Longitudinal increases in blood biomarkers of inflammation or cardiovascular disease and the incidence of venous thromboembolism.

Essentials Inflammatory and cardiac diseases are associated with increased venous thromboembolism (VTE) risk. Our prospective study assessed rise in inflammatory or cardiac biomarkers and VTE risk. A greater 6-year rise in N-terminal natriuretic peptide is associated with increased VTE incidence. Volume overload or impending cardiac disease may contribute to VTE occurrence. SUMMARY: Background We previously showed that participants in the population-based Atherosclerosis Risk in Communities (ARIC) cohort with elevated levels of blood biomarkers of inflammation or cardiac disease were at increased risk of venous thromboembolism (VTE). Objective We hypothesized that ARIC participants with larger 6-year increases in the levels of three biomarkers - C-reactive protein (CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and troponin T - would also have an increased subsequent risk of VTE. Methods We measured changes in the levels of these biomarkers in 9844 participants from 1990-1992 to 1996-1998, and then identified VTEs through 2015. Results A greater 6-year rise in the level of NT-proBNP, but not in that of CRP or troponin T, was significantly associated with increased VTE incidence over a median of 17.6 years of follow-up. After adjustment for other VTE risk factors, those whose NT-proBNP level rose from < 100 pg mL-1 to ≥ 100 pg mL-1 had a hazard ratio for VTE of 1.44 (95% confidence interval [CI] 1.15-1.80), as compared with the reference group with an NT-proBNP level of < 100 pg mL-1 at both times. This hazard ratio was slightly higher (1.66, 95% CI 1.19-2.31) during the first 10 years of follow-up, but was attenuated (1.24, 95% CI 0.99-1.56) after adjustment for prevalent and incident coronary heart disease, heart failure, and atrial fibrillation. Conclusions The two most likely explanations for our results are that: (i) an increasing NT-proBNP level reflects increasing subclinical volume overload and potentially increased venous stasis or subclinical PE that had gone unrecognized over time; or (ii) an increasing NT-proBNP level is a risk marker for impending cardiac disease that places patients at risk of VTE.

Atrial fibrillation and venous thromboembolism: evidence of bidirectionality in the Atherosclerosis Risk in Communities Study.

Essentials Atrial fibrillation (AF) may increase risk of venous thromboembolism (VTE), and vice versa. Bidirectionality was assessed prospectively via data from 15 129 black and white individuals. AF was associated with greater risk of developing VTE, and VTE with greater risk of AF. Associations were strongest among blacks and in the first 6 months after initial diagnosis. SUMMARY: Background Atrial fibrillation (AF) and venous thromboembolism (VTE) frequently co-occur. These conditions have shared risk factors and are accompanied by coagulation abnormalities. Furthermore, mechanistic pathways may directly link the disorders. Objectives To test the hypothesis that individuals with incident AF are at greater risk of developing VTE, and those with VTE are at elevated risk of AF. We also tested whether associations were stronger in the first 6 months after the initial diagnosis, and explored race differences. Patients/Methods A total of 15 129 ARIC study participants (45-64 years, 55% female, 26% Black) were followed from 1987 to 2011 for incident AF and VTE (median follow-up 19.8 years). Multivariable-adjusted Cox regression was used, with AF and VTE modeled as time-dependent exposures. Results Incident AF was associated with greater risk of subsequent incident VTE (hazard ratio [95% CI], 1.71 [1.32-2.22]); the association was stronger in Black people (2.30 [1.48-3.58]) and during the first 6 months after AF diagnosis (5.08 [3.08-8.38]). Similarly, incident VTE was associated with increased risk of incident AF (1.73 [1.34-2.24]), especially in Black people (2.40 [1.55-3.74]) and in the first 6 months after VTE diagnosis (4.50 [2.61-7.77]). Conclusions The occurrence of AF was associated with increased risk of incident VTE, and occurrence of VTE was associated with greater risk of incident AF. Associations were particularly strong among Black people and during the first 6 months after the initial diagnosis, although they remained elevated even after 6 months. These findings highlight patient populations that may be at increased risk of AF and VTE, and perhaps should be targeted with preventive strategies.

