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We examined the associations between haematological and inflammatory variables with future venous thromboembolism (VTE), in 3494 men aged 60-79 years, with no previous history of VTE or myocardial infarction, who were not receiving oral anticoagulants. After a mean follow-up period of 18 years, there were 149 confirmed cases of fatal or non-fatal VTE (deep vein thrombosis and/or pulmonary embolism). Among classical cardiovascular risk factors, only obesity and cigarette smoking were associated with VTE risk. After adjustment for age, obesity and smoking, VTE risk was associated with coagulation factor VIII, factor IX, von Willebrand factor (VWF), activated partial thromboplastin time (APTT), and fibrin D-dimer. Hazard ratios (95% CI) for top to bottom quarters (bottom to top for APTT), were respectively 2.17 (1.37, 3.44), 2.15 (1.30, 3.53), 2.02 (1.27, 3.22), 2.43 (1.47, 4.02) and 3.62 (2.18, 6.08). The 11% of men with both the shortest APTT and highest D-dimer combined had a 5.02 (2.37, 10.62) higher risk of VTE. VTE risk was not associated with fibrinogen, factor VII or activated protein C resistance; full blood count variables or with inflammatory markers, plasma viscosity, C-reactive protein or interleukin-6. The combination of D-dimer and APTT merits evaluation as an adjunct to VTE risk prediction scores.

Background: There is increasing evidence that blood viscosity and its major determinants (haematocrit and plasma viscosity) are associated with increased risks of cardiovascular disease (CVD) and premature mortality; however, their predictive value for CVD and mortality is not clear. Methods: We prospectively assessed the added predictive value of plasma viscosity and whole-blood viscosity and haematocrit in 3386 men and women aged 30-74 years participating in the Scottish Heart Health Extended Cohort study. Results: Over a median follow-up of 17 years, 819 CVD events and 778 deaths were recorded. Hazard ratios (95% confidence intervals) for a 1SD increase in plasma viscosity, adjusted for major CVD risk factors were 1.12 (1.04, 1.20) for CVD, and 1.20 (1.12, 1.29) for mortality. These remained significant after further adjustment for plasma fibrinogen: 1.09 (1.01, 1.18) and 1.13 (1.04, 1.22). Corresponding results for blood viscosity were 0.99 (0.90, 1.09) for CVD, and 1.11 (1.01, 1.22) for total mortality; and 0.97 (0.88, 1.08) and 1.06 (0.96, 1.18) after further adjustment for fibrinogen. Haematocrit showed similar associations to blood viscosity. When added to classical CVD risk factors, plasma viscosity improved discrimination of CVD and mortality by 2.4% (0.7, 4.4) and 4.1% (2.0, 6.5). Conclusion: While plasma and blood viscosity may play a role in pathogenesis of CVD and mortality, much of their associations with CVD and mortality are due to mutual effects of major CVD risk factors. However, plasma viscosity adds to discrimination of CVD and mortality and might be considered for inclusion in multivariable risk scores.

Background: \ud \ud Heightened blood pressure (BP) responses to mental stress predict raised BP levels over subsequent years, but evidence for associations with incident hypertension is limited, and the significance of inflammatory responses is uncertain.\ud \ud Purpose: \ud \ud We investigated the relationship between BP and plasma fibrinogen responses to stress and incident hypertension over an average 8-year follow-up.\ud \ud Method: \ud \ud Participants were 636 men and women (mean age 59.1 years) from the Whitehall II epidemiological cohort with no history of cardiovascular disease and hypertension. They performed standardized behavioral tasks (color/word conflict and mirror tracing), and hypertension was defined by clinic measures and medication status.\ud \ud Results: \ud \ud Of participants in the highest systolic BP reactivity tertile, 29.3 % became hypertensive over the follow-up period compared with 16.5 % of those in the lowest tertile, with an odds ratio of 2.02 (95 % CI 1.17–3.88, p = 0.012) after adjustment for age, sex, grade of employment, body mass index, smoking, alcohol consumption, physical activity, follow-up time, subjective stress response, perceived task difficulty, perceived task engagement, and baseline BP. Similar associations were observed for diastolic BP reactivity (odds ratio 2.05, 95 % CI 1.23–3.40, p = 0.006) and for impaired systolic BP post-stress recovery (odds ratio 2.06, 95 % CI 1.19–3.57, p = 0.010). Fibrinogen reactions to tasks also predicted future hypertension in women (odds ratio 2.64, 95 % CI 1.11–6.30, p = 0.029) but not men.\ud \ud Conclusions: \ud \ud These data suggest that heightened cardiovascular and inflammatory reactivity to mental stress is associated with hypertension risk, and may be a mechanism through which psychosocial factors impact on the development of hypertension.

