds ratios, (95% confidence intervals)]: 0.92 (0.66–1.27) for Lp-PLA2 activity and 1.06 (0.85–1.34) for mass. Additionally, no significant interaction was found according to ethnicity: p=0.43 for Lp-PLA2 activity and p=0.55 for Lp-PLA2 mass. We found no evidence of an association between Lp-PLA2 and incident PAD.

Highlights • Lower 25-hydroxyvitamin D is associated with insulin resistance and inflammation. • Lower 25-hydoxvitamin D is associated with obesity. • Low 25-hydroxyvitamin D is associated with poor metabolic health irrespective of race., Aims Vitamin D is a fat-soluble vitamin classically known for its role in calcium absorption and bone health. Growing evidence indicates that vitamin D deficiency may be associated with inflammation, insulin resistance, and obesity. However, prior studies examining the association of vitamin D with metabolic risk factors had relatively low representation of individuals of black race, limiting their ability to characterize associations of vitamin D and parameters of metabolic health in black vs. white individuals. Methods We examined associations of 25-hydroxyvitamin D (25(OH)D) concentrations with markers of inflammation (interleukin [IL]-6, IL-10, high sensitivity C-reactive protein [hsCRP]), insulin sensitivity (adiponectin, resistin, HOMA-IR), and obesity (body mass index [BMI], waist circumference) in 1042 participants from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a large national cohort of black and white adults 45 years or older. Results In unadjusted analyses, lower 25(OH)D concentrations were associated with higher IL-6 and hsCRP concentrations; lower adiponectin concentrations; higher HOMA-IR; and higher BMI and waist circumference (P 0.1). Conclusions Lower 25(OH)D concentrations are associated with disturbances in metabolic health in both blacks and whites. Whether correcting vitamin D deficiency could offer a beneficial therapy for disease prevention requires further study.

Objective— Vitamin K–dependent proteins (VKDPs), which require post-translational modification to achieve biological activity, seem to contribute to thrombus formation, vascular calcification, and vessel stiffness. Whether VKDP activity is prospectively associated with incident cardiovascular disease has not been studied. Approach and Results— VKDP activity was determined by measuring circulating des-γ-carboxy prothrombin concentrations in a random sample of 709 multiethnic adults free of cardiovascular disease drawn from the Multi-Ethnic Study of Atherosclerosis (MESA). Lower des-γ-carboxy prothrombin concentrations reflect greater VKDP activity. Subjects were followed up for the risk of ischemic cardiovascular disease (coronary heart disease, stroke, and fatal cardiovascular disease) for 11.0 years of follow-up. A total of 75 first ischemic CVD events occurred during follow-up. The incidence of ischemic cardiovascular disease increased progressively across des-γ-carboxy prothrombin quartiles, with event rates of 5.9 and 11.7 per 1000 person-years in the lowest and highest quartiles. In analyses adjusted for traditional cardiovascular risk factors and measures of vitamin K intake, a doubling of des-γ-carboxy prothrombin concentration was associated with a 1.53 (95% confidence interval, 1.09–2.13; P =0.008) higher risk of incident ischemic cardiovascular disease. The association was consistent across strata of participants with diabetes mellitus, hypertension, renal impairment, and low vitamin K nutritional intake. Conclusions— In this sample of middle-aged and older adults, VKDP activity was associated with incident ischemic cardiovascular events. Further studies to understand the role of this large class of proteins in cardiovascular disease are warranted.

Background Black individuals are at greater risk of stroke and vitamin D deficiency than white individuals. Epidemiologic studies have shown that low 25-hydroxyvitamin D concentrations are associated with increased risk of stroke, but these studies had limited representation of black individuals. Methods We examined the association of 25-hydroxyvitamin D with incident stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a cohort of black and white adults ≥45 years of age. Using a case–cohort study design, plasma 25-hydroxyvitamin D was measured in 610 participants who developed incident stroke (cases) and in 937 stroke-free individuals from a stratified cohort random sample of REGARDS participants (comparison cohort). Results In multivariable models adjusted for socio-demographic factors, co-morbidities and laboratory values including parathyroid hormone, lower 25-hydroxyvitamin D concentrations were associated with higher risk of stroke (25-hydroxyvitamin D >30 ng/mL reference; 25-hydroxyvitamin D concentrations 20–30 ng/mL, hazard ratio 1.33, 95% confidence interval (95% CI) 0.89,1.96; 25-hydroxyvitamin D interaction = 0.82). The associations were qualitatively unchanged when restricted to ischemic or hemorrhagic stroke subtypes or when using race-specific cut-offs for 25-hydroxyvitamin D categories. Conclusions Vitamin D deficiency is a risk factor for incident stroke and the strength of this association does not appear to differ by race.