Taller height as a risk factor for venous thromboembolism: a Mendelian randomization meta-analysis.

Essentials Observational data suggest taller people have a higher risk of venous thromboembolism (VTE). We used Mendelian randomization techniques to further explore this association in three studies. Risk of VTE increased by 30-40% for each 10 cm increment in height. Height was more strongly associated with deep vein thrombosis than with pulmonary embolism. SUMMARY: Background Taller height is associated with a greater risk of venous thromboembolism (VTE). Objectives To use instrumental variable (IV) techniques (Mendelian randomization) to further explore this relationship. Methods Participants of European ancestry were included from two cohort studies (Atherosclerosis Risk in Communities [ARIC] study and Cardiovascular Health Study [CHS]) and one case-control study (Mayo Clinic VTE Study [Mayo]). We created two weighted genetic risk scores (GRSs) for height; the full GRS included 668 single-nucleotide polymorphisms (SNPs) from a previously published meta-analysis, and the restricted GRS included a subset of 362 SNPs not associated with weight independently of height. Standard logistic regression and IV models were used to estimate odds ratios (ORs) for VTE per 10-cm increment in height. ORs were pooled across the three studies by the use of inverse variance-weighted random effects meta-analysis. Results Among 9143 ARIC and 3180 CHS participants free of VTE at baseline, there were 367 and 109 incident VTE events. There were 1143 VTE cases and 1292 controls included from Mayo. The pooled ORs from non-IV models and models using the full and restricted GRSs as IVs were 1.27 (95% confidence interval [CI] 1.11-1.46), 1.34 (95% CI 1.04-1.73) and 1.45 (95% CI 1.04-2.01) per 10-cm greater height, respectively. Conclusions Taller height is associated with an increased risk of VTE in adults of European ancestry. Possible explanations for this association, including taller people having a greater venous surface area, a higher number of venous valves, or greater hydrostatic pressure, need to be explored further.

Lung function, respiratory symptoms and venous thromboembolism risk: the Atherosclerosis Risk in Communities Study.

Essentials The association of lung function with venous thromboembolism (VTE) is unclear. Chronic obstructive pulmonary disease (COPD) patterns were associated with a higher risk of VTE. Symptoms were also associated with a higher risk of VTE, but a restrictive pattern was not. COPD may increase the risk of VTE and respiratory symptoms may be a novel risk marker for VTE. SUMMARY: Background The evidence for the association between chronic obstructive pulmonary disease (COPD) and venous thromboembolism (VTE) is limited. There is no study investigating the association between restrictive lung disease (RLD) and respiratory symptoms with VTE. Objectives To investigate prospectively the association of lung function and respiratory symptoms with VTE. Patients/Methods In 1987-1989, we assessed lung function by using spirometry, and obtained information on respiratory symptoms (cough, phlegm, and dyspnea) in 14 654 participants aged 45-64 years, without a history of VTE or anticoagulant use, and followed them through 2011. Participants were classified into four mutually exclusive groups: 'COPD' (forced expiratory volume in 1 s [FEV1 ]/forced vital capacity [FVC] below the lower limit of normal [LLN]), 'RLD' (FEV1 /FVC ≥ LLN and FVC < LLN), 'respiratory symptoms with normal spirometic results' (without RLD or COPD), and 'normal' (without respiratory symptoms, RLD, or COPD). Results We documented 639 VTEs (238 unprovoked and 401 provoked VTEs). After adjustment for VTE risk factors, VTE risk was increased for individuals with either respiratory symptoms with normal spirometric results (hazard ratio [HR] 1.40, 95% confidence interval [CI] 1.12-1.73) or COPD (HR 1.33, 95% CI 1.07-1.67) but not for those with RLD (HR 1.15, 95% CI 0.82-1.60). These elevated risks of VTE were derived from both unprovoked and provoked VTE. Moreover, FEV1 and FEV1 /FVC showed dose-response relationships with VTE. COPD was more strongly associated with pulmonary embolism than with deep vein thrombosis. Conclusions Obstructive spirometric patterns were associated with an increased risk of VTE, suggesting that COPD may increase the risk of VTE. Respiratory symptoms may represent a novel risk marker for VTE.