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

AIMS: Because low-grade inflammation may play a role in the pathogenesis of coronary heart disease (CHD), and pro-inflammatory cytokines govern inflammatory cascades, this study aimed to assess the associations of several pro-inflammatory cytokines and CHD risk in a new prospective study, including meta-analysis of prospective studies. METHODS AND RESULTS: Interleukin-6 (IL-6), IL-18, matrix metalloproteinase-9 (MMP-9), soluble CD40 ligand (sCD40L), and tumour necrosis factor-α (TNF-α) were measured at baseline in a case-cohort study of 1514 participants and 833 incident CHD events within population-based prospective cohorts at the Danish Research Centre for Prevention and Health. Age- and sex-adjusted hazard ratios (HRs) for CHD per 1-SD higher log-transformed baseline levels were: 1.37 (95% CI: 1.21-1.54) for IL-6, 1.26 (1.11-1.44) for IL-18, 1.30 (1.16-1.46) for MMP-9, 1.01 (0.89-1.15) for sCD40L, and 1.13 (1.01-1.27) for TNF-α. Multivariable adjustment for conventional vascular risk factors attenuated the HRs to: 1.26 (1.08-1.46) for IL-6, 1.12 (0.95-1.31) for IL-18, 1.21 (1.05-1.39) for MMP-9, 0.93 (0.78-1.11) for sCD40L, and 1.14 (1.00-1.31) for TNF-α. In meta-analysis of up to 29 population-based prospective studies, adjusted relative risks for non-fatal MI or CHD death per 1-SD higher levels were: 1.25 (1.19-1.32) for IL-6; 1.13 (1.05-1.20) for IL-18; 1.07 (0.97-1.19) for MMP-9; 1.07 (0.95-1.21) for sCD40L; and 1.17 (1.09-1.25) for TNF-α. CONCLUSIONS: Several different pro-inflammatory cytokines are each associated with CHD risk independent of conventional risk factors and in an approximately log-linear manner. The findings lend support to the inflammation hypothesis in vascular disease, but further studies are needed to assess causality.

Background and Purpose— Several prospective studies have shown significant associations between plasma fibrinogen, viscosity, C-reactive protein (CRP), fibrin d -dimer, or tissue plasminogen activator (tPA) antigen and the risk of primary cardiovascular events. Little has been published on the associations of these variables with recurrent stroke. We studied such associations in a nested case-control study derived from the Perindopril Protection Against Recurrent Stroke Study (PROGRESS). Methods— Nested case-control study of ischemic (n=472) and hemorrhagic (n=83) strokes occurring during a randomized, placebo-controlled multicenter trial of perindopril-based therapy in 6105 patients with a history of stroke or transient ischemic attack. Controls were matched for age, treatment group, sex, region, and most recent qualifying event at entry to the parent trial. Results— Fibrinogen and CRP were associated with an increased risk of recurrent ischemic stroke after accounting for the matching variables and adjusting for systolic blood pressure, smoking, peripheral vascular disease, and statin and antiplatelet therapy. The odds ratio for the last compared with the first third of fibrinogen was 1.34 (95% CI, 1.01 to 1.78) and for CRP was 1.39 (95% CI, 1.05 to 1.85). After additional adjustment for each other, these 2 odds ratios stayed virtually unchanged. Plasma viscosity, tPA, and d -dimer showed no relationship with recurrent ischemic stroke, although tPA was significant for lacunar and large artery subtypes. Although each of these variables showed a negative relationship with recurrent hemorrhagic stroke, none of these relationships achieved statistical significance. Conclusions— Fibrinogen and CRP are risk predictors for ischemic but not hemorrhagic stroke, independent of potential confounders.