BACKGROUND The importance of systemic inflammation, measured by C-reactive protein, in cognitive decline has been demonstrated; however, the role of vascular inflammation is less understood. Pentraxin 3 (PTX3) is a novel marker of vascular inflammation. METHODS We followed adults 65 and older, free of cardiovascular disease (CVD) for up to 9 years (n = 1,547) in the Cardiovascular Health Study. We evaluated the relationship between PTX3 and change in cognitive function, measured using the Modified Mini-Mental State Examination (3MSE), and incident cognitive impairment (3MSE < 80). Mediation by CVD events, and effect modification by sex and apolipoprotein E ɛ4 allele (APOE4) were also examined. RESULTS The average decline in 3MSE was 0.77 points per year. The association between PTX3 and change in 3MSE differed between women and men (p = .02). In the adjusted model, each standard deviation higher in PTX3 was associated with a 0.20 greater decline in 3MSE score per year in women over follow-up (95% CI: -0. 37, -0.03; p = .02), compared to no change in men (β = 0.07; 95% CI: -0.08, 0.22). CVD events had a minor effect on the associations. No effect modification by APOE4 was found, although we observed the association of PTX3 and cognitive impairment in women was attenuated and nonsignificant after adjustment for APOE4. There was a paradoxical protective association between PTX3 and reduced cognitive impairment in men, even after adjustment for APOE4. CONCLUSIONS We found that vascular inflammation was significantly associated with cognitive decline in older women, but not men.

Most studies of family caregiving use convenience samples of persons who are already caregivers before enrollment. Population-based studies of those who prospectively transition into family caregiving roles are rare and needed. Participants in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study were asked on two occasions if they were providing care to a family member or friend with a chronic illness or disability: at the REGARDS baseline telephone interview and at a 2nd interview 9–14 years later (M = 12 years). Those who transitioned into a significant caregiving role were recruited to participate in the Caregiving Transitions Study (CTS), which is examining health and serum biomarker responses to caregiving. Of 9,863 REGARDS participants who were not caregivers at baseline, 1073 (11%) transitioned into a family caregiving role. Of these caregivers, 251 (23%) met eligibility criteria for the CTS and were enrolled along with 251 demographically-matched noncaregiving controls. Enrolled caregivers are 65% female; 36% African American; 69.1 + 7.8 years of age; caring for a spouse/partner (52%), parent (25%), or another person (23%); and 46% are caring for a person with dementia. Initial longitudinal comparisons reveal that depressive symptoms increased (d = 1.12 standard deviation units (SDUs), p < .0001) and health-related quality of life decreased (d = 0.35 SDUs, p < .0001) over the 12-year period for those who became caregivers. A unique sample of incident caregivers and matched controls has been assembled and analyses are currently examining changes on self-report and serum biomarker indicators of health.

E-selectin mediates the rolling of circulating leukocytes during inflammatory processes. Previous genome-wide association studies in European and Asian individuals have identified the ABO locus associated with E-selectin levels. Using Trans-Omics for Precision Medicine whole genome sequencing data in 2249 African Americans (AAs) from the Jackson Heart Study, we examined genome-wide associations with soluble E-selectin levels. In addition to replicating known signals at ABO, we identified a novel association of a common loss-of-function, missense variant in Fucosyltransferase 6 (FUT6; rs17855739,p.Glu274Lys, P = 9.02 × 10(−24)) with higher soluble E-selectin levels. This variant is considerably more common in populations of African ancestry compared to non-African ancestry populations. We replicated the association of FUT6 p.Glu274Lys with higher soluble E-selectin in an independent population of 748 AAs from the Women’s Health Initiative and identified an additional pleiotropic association with vitamin B12 levels. Despite the broad role of both selectins and fucosyltransferases in various inflammatory, immune and cancer-related processes, we were unable to identify any additional disease associations of the FUT6 p.Glu274Lys variant in an electronic medical record-based phenome-wide association scan of over 9000 AAs.

Background We previously reported association of SCARB1 SNP rs10846744 with common carotid IMT (cIMT) and cardiovascular disease (CVD) events. Since rs10846744 has been reported in association with Lp-PLA2 mass and activity, we hypothesized that inflammatory pathways might mediate the association of rs10846744 with atherosclerosis. Methods We first examined association of rs10846744 in CVD in multiple large-scale consortium-based genome-wide association studies. We further examined 27 parameters of interest, including Lp-PLA2 mass and activity, inflammatory markers, and plasma phospholipid fatty acids, and fatty acid ratios in participants from the Multi-Ethnic Study of Atherosclerosis (MESA), as potential mediators in the pathway linking rs10846744 with cIMT and incident CVD. Finally, we examined the association of rs10846744 with Lp-PLA2 activity, cardiovascular outcomes, and interaction with the Lp-PLA2 inhibitor, darapladib, in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) and Stabilization of Plaque using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) studies. Results SCARB1 rs10846744 was associated with coronary artery disease events in CARDIoGRAMplusC4D (odds ratio 1.05; 95% CI [1.02, 1.07]; P = 1.4x10-4). In combined analysis across race/ethnic groups in MESA, rs10846744 was associated with Lp-PLA2 mass (P = 0.04) and activity (P = 0.001), homocysteine (P = 0.03), LDL particle number (P = 0.01), docosahexaenoic acid [DHA] (P = 0.01), docosapentaenoic acid [DPA] (P = 0.04), DPA/ eicosapentaenoic acid [EPA] ratio (P = 0.002), and DHA/EPA ratio (P = 0.008). Lp-PLA2 activity was identified as a mediator of rs10846744 with cIMT in a basic model (P = 8x10-5), but not after adjustment for CVD risk factors. There was no interaction or modifier effect of the Lp-PLA2 inhibitor darapladib assignment on the relationship between rs10846744 and major CVD events in either STABILITY or SOLID-TIMI 52. Summary SCARB1 rs10846744 is significantly associated with Lp-PLA2 activity, atherosclerosis, and CVD events, but Lp-PLA2 activity is not a mediator in the association of rs10846744 with cIMT in MESA.