Replication of a genetic risk score for venous thromboembolism in whites but not in African Americans.

UNLABELLED: ESSENTIALS: There is little prospective information on genetic risk scores to predict venous thromboembolism (VT). Community based cohort followed a median of 22.6 years for VT occurrence. A 5-SNP risk score identified whites at risk of VT, but not African Americans. The utility of genetic risk scores for VT is yet to be established. BACKGROUND: Case-control studies have created genetic risk scores of single nucleotide polymorphisms (SNPs) associated with venous thromboembolism (VTE) and documented their ability to predict VTE, but prospective data are lacking. OBJECTIVE: To test the ability of a genetic risk score to predict VTE incidence in a prospective study, particularly in African Americans. METHODS: We computed a previously proposed genetic risk score, based on five established VTE SNPs in the F5, F2, ABO, FGG, and F11 genes, in 9520 whites and 3049 African Americans initially free of VTE. We followed them a median of 22.6 years for VTE occurrence (n = 380 events in whites and n = 187 in African Americans). RESULTS: In whites, the five-SNP weighted genetic risk score ranged from 0 to 5.8, and VTE risk increased 1.41-fold (95% confidence interval [CI] 1.27-fold to 1.56-fold) per allele increment. In African Americans, the weighted genetic risk score ranged from 0 to 4.6 and the hazard ratio per risk allele was 1.14 (95% CI 0.94-1.38), with adjustment for 10 principal components of ancestry. The area under the receiver operating characteristic curve for 20-year prediction of VTE from the weighted genetic risk score was 0.59 (95% CI 0.56-0.63) in whites and 0.56 (95% CI 0.51-0.61) in African Americans. Adding non-genetic factors increased the area under the curve to 0.67 in whites and to 0.66 in African Americans. CONCLUSIONS: Higher values for a five-SNP genetic risk score helped identify white adults at risk of VTE. The genetic risk score did not identify future VTE occurrence in African Americans.

Changes in N-terminal pro-B-type natriuretic peptide and incidence of diabetes: The Multi-Ethnic Study of Atherosclerosis (MESA).

AIMS: This study looked at whether the inverse association of circulating N-terminal pro-B-type natriuretic peptide (NT-proBNP) with incident diabetes is modified by changes in NT-proBNP (ΔNT-proBNP) levels. METHODS: Plasma NT-proBNP was assayed at baseline and 3.2 years later (visit 3) in the Multi-Ethnic Study of Atherosclerosis (MESA). ΔNT-proBNP was calculated as NT-proBNP visit3-NT-proBNP baseline. A Poisson distribution was fitted to determine the incidence density of diabetes, adjusted for age, race, gender, educational attainment, antihypertensive medication, total intentional exercise and plasma IL-6 levels. In the primary analysis (n=3236 without diabetes up to visit 3, followed for a mean of 6.3 years), incidence density was regressed for the following categories of baseline NT-proBNP: (1)<54.4 pg/mL; (2) 54.4-85.9 pg/mL; and (3) 86-54.2 pg/mL. This was crossed with categories of ΔNT-proBNP as medians (ranges): (1) -6.2 (-131-11.7) pg/mL; (2) 19.8 (11.8-30.1) pg/mL; (3) 44.0 (30.2-67.9) pg/mL; and (4) 111.2 (68.0-3749.9) pg/mL. RESULTS: The incidence density of diabetes followed a U-shaped association across categories of ΔNT-proBNP within categories of baseline NT-proBNP after adjusting for other covariates (P=0.02). At each level of baseline NT-proBNP, the incidence density of diabetes was lowest for small-to-moderate increases in NT-proBNP. CONCLUSION: This analysis suggests that NT-proBNP has a biphasic association with diabetes in which the risk of incident diabetes decreases within a 'physiological range' of ΔNT-proBNP, and plateaus or increases as NT-proBNP concentrations increase, probably in response to pathophysiological conditions leading to high levels of NT-proBNP.