Low von Willebrand factor (VWF) levels are associated with bleeding symptoms and are a diagnostic criterion for von Willebrand disease, the most common inherited bleeding disorder. To date, it is unclear which genetic loci are associated with reduced VWF levels. Therefore, we conducted a meta-analysis of genome-wide association studies to identify genetic loci associated with low VWF levels. For this meta-analysis, we included 31 149 participants of European ancestry from 11 community-based studies. From all participants, VWF antigen (VWF:Ag) measurements and genome-wide single-nucleotide polymorphism (SNP) scans were available. Each study conducted analyses using logistic regression of SNPs on dichotomized VWF: Ag measures (lowest 5% for blood group O and non-O) with an additive genetic model adjusted for age and sex. An inverse-variance weighted meta-analysis was performed for VWF:Ag levels. A total of 97 SNPs exceeded the genome-wide significance threshold of 5 x 10(-8) and comprised five loci on four different chromosomes: 6q24 (smallest P-value 5.8 x 10(-10)), 9q34 (2.4 x 10(-64)), 12p13 (5.3x 10(-22)), 12q23 (1.2 x 10(-8)) and 13q13 (2.6 x 10(-8)). All loci were within or close to genes, including STXBP5 (Syntaxin Binding Protein 5) (6q24), STAB5 (stabilin-5) (12q23), ABO (9q34), VWF (12p13) and UFM1 (ubiquitin-fold modifier 1) (13q13). Of these, UFM1 has not been previously associated with VWF: Ag levels. Four genes that were previously associated with VWF levels (VWF, ABO, STXBP5 and STAB2) were also associated with low VWF levels, and, in addition, we identified a new gene, UFM1, that is associated with low VWF levels. These findings point to novel mechanisms for the occurrence of low VWF levels.

We have previously shown that there is a complex and dynamic biological interaction between acute mental stress and acute release of inflammatory factors into the blood stream in relation to heart disease. We now hypothesize that the presence of chronic psychosocial stress may modify the weight of single test results for inflammation as a predictor of heart disease. Using a cross-sectional design, 500 participants free from heart disease drawn from the Whitehall II study in UK in 2006–2008 were tested for plasma fibrinogen as an inflammatory factor, financial strain as a marker of chronic psychosocial stress, coronary calcification measured using computed tomography, and for plasma high-sensitivity cardiac troponin T (HS-CTnT) as a marker of cardiac risk. Fibrinogen concentration levels above the average were associated with a 5-fold increase in the odds of HS-CTnT positivity only among individuals with financial strain (N = 208, OR = 4.73, 95%CI = 1.67 to 13.40, P = 0.003). Fibrinogen was in fact not associated with HS-CTnT positivity in people without financial strain despite the larger size of that subsample (n = 292, OR = 0.84, 95%CI = 0.42 to 1.67, P = 0.622). A test for interaction on the full sample (N = 500) showed a P value of 0.010 after adjusting for a range of demographics, health behaviours, traditional cardiovascular risk factors, psychosocial stressors, inflammatory cytokines, and coronary calcification. In conclusion, elevated fibrinogen seems to be cardio-toxic only when is combined with financial strain. Chronic psychosocial stress may modify the meaning that we should give to single test results for inflammation. Further research is needed to confirm our results., Highlights • Chronic psychosocial stress modifies the association between inflammation and CVD. • A single test result of elevated fibrinogen can be the result of a healthy acute response to stress. • Therefore a finding of elevated fibrinogen cannot always be interpreted as a sign of poor health. • Elevated fibrinogen is associated with CVD only in individuals with chronic stress.

Background and Objective Recent studies suggest perivascular spaces are a marker of small vessel disease, blood–brain barrier permeability, and inflammation, but little is known about their risk factors and associations with peripheral blood markers. Materials and Methods In prospectively recruited patients with recent minor ischemic stroke, we investigated the influence of age, sex, hypertension, diabetes, and smoking on the severity of perivascular spaces in the basal ganglia seen on T2-weighted magnetic resonance imaging. We assessed plasma markers of endothelial function (von Willebrand factor, intracellular adhesion molecule-1), inflammation (interleukin-6, tumor necrosis factor-alpha, C-reactive protein), and thrombosis (fibrinogen, prothrombin fragments 1 + 2, thrombin–antithrombin complex, tissue plasminogen activator, D-dimer). We used a validated semi-automated method to measure basal ganglia perivascular spaces count and volume. We tested uni- and multivariable associations between blood markers and basal ganglia perivascular spaces count and volume. Findings In 100 patients (median age: 67 years, range: 37-92), on adjusted analysis, basal ganglia perivascular spaces count was associated with age (r = .117, P = .003) and hypertension (r = 2.225, P = .013). On multivariable linear regression, adjusted for age, sex, hypertension, smoking and diabetes, reduced von Willebrand factor was associated with increased basal ganglia perivascular spaces count (r = −.025, P = .032). Conclusion The association of increased basal ganglia perivascular spaces count with reduced von Willebrand factor is novel. As von Willebrand factor may promote cerebral endothelial integrity, insufficient von Willebrand factor is consistent with dysfunctional cerebral endothelium and increased basal ganglia perivascular spaces in cerebral small vessel disease. Quantitative perivascular spaces measurement may increase sensitivity to detect cerebral endothelial dysfunction.