BACKGROUND: Low baseline plasma 25-hydroxyvitamin D (25(OH)D) is associated with increased risk of acute respiratory infections, but its association with long-term risk of sepsis remains unclear. METHODS: We performed a case-cohort analysis of participants selected from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a US cohort of 30239 adults aged ≥45 years. We measured baseline plasma 25(OH)D in 711 sepsis cases and in 992 participants randomly selected from the REGARDS cohort. We captured sepsis events by screening records with International Classification of Disease methods and then adjudicating clinical charts for significant, suspected infection and severe inflammatory response syndrome criteria on presentation. RESULTS: In the study sample, the median age of participants was 65.0 years, 41% self-identified as black, and 45% were male. Mean plasma 25(OH)D concentration was 25.8 ng/mL; for 31% of participants, it was 33.6 ng/mL, lower 25(OH)D groups were associated with higher hazards of sepsis (16.5–22.4 ng/mL; hazard ratio [HR]; 3.21; 95% confidence interval [CI], 1.98 to 5.21 and

RationaleThe association between obstructive sleep apnea (OSA) and cardiovascular disease (CVD) is complex, bidirectional, and may vary across groups. Understanding which cardiovascular risk factors vary in their relationship to OSA across population groups may improve knowledge of OSA-related CVD susceptibility.ObjectivesTo better understand the heterogeneity of associations, we assessed whether associations of OSA with cardiovascular risk factors vary by age, sex, and race/ethnicity.MethodsWe performed cross-sectional analyses of 1,344 Multi-Ethnic Study of Atherosclerosis participants who underwent overnight full polysomnography, assays of fasting blood, and assessments of cardiovascular risk factors. Risk factors considered were blood pressure, glucose/lipid concentrations, white blood cell (WBC) total and subset counts, and cystatin C. The outcome was the apnea-hypopnea index (AHI). Linear regression analyses with tests for interactions were conducted.ResultsThe sample had a mean age of 68 ± 9 years. Forty-seven percent of the sample was male, and 32% had moderate or severe OSA (AHI, ≥15). Multivariable adjusted analysis showed significant associations between higher AHI with lower high-density lipoprotein cholesterol and higher diastolic blood pressure and neutrophil counts. Significant interactions with demographic factors were observed. Stronger associations were shown between AHI and higher total WBC count (Pint = 0.006) and glucose concentrations (Pint = 0.006) in younger (

Background Obstructive sleep apnea (OSA) associates with increased risk of cardiovascular diseases (CVD). Immune abnormalities and surges in sympathetic activity accompany OSA and CVD. We hypothesized that OSA associates with leukocytosis partially by abnormalities in autonomic nervous system (ANS) function that would suggest a pathway linking OSA and CVD. Methods Participants from the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective cohort of individuals initially without overt CVD, underwent polysomnography and assays for white blood cells (WBC) and subsets. Heart rate (HR) and heart rate variability (HRV), indirect measurements of ANS, were obtained from overnight electrocardiography. A formal statistical mediation analysis tested the indirect effect that mean HR and HRV measures contribute to associations between OSA and leukocytosis. Results The analytical sample consisted of 1298 participants (54% female), ages 54–93 years, 14% with severe OSA (apnea-hypopnea-index, AHI ≥ 30). Severe OSA associated with a higher prevalence of obesity, diabetes, and increased levels of WBC total and subsets. Neutrophil count associated with severe OSA after adjusting for confounders (p = 0.017). Mean HR positively associated with OSA indices and neutrophils. A mediation analysis revealed an “indirect” effect of mean HR that explained an estimated 11% of the association between AHI and neutrophils. Overnight hypoxia also associated with neutrophil count (p = 0.009), and mean HR explained 14% of the association between neutrophils and hypoxia. Conclusions In the MESA cohort, OSA measures associate with elevated neutrophil counts and increases in overnight mean HR. These data link innate immune dysregulation with OSA and provide a potential pathophysiologic pathway between CVD and OSA.