Vitamin D, vitamin D binding protein gene polymorphisms, race and risk of incident stroke: the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND AND PURPOSE: Low vitamin D levels, measured by serum 25-hydroxyvitamin D [25(OH)D], are associated with increased stroke risk. Less is known about whether this association differs by race or D binding protein (DBP) single nucleotide polymorphism (SNP) status. Our objective was to characterize the associations of and interactions between 25(OH)D levels and DBP SNPs with incident stroke. It was hypothesized that associations of low 25(OH)D with stroke risk would be stronger amongst persons with genotypes associated with higher DBP levels. METHODS: 25(OH)D was measured by mass spectroscopy in 12 158 participants in the Atherosclerosis Risk in Communities (ARIC) study (baseline 1990-1992, mean age 57 years, 57% female, 23% black) and they were followed through 2011 for adjudicated stroke events. Two DBP SNPs (rs7041, rs4588) were genotyped. Cox models were adjusted for demographic/behavioral/socioeconomic factors. RESULTS: During a median of 20 years follow-up, 804 incident strokes occurred. The lowest quintile of 25(OH)D (<17.2 ng/ml) was associated with higher stroke risk [hazard ratio (HR) 1.34 (1.06-1.71) versus highest quintile]; this association was similar by race (P interaction 0.60). There was weak evidence of increased risk of stroke amongst those with 25(OH)D < 17.2 ng/ml and either rs7041 TG/GG [HR = 1.29 (1.00-1.67)] versus TT genotype [HR = 1.19 (0.94-1.52)] (P interaction 0.28) or rs4588 CA/AA [HR = 1.37 (1.07-1.74)] versus CC genotype [HR = 1.14 (0.91-1.41)] (P interaction 0.11). CONCLUSIONS: Low 25(OH)D is a risk factor for stroke. Persons with low 25(OH)D who are genetically predisposed to high DBP (rs7041 G, rs4588 A alleles), who therefore have lower predicted bioavailable 25(OH)D, may be at greater risk for stroke, although our results were not conclusive and should be interpreted as hypothesis generating.

Prospective study of sickle cell trait and venous thromboembolism incidence.

BACKGROUND: Sickle cell trait may increase risk of venous thromboembolism, but this is not fully established. OBJECTIVES: We sought to determine the association of sickle cell trait with deep vein thrombosis and pulmonary embolism. METHODS: Middle-aged African Americans participating in a prospective, population-based cohort investigation, the Atherosclerosis Risk in Communities Study, were followed from 1987 through 2011 for incident hospitalized pulmonary embolism (n = 111) or isolated deep vein thrombosis (n = 138), verified by physician review of medical records. Sickle cell trait (heterozygosity for hemoglobin S, n = 268) was compared with no sickle cell trait (n = 3748). RESULTS: Over a median of 22 years of follow-up, 249 participants had an incident venous thromboembolism. The hazard ratio of venous thromboembolism was 1.50 (95% confidence interval [CI] 0.96-2.36) for participants with vs. without sickle cell trait, after adjustment for age, sex, ancestry, hormone replacement therapy (women), body mass index, diabetes, and estimated glomerular filtration rate. This hazard ratio was 2.05 (95% CI 1.12-3.76) for pulmonary embolism and 1.15 (95% CI 0.58-2.27) for deep vein thrombosis without pulmonary embolism. CONCLUSIONS: Sickle cell trait in African Americans carries a 2-fold increased risk of pulmonary embolism but does not elevate deep vein thrombosis risk. Because neonatal screening for sickle hemoglobin is being conducted in the United States, consideration should be paid to the increased pulmonary embolism risk of individuals with sickle cell trait.

Inflammation markers and incident venous thromboembolism: the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort.