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including similar to 120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci ; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

Activated partial thromboplastin time (aPTT) and prothrombin time (PT) are clinical tests commonly used to screen for coagulation-factor deficiencies. One genome-wide association study (GWAS) has been reported previously for aPTT, but no GWAS has been reported for PT. We conducted a GWAS and meta-analysis to identify genetic loci for aPTT and PT. The GWAS for aPTT was conducted in 9,240 individuals of European ancestry from the Atherosclerosis Risk in Communities (ARIC) study, and the GWAS for PT was conducted in 2,583 participants from the Genetic Study of Three Population Microisolates in South Tyrol (MICROS) and the Lothian Birth Cohorts (LBC) of 1921 and 1936. Replication was assessed in 1,041 to 3,467 individuals. For aPTT, previously reported associations with KNG1, HRG, F11, F12, and ABO were confirmed. A second independent association in ABO was identified and replicated (rs8176704, p = 4.26 × 10(-24)). Pooling the ARIC and replication data yielded two additional loci in F5 (rs6028, p = 3.22 × 10(-9)) and AGBL1 (rs2469184, p = 3.61 × 10(-8)). For PT, significant associations were identified and confirmed in F7 (rs561241, p = 3.71 × 10(-56)) and PROCR/EDEM2 (rs2295888, p = 5.25 × 10(-13)). Assessment of existing gene expression and coronary artery disease (CAD) databases identified associations of five of the GWAS loci with altered gene expression and two with CAD. In summary, eight genetic loci that account for ∼29% of the variance in aPTT and two loci that account for ∼14% of the variance in PT were detected and supported by functional data.

Objective: Both brain and body temperature rise after stroke but the cause of each is uncertain. We investigated the relationship between circulating markers of inflammation with brain and body temperature after stroke. Methods: We recruited patients with acute ischemic stroke and measured brain temperature at hospital admission and 5 days after stroke with multivoxel magnetic resonance spectroscopic imaging in normal brain and the acute ischemic lesion (defined by diffusion-weighted imaging [DWI]). We measured body temperature with digital aural thermometers 4-hourly and drew blood daily to measure interleukin-6, C-reactive protein, and fibrinogen, for 5 days after stroke. Results: In 44 stroke patients, the mean temperature in DWI-ischemic brain soon after admission was 38.4°C (95% confidence interval [CI] 38.2–38.6), in DWI-normal brain was 37.7°C (95% CI 37.6–37.7), and mean body temperature was 36.6°C (95% CI 36.3–37.0). Higher mean levels of interleukin-6, C-reactive protein, and fibrinogen were associated with higher temperature in DWI-normal brain at admission and 5 days, and higher overall mean body temperature, but only with higher temperature in DWI-ischemic brain on admission. Conclusions: Systemic inflammation after stroke is associated with elevated temperature in normal brain and the body but not with later ischemic brain temperature. Elevated brain temperature is a potential mechanism for the poorer outcome observed in stroke patients with higher levels of circulating inflammatory markers.

This study investigated associations between chronic inflammation and coagulation and incident locomotor disability using prospective data from the British Women's Heart and Health Study. Locomotor disability was assessed using self-reported questionnaires in 1999/2000, and 3 and 7 years later. Scores for inflammation and coagulation were obtained from summation of quartile categories of all available biomarkers from blood samples taken at baseline. 534 women developed locomotor disability after 3 years, 260 women after 7 years, while 871 women remained free of locomotor disability over the whole study period. After adjustment for demographic characteristics, lifestyle factors and health conditions, we found associations between inflammation and incident locomotor disability after three (OR per unit increase in score = 1.08, 95 % confidence interval (CI): 1.03, 1.13) and 7 years (OR = 1.10, 95 % CI: 1.03, 1.18) and between coagulation and incident locomotor disability after 3 (OR = 1.06, 95 % CI: 0.98, 1.14) and 7 years (OR = 1.09, 95 % CI: 1.00, 1.18). This corresponds to ORs between 1.8 and 2.4 comparing women with highest to lowest inflammation or coagulation scores. These results support the role of inflammation and coagulation in the development of locomotor disability in elderly women irrespective of their lifestyle factors and underlying age-related chronic diseases.