BACKGROUND AND AIMS:Several biomarkers of inflammation and coagulation have been implicated in lower extremity atherosclerosis. We utilized an exploratory factor analysis (EFA) to identify distinct factors derived from circulating inflammatory and coagulation biomarkers then examined the associations of these factors with measures of lower extremity subclinical atherosclerosis, including the ankle-brachial index (ABI), common and superficial femoral intima-media thickness (IMT), and atherosclerotic plaque presence, burden, and characteristics. METHODS:The San Diego Population Study (SDPS) is a prospective, community-living, multi-ethnic cohort of 1103 men and women averaged age 70. Regression analysis was used to assess cross-sectional associations between the identified groupings of biomarkers (factors) and the ABI and femoral artery atherosclerosis measurements. RESULTS:Two biomarker factors emerged from the factor analysis. Factor 1 consisting of C-reactive protein (CRP), interleukin (IL)-6, and fibrinogen was significantly associated with higher odds (OR = 1.99, p

Introduction: Clinically, natural killer (NK) cells are important in inflammatory and autoimmune diseases. As part of innate immunity, NK cells produce chemokines and inflammatory cytokines, potentially linking them to cardiovascular disease (CVD) development and progression as well. However, their role in human CVD is not clear. Hypothesis: NK cells are proatherogenic in humans and are associated with CVD risk factors and subclinical CVD measures. Methods: We examined cross-sectional associations of circulating NK cell levels with CVD risk factors, subclinical CVD measures and coronary artery calcium (CAC) in 891 White, Black, Chinese and Hispanic men and women (mean age 66 y) in the Multi-Ethnic Study of Atherosclerosis (MESA) at Exam 4 (2005-07). NK cell percent, percent of circulating lymphocytes that were CD3 - CD56 + CD16 + , was measured in whole blood by flow cytometry. CAC presence was defined as Agatston score > 0. Results: Mean (standard deviation) NK percent differed by race/ethnicity; 8.2% (4.7) in Whites, 11.3% (7.5) in Chinese (p Conclusions: Of clinical interest, CD3 - CD56 + CD16 + NK cell percent varied significantly by race/ethnicity in these men and women from MESA. However, NK cell percent was inconsistently associated with CVD risk factors; positively with age and systolic blood pressure, and negatively with smoking. NK cell percent was also negatively associated with common carotid IMT. Larger sample sizes and longitudinal analyses will be required to clarify the potential relationship between NK cells and atherosclerosis in humans.

Introduction: In the US, blacks are at higher risk of hypertension than whites. The single largest contributor to this disparity is the Southern Diet pattern. Inflammation biomarkers are associated with risk of hypertension, and C-reactive protein (CRP) is higher in blacks than whites. We studied whether elevated CRP in blacks relative to whites contributes to the racial disparity in hypertension in blacks. Methods: We included 6,548 black and white men and women age ≥45 years from the REGARDS cohort without hypertension at baseline ('03-'07) and who completed visit 2 in '13-'16. Incident hypertension was defined as BP ≥140/90 mm Hg or hypertension medication use at visit 2. Using logistic regression, the black:white odds ratio (OR) for incident hypertension was calculated adjusting for age, sex, race, and baseline SBP. We assessed the percent change in the black:white OR for incident hypertension after adding CRP. The 95% CI was calculated using 1,000 bootstrapped samples. We determined the impact of known hypertension risk factors and anti-inflammatory medications on the percent mediation by CRP. Results: Hypertension developed in 46% of blacks and 33% of whites. Adjusting for demographics, the black:white OR (95% CI) was 1.51, which was reduced to 1.46, a 9.3% reduction (95% CI 5.4%, 13.2%) by CRP (Table). In models including exercise, waist circumference, BMI, and depressive symptoms, the percent mediation by CRP was 3.7% (1.0%, 6.4%). Similar patterns were seen for models incorporating socioeconomic factors and medication use. After adding Southern diet pattern and dietary Na/K ratio, CRP no longer attenuated the association (1.3% mediation; -1.5, 4.1). Conclusions: CRP significantly attenuated the black-white difference in incident hypertension; however, once dietary factors were accounted for, CRP had no impact on the black:white difference in incident hypertension. Thus, inflammation as measured by CRP, may be part of the reason that dietary factors influence the black:white disparity in incident hypertension.

Importance Higher circulating fibroblast growth factor 23 (FGF23) concentrations are associated with cardiovascular disease events linked to heart failure, but associations of FGF23 with coronary heart disease (CHD) have been less consistent. Objective To determine the association of plasma FGF23 concentrations with incident CHD and whether this association differs by race, sex, or chronic kidney disease status. Design, Setting, and Participants We examined the association of FGF23 concentrations with incident CHD risk within the Reasons for Geographic and Racial Differences in Stroke study, a prospective cohort of black and white adults 45 years and older enrolled between January 2003 and October 2007 with follow-up through December 31, 2011. Using a case-cohort design, we measured FGF23 concentrations in 829 participants who developed incident CHD and in 812 participants randomly selected from the Reasons for Geographic and Racial Differences in Stroke study cohort (cohort random sample). To account for the stratified sampling design, the cohort random sample was weighted back to the original cohort overall (n = 22 127). Cox proportional hazards models were used to examine the association of FGF23 concentration with incident CHD, adjusting for CHD risk factors and kidney function. In prespecified analyses, we examined whether race, sex, or chronic kidney disease modified the association of FGF23 concentration with incident CHD. Exposures Plasma C-terminal FGF23 concentrations. Main Outcomes and Measures Investigator-adjudicated incident CHD events. Results Of the 22 127 participants in the weighted cohort random sample, 13 059 (58.9%) were female and 9435 (42.6%) were black, and the mean age was 64.3 (95% CI, 63.7-64.9) years. Greater age, lower estimated glomerular filtration rate, higher urine albumin to creatinine ratio, and female sex were associated with higher FGF23 concentration at baseline. In multivariable models adjusted for established CHD risk factors and kidney function, higher FGF23 concentrations were associated with greater risk of CHD (hazard ratio [HR] comparing fourth with first quartile, 2.15; 95% CI, 1.35-3.42). The magnitude and strength of these associations differed by sex. However, these differences were no longer observed when adjusting for hormone therapy in women (men: HR comparing fourth with first quartile, 2.40; 95% CI, 1.30-4.42; women: HR comparing fourth with first quartile, 2.34; 95% CI, 1.04-5.27) or when using sex-specific FGF23 quartiles (men: HR comparing fourth with first quartile, 2.65; 95% CI, 1.43-4.90; women: HR comparing fourth with first quartile, 2.26; 95% CI, 1.02-5.03). Conclusions and Relevance Higher FGF23 concentrations were associated with greater risk of CHD. Heterogeneity in the association by sex may be caused by differences in the distribution of plasma FGF23 concentrations or the use of hormone therapy in men vs women.