BACKGROUND: Inflammation biomarkers are associated with the venous thromboembolism (VTE) risk factors obesity and age; however, the relationships of inflammation with VTE risk remain controversial. OBJECTIVES: To examine associations of four inflammation biomarkers, i.e. C-reactive protein (CRP), serum albumin, white blood cell (WBC) count, and platelet count (PLTC), with incident VTE, and to determine whether they mediate the association of age or obesity with VTE. PATIENTS/METHODS: Hazards models adjusted for VTE risk factors were used to calculate the prospective association of each biomarker with incident VTE in 30,239 participants of the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Mediation of the associations of obesity and age with VTE were examined by bootstrapping. Over a period of 4.6 years, there were 268 incident VTE events. After adjustment for VTE risk factors, the hazard ratios (HRs) were 1.25 (95% confidence interval [CI] 1.09-1.43) per standard deviation (SD) higher log-CRP and 1.25 (95% CI 1.06-1.48) per SD lower albumin; there were no associations for WBC count or PLTC. The association of body mass index (BMI), but not age, with VTE was partially mediated by CRP and albumin. In risk factor-adjusted models, the percentage attenuations of the BMI HR for VTE after introduction of CRP or albumin into the models were 15.4% (95% CI 7.7-33.3%) and 41.0% (95% CI 12.8-79.5%), respectively. CONCLUSION: Higher CRP levels and lower serum albumin levels were associated with increased VTE risk, and statistically mediated part of the association of BMI with VTE. These data suggest that inflammation may be a potential mechanism underlying the relationship between obesity and VTE risk.

Serum 25-hydroxyvitamin D and risk of venous thromboembolism: the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Some evidence suggests that an inadequate vitamin D level may increase the risk for atherosclerotic cardiovascular disease. Whether a low vitamin D level plays a role in venous thromboembolism (VTE), that is, venous thrombosis and pulmonary embolism, is largely unexplored. OBJECTIVES: We tested prospectively, in the Atherosclerosis Risk in Communities (ARIC) cohort, whether the serum level of 25-hydroxyvitamin D (25[OH]D) is inversely associated with VTE incidence, and whether it partly explains the African American excess of VTE in the ARIC Study. PATIENTS AND METHODS: We measured 25(OH)D by using mass spectroscopy in stored samples of 12 752 ARIC Study participants, and followed them over a median of 19.7 years (1990-1992 to 2011) for the incidence of VTE (n = 537). RESULTS: The seasonally adjusted 25(OH)D level was not associated with VTE incidence. In a model adjusted for age, race, sex, hormone replacement therapy, and body mass index, the hazard ratios of VTE across 25(OH)D quintiles 5 (high) to 1 (low) were: 1 (ref.), 0.84 (95% confidence interval [CI] 0.65-1.08), 0.88 (95% CI 0.68-1.13), 1.04 (95% CI 0.78-1.38), and 0.90 (95% CI 0.64-1.27). The lowest 25(OH)D quintile contained 59% African Americans, whereas the highest quintile contained 7% African Americans. However, lower 25(OH)D levels explained little of the 63% greater VTE risk of African Americans over whites in this cohort. CONCLUSIONS: A low 25(OH)D level was not a risk factor for VTE in this prospective study. However, the totality of the literature (three studies) suggests that a low 25(OH)D level might modestly increase VTE risk in whites, but this needs further confirmation.

Development and validation of an ankle brachial index risk model for the prediction of cardiovascular events.

BACKGROUND: The ankle brachial index (ABI) is related to risk of cardiovascular events independent of the Framingham risk score (FRS). The aim of this study was to develop and evaluate a risk model for cardiovascular events incorporating the ABI and FRS. DESIGN: An analysis of participant data from 18 cohorts in which 24,375 men and 20,377 women free of coronary heart disease had ABI measured and were followed up for events. METHODS: Subjects were divided into a development and internal validation dataset and an external validation dataset. Two models, comprising FRS and FRS + ABI, were fitted for the primary outcome of major coronary events. RESULTS: In predicting events in the external validation dataset, C-index for the FRS was 0.672 (95% CI 0.599 to 0.737) in men and 0.578 (95% CI 0.492 to 0.661) in women. The FRS + ABI led to a small increase in C-index in men to 0.685 (95% CI 0.612 to 0.749) and large increase in women to 0.690 (95% CI 0.605 to 0.764) with net reclassification improvement (NRI) of 4.3% (95% CI 0.0 to 7.6%, p = 0.050) and 9.6% (95% CI 6.1 to 16.4%, p < 0.001), respectively. Restricting the FRS + ABI model to those with FRS intermediate 10-year risk of 10 to 19% resulted in higher NRI of 15.9% (95% CI 6.1 to 20.6%, p < 0.001) in men and 23.3% (95% CI 13.8 to 62.5%, p = 0.002) in women. However, incorporating ABI in an improved newly fitted risk factor model had a nonsignificant effect: NRI 2.0% (95% CI 2.3 to 4.2%, p = 0.567) in men and 1.1% (95% CI 1.9 to 4.0%, p = 0.483) in women. CONCLUSIONS: An ABI risk model may improve prediction especially in individuals at intermediate risk and when performance of the base risk factor model is modest.