Background and Purposes— Abnormalities in blood coagulation and the fibrinolytic system have been associated with increased risk of stroke, but few prospective studies have studied the associations in older adults. We have examined the associations between fibrin D-dimer, tissue-type plasminogen activator, and von Willebrand factor (vWF) and risk of stroke in older men and examined their predictive roles separately in normotensive and hypertensive men. Methods— Prospective study of 3358 men aged 60 to 79 years with no previous diagnosis of myocardial infarction or stroke and without atrial fibrillation followed-up for an average of 9 years, during which there were 187 incident stroke events. Results— Increased levels of D-dimer and vWF were associated with significantly increased risk of major stroke events after adjustment for potential confounders, including systolic blood pressure (adjusted hazard ratios and 95% confidence interval per standard deviation increase in D-dimer and vWF were 1.24 [95% confidence interval, 1.08–1.44] and 1.25 [95% confidence interval, 1.09–1.45], respectively). No associations were seen with tPA after adjustment. The positive associations between D-dimer and vWF and incident stroke remained after additional adjustment for markers of inflammation (C-reactive protein, IL-6). D-dimer was associated with stroke in both normotensive and hypertensive men; vWF showed stronger associations in normotensive than in hypertensive men (test for interaction: P =0.52 for D-dimer; P Conclusions— Fibrin D-dimer and vWF are associated with increased risk of stroke in older men. These associations were not explained by their associations with inflammation. D-dimer may be a useful marker to identify those at high risk for stroke among hypertensive men.

ObjectivesWe aimed to compare the predictive capabilities of N-terminal pro-brain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) for risk of cardiovascular disease (CVD) in older men with and without pre-existing CVD.BackgroundThe clinical utility of NT-proBNP in CVD risk stratification in the general population remains unclear.MethodsA prospective study of 3,649 men age 60 to 79 years were followed for a mean of 9 years during which there were 608 major CVD events (major fatal and nonfatal coronary heart disease, stroke, and CVD death).ResultsNT-proBNP was significantly associated with risk of all major CVD outcomes after adjustment for CV risk factors in both men with and without CVD. The adjusted standardized hazard ratios for CVD events in those without pre-existing CVD and those with pre-existing CVD were 1.49 (95% confidence interval [CI]: 1.33 to 1.65) and 1.52 (95% CI: 1.33 to 1.75), respectively. CRP was associated with CVD outcomes only in men without pre-existing CVD (adjusted standardized hazard ratios: 1.22 [95% CI: 1.10 to 1.34] and 1.00 [95% CI: 0.86 to 1.38], respectively). NT-proBNP was more strongly associated with CVD outcome than CRP, particularly among those with pre-existing CVD. Inclusion of NT-proBNP in a Framingham-based model yielded significant improvement in C-statistics in both men with and without CVD and resulted in a net reclassification improvement of 8.8% (p = 0.0009) and 8.2% (p < 0.05), respectively, for major CVD events. Inclusion of CRP in the Framingham-based model did not improve prediction in either group (net reclassification improvement 3.8% and 0.6%, respectively).ConclusionsNT-proBNP, but not CRP, improved prediction of major CVD events in older men with and without pre-existing CVD.

We have used the gene-centric Illumina HumanCVD BeadChip to identify common genetic determinants of Von Willebrand factor (vWF) levels in healthy men and women. The Whitehall II (WHII) study (n= 5592) and the British Women's Heart and Health Study (BWHHS) (n= 3445) were genotyped using the HumanCVD BeadChip. Replication was conducted in the British Regional Heart Study (n= 3897) and 1958 Birth Cohort (n= 5048). We identified 48 single nucleotide polymorphisms (SNPs) in four genes/regions associated with vWF at P < 10(-4) . These included 19 SNPs at the ABO blood group locus with the lead variant being rs657152 (P= 9.7 × 10(-233) ). The lead variant in the 24 VWF SNPs was rs1063856 (P= 2.3 × 10(-20) ). SNPs at ESR1 (rs6909023) and NRG1(rs1685103) showed modest associations with vWF, but these were not confirmed in a meta-analysis. Using variable selection, five SNPs at the locus for ABO and two for VWF were found to have independent associations with vWF levels. After adjustment for age and gender, the selected ABO SNPs explained 15% and the VWF SNPs an additional 2% of the variance in vWF levels. Individuals at opposite tails of the additive seven SNP allele score exhibited substantial differences in vWF levels. These data demonstrate that multiple common alleles with small effects make, in combination, important contributions to individual differences in vWF levels.