Background The importance of systemic inflammation, measured by C-reactive protein, in cognitive decline has been demonstrated; however, the role of vascular inflammation is less understood. Pentraxin 3 (PTX3) is a novel marker of vascular inflammation. Methods We followed adults 65 and older, free of cardiovascular disease (CVD) for up to 9 years (n = 1,547) in the Cardiovascular Health Study. We evaluated the relationship between PTX3 and change in cognitive function, measured using the Modified Mini-Mental State Examination (3MSE), and incident cognitive impairment (3MSE < 80). Mediation by CVD events, and effect modification by sex and apolipoprotein E ɛ4 allele (APOE4) were also examined. Results The average decline in 3MSE was 0.77 points per year. The association between PTX3 and change in 3MSE differed between women and men (p = .02). In the adjusted model, each standard deviation higher in PTX3 was associated with a 0.20 greater decline in 3MSE score per year in women over follow-up (95% CI: −0. 37, −0.03; p = .02), compared to no change in men (β = 0.07; 95% CI: −0.08, 0.22). CVD events had a minor effect on the associations. No effect modification by APOE4 was found, although we observed the association of PTX3 and cognitive impairment in women was attenuated and nonsignificant after adjustment for APOE4. There was a paradoxical protective association between PTX3 and reduced cognitive impairment in men, even after adjustment for APOE4. Conclusions We found that vascular inflammation was significantly associated with cognitive decline in older women, but not men.

Telomere length (TL) is considered as a marker of cell senescence, but factors influencing the rate of TL attrition are not well understood. While one previous study reported the association of occupation and TL, many subsequent studies have failed to find the association. This may be due to heterogeneity within the samples and cross-sectional designs. This longitudinal study examines two occupational characteristics, occupational complexity and hazardous conditions, as predictors of TL attrition in gender- and race/ethnicity-stratified analysis. Leukocyte TL (expressed as T/S ratio) was measured twice over a 10-year period in a multi-racial sample (n = 914). Linear mixed effect models were used to estimate TL attrition associated with occupational complexity and hazardous conditions. Analysis was stratified by gender and race/ethnicity (white, African American, and Latino) and controlled for baseline age, baseline TL, and time since baseline. Higher occupational complexity was associated with slower rates of TL attrition only among white men. Hazardous conditions were not associated with TL attrition for any gender-and-race/ethnicity stratified group. Occupational complexity may influence TL attrition, but the different findings for white men and other groups suggest that a more comprehensive framework is needed to better understand the potential link between occupational characteristics and biological aging.

ObjectiveProspective studies reporting a positive association of lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity with incident cardiovascular disease (CVD) have included primarily white individuals. We evaluated associations of Lp-PLA2 and first-time cardiovascular events in a healthy multi-ethnic cohort characterized by presence or absence of baseline subclinical atherosclerosis.MethodsLp-PLA2 mass and activity were measured at baseline in 5456 participants in the Multi-Ethnic Study of Atherosclerosis. Individuals were characterized for presence of baseline subclinical disease (coronary artery calcium score>0 or carotid intima-media thickness value>80th percentile) and followed prospectively for development of CVD events (coronary heart disease, ischemic stroke, and cardiovascular death).Results516 incident CVD events occurred over median follow-up of 10.2 years. In adjusted Cox proportional hazards models, each higher standard deviation of both Lp-PLA2 activity and mass was associated with an increased risk of cardiovascular events; hazard ratios (HR; 95% confidence intervals (CI)) 1.12 (1.01-1.26) for Lp-PLA2 activity and 1.10 (1.01-1.21) for mass. Associations did not differ by subclinical disease status (p-value for interaction 0.99 for Lp-PLA2 activity and 0.32 for Lp-PLA2 mass) and there was no confounding by subclinical atherosclerosis measures. Associations of Lp-PLA2 activity but not mass were weaker in Chinese participants but there were relatively few events among Chinese in race-stratified analysis.ConclusionIn this multi-ethnic cohort, Lp-PLA2 was positively associated with CVD risk, regardless of the presence of coronary artery calcium or a thickened carotid-intimal media.