Statin therapy and levels of hemostatic factors in a healthy population: the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: HMG-CoA reductase inhibitors (statins) reduce the risk of venous thromboembolism (VTE) in healthy people. Statins reduce levels of inflammation biomarkers; however, the mechanism for the reduction in VTE risk is unknown. AIM: In a large cohort of healthy people, we studied associations of statin use with plasma hemostatic factors related to VTE risk. METHODS: Cross-sectional analyses were performed in the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study of 6814 healthy men and women aged 45-84 years, free of clinical cardiovascular disease at baseline; 1001 were using statins at baseline. Twenty-three warfarin users were excluded. Age, race and sex-adjusted mean hemostatic factor levels were compared between statin users and non-users, and multivariable linear regression models were used to assess associations of statin use with hemostatic factors, adjusted for age, race/ethnicity, education, income, aspirin use, hormone replacement therapy (in women), and major cardiovascular risk factors. RESULTS: Participants using statins had lower adjusted levels of D-dimer (- 9%), C-reactive protein (- 21%) and factor VIII (- 3%) than non-users (P < 0.05). Homocysteine and von Willebrand factor levels were non-significantly lower with statin use. Higher fibrinogen (2%) and plasminogen activator inhibitor-1 (22%) levels were observed among statin users than among non-users (P < 0.05). Further adjustment for LDL and triglyceride levels did not attenuate the observed differences in these factors with statin use. CONCLUSIONS: Findings of lower D-dimer, FVIII and C-reactive protein levels with statin use suggest hypotheses for mechanisms whereby statins might lower VTE risk. A prospective study or clinical trial linking these biochemical differences to VTE outcomes in statin users and non-users is warranted.

Genetic admixture is associated with plasma hemostatic factor levels in self-identified African Americans and Hispanics: the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Epidemiologic studies report that self-identified African Americans typically have higher hemostatic factor levels than do self-identified Caucasians or Hispanics. OBJECTIVE: To enhance understanding of phenotypic variation in hemostatic factor levels by race/ethnicity, we evaluated the relationship between genetic ancestry and hemostatic factor levels among Multi-Ethnic Study of Atherosclerosis (MESA) study participants. PATIENTS/METHODS: Our sample included 712 African American and 701 Hispanic men and women aged 45 to 84 years. Individual global ancestry was estimated from 199 genetic markers using STRUCTURE. Linear regression models were used to evaluate the relationship between ancestry and hemostatic factor levels, adjusting for age, gender, education, income and study site. RESULTS: Among African Americans, mean ± standard deviation (SD) ancestry was estimated as 79.9% ± 15.9% African and 20.1% ± 15.9% European. Each SD (16%) greater African ancestry was associated with 2.1% higher fibrinogen levels (P = 0.007) and 3.5% higher plasmin-antiplasmin (PAP) levels (P = 0.02). Ancestry among African Americans was not related to levels of factor (F)VIII or D-dimer. Mean ± SD estimated ancestry among Hispanics was 48.3% ± 23.8% Native American, 38.8% ± 21.9% European, and 13.0% ± 8.9% African. In Hispanics, each SD (19%) greater African ancestry was associated with 2.7% higher fibrinogen levels (P = 0.009) and 7.9% higher FVIII levels (P = 0.0002). In Hispanics, there was no relation between African ancestry and D-dimer or PAP levels, or between European ancestry and hemostatic factor levels. CONCLUSIONS: Greater African ancestry among African Americans and Hispanics was associated with higher levels of several hemostatic factors, notably fibrinogen. These results suggest that genetic heterogeneity contributes, albeit modestly, to racial/ethnic differences in hemostatic factor levels.