BACKGROUND: Multiple prospective studies have established an association between inflammation and higher risk of atrial fibrillation (AF), but the association between lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) mass and activity and incident AF has not been extensively evaluated. METHODS: Using data from 10794 Atherosclerosis Risk In Communities (ARIC) study participants aged 53–75 years, 5181 Cardiovascular Health Study (CHS) participants aged 65 to 100 years, and 5425 Multi-Ethnic Study of Atherosclerosis (MESA) participants aged 45–84 years, we investigated the association between baseline Lp-PLA(2) levels and the risk of developing AF. Incident AF was identified in each cohort by follow-up visit electrocardiograms, hospital discharge coding of AF, or Medicare claims data. RESULTS: Over a mean of 13.1, 11.5, and 10.0 years of follow-up, 1439 (13%), 2084 (40%), and 615 (11%) incident AF events occurred in ARIC, CHS, and MESA respectively. In adjusted analyses, each standard deviation increment in Lp-PLA(2) activity was associated with incident AF in both ARIC (hazard ratio (HR) 1.13; 95% confidence interval (CI) 1.06, 1.20) and MESA (HR 1.24; 95% CI 1.05, 1.46). Each standard deviation increment in Lp-PLA(2) mass was also associated with incident AF in MESA (HR 1.25; 95% CI 1.11, 1.41). No significant associations were observed among CHS participants. CONCLUSIONS: While higher Lp-PLA(2) mass and activity were associated with development of AF in ARIC and MESA, this relationship was not observed in CHS, a cohort of older individuals.

Background The ankle‐brachial index (ABI) is inadequate to detect early‐stage atherosclerotic disease, when interventions to prevent functional decline may be the most effective. We determined associations of femoral artery atherosclerosis with physical functioning, across the spectrum of the ABI, and within the normal ABI range. Methods and Results In 2007–2011, 1103 multiethnic men and women participated in the San Diego Population Study, and completed all components of the summary performance score. Using Doppler ultrasound, superficial and common femoral intima media thickness and plaques were ascertained. Logistic regression was used to assess associations of femoral atherosclerosis with the summary performance score and its individual components. Models were adjusted for demographics, lifestyle factors, comorbidities, lipids, and kidney function. In adjusted models, among participants with a normal‐range ABI (1.00–1.30), the highest tertile of superficial intima media thickness was associated with lower odds of a perfect summary performance score of 12 (odds ratio=0.56 [0.36, 0.87], P =0.009), and lower odds of a 4‐m walk score of 4 (0.34 [0.16, 0.73], P =0.006) and chair rise score of 4 (0.56 [0.34, 0.94], P =0.03). Plaque presence (0.53 [0.29, 0.99], P =0.04) and greater total plaque burden (0.61 [0.43, 0.87], P =0.006) were associated with worse 4‐m walk performance in the normal‐range ABI group. Higher superficial intima media thickness was associated with lower summary performance score in all individuals ( P =0.02). Conclusions Findings suggest that use of femoral artery atherosclerosis measures may be effective in individuals with a normal‐range ABI, especially, for example, those with diabetes mellitus or a family history of peripheral artery disease, when detection can lead to earlier intervention to prevent functional declines and improve quality of life.

PurposePhysical activity is associated with decreased adiposity-related inflammation in adults. Whether this association is independent of central obesity is unknown but important for understanding the mechanisms associated with reducing cardiometabolic disease risk through physical activity. This study examined whether associations of physical activity and obesity-related inflammatory markers were independent of central adiposity.MethodsBetween 2002 and 2005, 1970 participants from the Multi-Ethnic Study of Atherosclerosis completed detailed health history and physical activity questionnaires, underwent physical measurements including computed tomography to quantify abdominal visceral and subcutaneous fat, and measurements of adiponectin, leptin, interleukin-6, tumor necrosis factor-alpha, and resistin. Statistical analyses included analysis of covariance and multivariable-adjusted regression.ResultsThe mean (range) age of participants was 64.7 (55-84) yr and 50% were women. After adjustment for age and sex, and compared with the lowest quartile, inflammatory markers in the highest quartile of moderate-to-vigorous physical activity were 16% higher for adiponectin and 30%, 26%, and 9% lower for leptin, interleukin-6, and resistin, respectively (P < 0.05 for all). In linear regression adjusted for demographics, dyslipidemia, hypertension, diabetes, smoking, glomerular filtration rate, renin, and aldosterone, each standard deviation increment of moderate-to-vigorous physical activity was associated with significantly higher levels of adiponectin (β = 0.04) and lower levels of leptin (β = -0.06), interleukin-6 (β = -0.08), and resistin (β = -0.05, P < 0.05 for all). The associations with leptin, interleukin-6, and resistin were independent of total and central adiposity (P < 0.05), whereas the association between moderate-to-vigorous physical activity and adiponectin was attenuated by central adiposity (P > 0.05). There were no significant interactions by race/ethnicity or sex.ConclusionsModerate-to-vigorous physical activity was associated with a more favorable profile of inflammatory markers, independent of relevant cardiometabolic disease risk factors including central obesity.

Background and purpose Galectin-3 is a biomarker of atherosclerotic and cardiovascular disease, and may be a useful marker for ischaemic stroke risk. Methods The Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort enrolled and examined 30 239 US participants between 2003 and 2007 (41% black, 59% white and 55% in the southeastern stroke belt). Baseline galectin-3 was measured in 526 subjects with incident ischaemic stroke over 5.4 years and in a cohort random sample (CRS) of 947 participants. Cox proportional hazards models were used to calculate hazard ratios (HRs) of ischaemic stroke by quartiles of galectin-3. Results In the CRS, galectin-3 was significantly higher with older age, black race, female sex, body mass index, hypertension, diabetes mellitus and kidney disease, and also in those who developed incident stroke. Participants with galectin-3 levels in the fourth versus first quartile had a 2.3-fold increased stroke risk [95% confidence interval (CI) 1.6, 3.4] in an unadjusted model. An interaction with age was found (P = 0.06), and therefore age-stratified analyses were performed. Amongst those younger than age 64, baseline galectin-3 in the second–fourth quartiles was associated with increased stroke risk (HR 3.0, 95% CI 1.6, 5.5) compared to the first quartile in an age-, race- and sex-adjusted model. The HR was 2.0 (95% CI 1.0, 4.0) with multivariable adjustment. There was no association amongst older participants. Conclusions Galectin-3 was associated with incident ischaemic stroke in younger but not older individuals. Confirmation of this finding, and elucidation of its implications for stroke pathophysiology and prevention, is needed.

Purpose: Physical activity is associated with decreased adiposity-related inflammation in adults. Whether this association is independent of central obesity is unknown but important for understanding the mechanisms associated with reducing cardiometabolic disease risk through physical activity. This study examined whether associations of physical activity and obesity-related inflammatory markers were independent of central adiposity. Methods: Between 2002 and 2005, 1970 participants from the Multi-Ethnic Study of Atherosclerosis completed detailed health history and physical activity questionnaires, underwent physical measurements including computed tomography to quantify abdominal visceral and subcutaneous fat, and measurements of adiponectin, leptin, interleukin-6, tumor necrosis factor-alpha, and resistin. Statistical analyses included analysis of covariance and multivariable-adjusted regression. Results: The mean (range) age of participants was 64.7 (55-84) years and 50% were female. After adjustment for age and sex, and compared to the lowest quartile, inflammatory markers in the highest quartile of moderate-to-vigorous physical activity were 16% higher for adiponectin and 30%, 26% and 9% lower for leptin, interleukin-6, and resistin, respectively (p0.05). There were no significant interactions by race/ethnicity or sex. Conclusions: Moderate-to-vigorous physical activity was associated with a more favorable profile of inflammatory markers, independent of relevant cardiometabolic disease risk factors including central obesity.

Prospective studies supporting a relationship between elevated lipoprotein-associated phospholipase A

To evaluate associations between Lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity with risk of dementia and its subtypes.Analysis were completed on 3320 participants of the Cardiovascular Health Study (CHS), a population-based longitudinal study of community-dwelling adults age ≥65 years followed for an average of 5.4 years. Baseline serum Lp-PLA2 mass was measured using a sandwich enzyme immunoassay and Lp-PLA2 activity utilized a tritiated-platelet activating factor activity assay. Cox proportional hazards regression assessed the relative risk of incident dementia with higher baseline Lp-PLA2 adjusting for demographics, cardiovascular disease (CVD) and risk factors, inflammation markers and apolipoprotein E (APOE) genotype.Each standard deviation higher Lp-PLA2 mass and activity were related to increased risk of dementia (fully adjusted HR: 1.11 per SD, 95% CI: 1.00-1.24 for mass; HR: 1.12 per SD, 95% CI: 1.00-1.26 for activity). Persons in the highest quartile of Lp-PLA2 mass were 50% more likely to develop dementia than those in the lowest quartile in adjusted models (HR: 1.49; 95% CI: 1.08-2.06). Among dementia subtypes, the risk of AD was increased two-fold in the highest compared to lowest quartile of Lp-PLA2 mass (adjusted HR: 1.98, 95% CI: 1.22-3.21). Results were attenuated in models of mixed dementia and VaD. Lp-PLA2 activity also doubled the risk of mixed dementia in the highest compared to lowest quartile (HR: 2.21, 95% CI: 1.12-4.373).These data support Lp-PLA2 as a risk factor for dementia independent of CVD and its risk factors. Further study is required to clarify the role of Lp-PLA2-related mechanisms in dementia subtypes.