Association of blood monocyte and platelet markers with carotid artery characteristics: the atherosclerosis risk in communities carotid MRI study.

BACKGROUND: Atherosclerosis is characterized by infiltration of inflammatory cells from circulating blood. Blood cell activation could play an important role in plaque formation. METHODS: We analyzed the relationship between blood cellular markers and quantitative measures of carotid wall components in 1,546 participants from the ARIC (Atherosclerosis Risk in Communities) Carotid MRI Study. Carotid imaging was performed using a gadolinium contrast-enhanced MRI and cellular phenotyping by flow cytometry. RESULTS: Monocyte Toll-like receptor (TLR)-2 is associated with larger plaques, while CD14, myeloperoxidase, and TLR-4 associate with smaller. Platelet CD40L is associated with smaller plaques and thinner caps, while P-selectin is associated with smaller core size. CONCLUSIONS: Blood cell activation is significantly associated with atherosclerotic changes of the carotid wall.

Traffic exposure and incident venous thromboembolism in the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Two recent case-control studies in Italy reported that long-term exposure to particulate air pollution or living near major traffic roads was associated with an increased risk of deep vein thrombosis (DVT). No prospective evidence exists on the possible association between long-term traffic-related air pollution and incident venous thromboembolism (VTE). OBJECTIVES: To examine the association between long-term traffic exposure and incident VTE in a population-based prospective cohort study. METHODS: We studied 13,143 middle-aged men and women in the Atherosclerosis Risk in Communities Study without a history of DVT or pulmonary embolism at baseline examination (1987-1989). The Geographical Information System-mapped traffic density and distance to major roads in the four study communities served as measures of traffic exposure. We examined the association between traffic exposure and incident VTE with proportional hazards regression models. RESULTS: A total of 405 subjects developed VTE in 2005. Traffic density was not significantly associated with VTE. Relative to those in the lowest quartile of traffic density, the adjusted hazard ratios across increasing quartiles were 1.18 (95% confidence interval [CI] 0.88-1.57), 0.99 (95% CI 0.74-1.34) and 1.14 (95% CI 0.86-1.51) (P-value for trend across quartiles = 0.64). For residents living within 150 m of major roads, as compared with subjects living further away, the adjusted hazard ratio was 1.16 (95% CI 0.95-1.42, P = 0.14). CONCLUSIONS: This first prospective study in the general population does not support an association between air pollution exposure or traffic proximity and risk of DVT. More data may be needed to clarify whether traffic or air pollution influences the risk of VTE.

Cross-cultural comparison of the sleep-disordered breathing prevalence among Americans and Japanese.

The aim of the present study was to compare the prevalence of sleep-disordered breathing among Hispanic and white Americans and Japanese. A 1-night sleep study using a single-channel airflow monitor was performed on 211 Hispanics and 246 Whites from the Minnesota field centre (St Paul, MN, USA) of the Multi-Ethnic Study of Atherosclerosis (MESA), and 978 Japanese from three community-based cohorts of the Circulatory Risk in Communities Study (CIRCS) in Japan. The respiratory disturbance index and sleep-disordered breathing, defined as a respiratory disturbance index of > or =15 events x h(-1), were estimated. The prevalence of sleep-disordered breathing was higher in males (34.2%) than females (14.7%), and among Hispanics (36.5%) and Whites (33.3%) than among Japanese (18.4%), corresponding to differences in body mass index. Within body mass index strata, the race difference in sleep-disordered breathing was attenuated. This was also true when body mass index was adjusted for instead of stratification. The strong association between body mass index and sleep-disordered breathing was similar in Japanese and Americans. The prevalence of sleep-disordered breathing was lower among Japanese than among Americans. However, the association of body mass index with sleep-disordered breathing was strong, and similar among the race/ethnic groups studied. The majority of the race/ethnic difference in sleep-disordered breathing prevalence was explained by a difference in body mass index distribution.

Hemostatic factors and subclinical brain infarction in a community-based sample: the ARIC study.