OBJECTIVE We evaluate associations of metabolic syndrome (MetS), C-reactive protein (CRP), and a CRP-incorporated definition of MetS (CRPMetS) with risk of all-cause mortality in a biracial population. RESEARCH DESIGN AND METHODS We studied 23,998 participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, an observational study of black and white adults ≥45 years old across the U.S. Elevated CRP was defined as ≥3 mg/L and MetS by the revised Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III; ATP III) criteria (three of five components). CRPMetS was defined as presence of three out of six components, with elevated CRP added to ATP III criteria as a sixth component. Cox models were used to calculate hazard ratios (HRs) for all-cause mortality, and population attributable risk (PAR) was calculated. Stratified analyses based on race and diabetes status were performed. RESULTS There were 9,741 participants (41%) with MetS and 12,179 (51%) with CRPMetS at baseline. Over 4.8 years of follow-up, 2,050 participants died. After adjustment for multiple confounders, MetS, elevated CRP, and CRPMetS were each significantly associated with increased mortality risk (HRs 1.26 [95% CI 1.15–1.38], 1.55 [1.41–1.70], and 1.34 [1.22–1.48], respectively). The PAR was 9.5% for MetS, 18.1% for CRP, and 14.7% for CRPMetS. Associations of elevated CRP and of CRPMetS with mortality were significantly greater in whites than blacks, while no differences in associations were observed based on diabetes status. CONCLUSIONS By definition, CRPMetS identifies more people at risk than MetS but still maintains a similar mortality risk. Incorporating CRP into the definition for MetS may be useful in identifying additional high-risk populations to target for prevention.

Among obese individuals, increased sympathetic nervous system (SNS) activity results in increased renin and aldosterone production, as well as renal tubular sodium reabsorption. This study determined the associations between adipokines and selected measures of the renin-angiotensinogen-aldosterone system (RAAS). The sample consisted of 1970 men and women from the Multi-Ethnic Study of Atherosclerosis who were free of clinical cardiovascular disease at baseline and had blood assayed for adiponectin, leptin, plasma renin activity (PRA) and aldosterone. The mean age was 64.7 years and 50% were female. The mean (s.d.) PRA and aldosterone were 1.45 (0.56) ng ml(-1) and 150.1 (130.5) pg ml(-1), respectively. After multivariable adjustment, a 1-s.d. increment of leptin was associated with a 0.55 ng ml(-1) higher PRA and 8.4 pg ml(-1) higher aldosterone (P

Pentraxin 3 (PTX3) is probably a specific marker of vascular inflammation. However, associations of PTX3 with cardiovascular disease (CVD) risk have not been well studied in healthy adults or multi-ethnic populations. We examined associations of PTX3 with CVD risk factors, measures of subclinical CVD, coronary artery calcification (CAC) and CVD events in the Multi-Ethnic Study of Atherosclerosis.Two thousand eight hundred and thirty-eight participants free of prevalent CVD with measurements of PTX3 were included in the present study. After adjustment for age, sex, and ethnicity, PTX3 was positively associated with age, obesity, insulin, systolic blood pressure, C-reactive protein (CRP), and carotid intima-media thickness (all P0.045). A one standard deviation increase in PTX3 level (1.62 ng mL(-1) ) was associated with the presence of CAC in fully adjusted models including multiple CVD risk factors (relative risk of 1.05; 95% confidence interval [CI] 1.01-1.08). In fully adjusted models, a standard deviation higher level of PTX3 was associated with an increased risk of myocardial infarction (hazard ratio [HR] 1.51; 95% [CI] 1.16-1.97), combined CVD events (HR 1.23; 95% [CI] 1.05-1.45), and combined CHD events (HR 1.33; 95% [CI] 1.10-1.60), but not stroke, CVD-related mortality, or all-cause death.In these apparently healthy adults, PTX3 was associated with CVD risk factors, subclinical CVD, CAC and incident coronary heart disease events independently of CRP and CVD risk factors. These results support the hypothesis that PTX3 reflects different aspects of inflammation than CRP, and may provide additional insights into the development and progression of atherosclerosis.

Background— C-reactive protein (CRP) is a biomarker of inflammation. Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with CRP concentrations and inflammation-related traits such as cardiovascular disease, type 2 diabetes mellitus, and obesity. We aimed to replicate previous CRP–SNP associations, assess whether these associations generalize to additional race/ethnicity groups, and evaluate inflammation-related SNPs for a potentially pleiotropic association with CRP. Methods and Results— We selected and analyzed 16 CRP-associated and 250 inflammation-related GWAS SNPs among 40 473 African American, American Indian, Asian/Pacific Islander, European American, and Hispanic participants from 7 studies collaborating in the Population Architecture using Genomics and Epidemiology (PAGE) study. Fixed-effect meta-analyses combined study-specific race/ethnicity-stratified linear regression estimates to evaluate the association between each SNP and high-sensitivity CRP. Overall, 18 SNPs in 8 loci were significantly associated with CRP (Bonferroni-corrected P −3 for replication, P −4 for pleiotropy): Seven of these were specific to European Americans, while 9 additionally generalized to African Americans (1), Hispanics (5), or both (3); 1 SNP was seen only in African Americans and Hispanics. Two SNPs in the CELSR2/PSRC1/SORT1 locus showed a potentially novel association with CRP: rs599839 ( P =2.0×10 −6 ) and rs646776 ( P =3.1×10 −5 ). Conclusions— We replicated 16 SNP–CRP associations, 10 of which generalized to African Americans and/or Hispanics. We also identified potentially novel pleiotropic associations with CRP for two SNPs previously associated with coronary artery disease and/or low-density lipoprotein–cholesterol. These findings demonstrate the benefit of evaluating genotype–phenotype associations in multiple race/ethnicity groups and looking for pleiotropic relationships among SNPs previously associated with related phenotypes.