BACKGROUND: Previous data are conflicting as to whether imbalance between hemostatic factors is associated with clinical strokes. We evaluated the association between hemostatic factor levels and subclinical lacunar infarcts in a nested sample from a subset of the Atherosclerosis Risk in Communities (ARIC) cohort. METHODS: 196 cases without clinical strokes had lacunar infarcts by MRI, and 214 controls without radiographic infarcts were frequency-matched by age group and sex. Logistic regression models were fitted to assess the association between levels of hemostatic markers and case status. RESULTS: In age-, race- and sex-adjusted models, von Willebrand factor (vWF) and D-dimer were positively associated with case status, with odds ratios for the highest vs. lowest tertile of 2.0 (95% CI 1.2-3.6) for vWF and 1.76 (95% CI 1.02-3.0) for D-dimer. Plasminogen had nonsignificant inverse associations with presence of silent lacunar infarcts. CONCLUSIONS: vWF and D-dimer were positively associated, and plasminogen was nonsignificantly inversely associated with subclinical radiographic infarct. Further studies on the role of these hemostatic factors in the development of silent lacunar infarcts may help elucidate the mechanisms behind this injury and may even point to potential targets for future intervention.

Low protein C and incidence of ischemic stroke and coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Protein C is an important plasma natural anticoagulant. Although protein C deficiency increases risk of venous thrombosis, it remains uncertain whether low protein C increases risk of atherothrombosis. OBJECTIVE: To examine whether low protein C may be a risk factor for ischemic stroke or coronary events in a prospective population-based study. PATIENTS/METHODS: The Atherosclerosis Risk in Communities Study assessed protein C antigen by ELISA at baseline in 1987-89 and followed participants (n = 13 879) for incident ischemic stroke or coronary events through 2005. RESULTS: Over a median of 16.9 years of follow-up, 613 ischemic strokes and 1257 coronary heart disease events occurred. Protein C was inversely associated with incidence of ischemic stroke. Adjusted for multiple risk factors, the rate ratios (95% CIs) from highest to lowest quintiles were 1.0, 1.16 (0.90-1.50), 1.22 (0.94-1.58), 1.18 (0.90-1.55) and 1.52 (1.17-1.98). This inverse association was stronger for non-lacunar and cardioembolic stroke than for lacunar stroke. In contrast, there was a positive association between protein C and coronary heart disease in incompletely adjusted models, but no association after adjustment for plasma lipids. CONCLUSIONS: In this cohort study, low protein C was a risk factor for incident ischemic stroke but not coronary heart disease. Levels of protein C associated with stroke risk were not restricted to the traditional 'deficient' range for protein C (< 0.5 percentile), suggesting that other etiologies for a lower protein C, or genetic variants associated with more subtle changes in protein C, are playing a role in disease pathogenesis.

Peak thrombin generation and subsequent venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE) study.

BACKGROUND: Thrombin is an enzyme that is essential for the acceleration of the coagulation cascade and the conversion of fibrinogen to clottable fibrin. OBJECTIVES: We evaluated the relationship of basal peak thrombin generation with the risk of future venous thromboembolism (VTE), and determined whether associations were independent of other coagulation markers. METHODS: The Longitudinal Investigation of Thromboembolism Etiology (LITE) study investigated VTE in two prospective population-based cohorts: the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS). Peak thrombin generation was measured on stored plasma in a nested case-control sample (434 cases and 1004 controls). Logistic regression was used to estimate the relationship of peak thrombin generation with VTE, adjusted for age, sex, race, center, and body mass index. Mediation was evaluated by additionally adjusting for factor VIII and D-dimer. RESULTS: Relative to the first quartile of peak thrombin generation, the odds ratio (OR) of VTE for those above the median was 1.74 [95% confidence interval (CI) 1.28-2.37]. The association was modestly attenuated by adjustment for FVIII and D-dimer (OR 1.47, 95% CI 1.05-2.05). Associations appeared to be stronger for idiopathic than for secondary VTE. Elevated peak thrombin generation more than added to the VTE risk associated with FV Leiden or low activated partial thromboplastin time. CONCLUSIONS: In this prospective study of two independent cohorts, elevated basal peak thrombin generation was associated with subsequent risk of VTE, independently of established VTE risk factors.