Background— Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search. Methods and Results— A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ≈2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log–transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 ( P =6.4×10 −52 ) was 46.0 kb upstream from F3 , coagulation factor III (tissue factor). At 1q24, rs6687813 ( P =2.4×10 −14 ) was 79.7 kb downstream of F5 , coagulation factor V. At 4q32, rs13109457 ( P =2.9×10 −18 ) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA . Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log–transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus. Conclusions— Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.

Background: The diagnosis of stroke or TIA in the emergency department is difficult, though important for early treatment. Circulating biomarkers might improve upon clinical assessment at admission. Methods: We recruited symptomatic patients with suspected stroke or TIA and drew blood soon after admission. Each patient was assessed with the Face Arm Speech Test (FAST). We measured a panel of 15 circulating inflammatory, thrombotic, cardiac, and cerebral tissue damage biomarkers. Improvement in diagnostic performance was assessed by adding biomarkers to the FAST in logistic regression models to predict a final diagnosis of stroke or TIA (verified by expert review and imaging). Results: 405 patients had suspected stroke: 285 with TIA or stroke (230 definite or probable ischemic stroke, 40 TIA, 15 hemorrhagic stroke) and 120 with other diagnoses. Only the markers t-PA and NT-proBNP were associated positively and significantly (p < 0.01) with a diagnosis of TIA or stroke. The FAST had a sensitivity of 82% (95% CI 78–87) and specificity of 38% (95% CI 29–46) for the diagnosis of TIA or stroke. No biomarker individually improved the sensitivity or specificity of the FAST. A model containing the FAST, age, systolic blood pressure, NT-proBNP and t-PA had a better sensitivity (88%, p < 0.006) and a better specificity (48%, p = 0.04) than the FAST test alone. Conclusions: No single blood marker improved the diagnostic performance of a validated clinical stroke scale. Panels of biomarkers may marginally improve diagnosis, but their practicability is uncertain, and requires further study.

Background: The pro-inflammatory cytokines, interleukin (IL)-18 and tumour necrosis factor-α (TNFα) may play a role in coronary heart disease (CHD). We aimed to extend data on their relationships to the risk of CHD in generally healthy populations. Methods: During 5.5 years follow-up in the Fletcher Challenge general population cohort there were 256 CHD cases, and 615 controls were matched for age and sex. Baseline plasma levels of IL-18 and TNFα were related to CHD risk in available samples (77%). Results: Plasma levels of IL-18 (11% increase in mean, p = 0.01) and TNFα (10% increase in mean p = 0.024) were significantly elevated in CHD cases versus controls. In univariable models IL-18 was associated with CHD risk (odds ratio [OR] upper third to lower third, 1.63; 95% CI 1.08, 2.46), but TNFα was not (OR 1.33; 95% CI 0.87, 2.02).After adjusting for major CHD risk factors and CRP, the association of IL-18 with CHD risk was attenuated (OR 1.69; 95% CI 0.94, 3.03). Conclusions: IL-18, but not TNFα, had a non-negligible association with CHD risk, although the association of IL-18 with risk was weak after full adjustment. These cytokines may play a role in CHD pathology, but may not be robust risk biomarkers.

Regular physical activity is inversely associated with risk of coronary heart disease, but the precise mechanisms remain unclear. Active commuting is an environmental friendly way to achieve the recommended 30 min of daily physical activity. The aim of this study was to explore the relative contribution of markers from different potential mediating pathways on the association between active commuting and risk of myocardial infarction (MI) in a general population.Prospective incident nested case-control study.Commuting habits, traditional risk factors and biomarkers were assessed at baseline and compared in 204 MI cases and 327 matched controls.Car commuting was significantly associated with MI risk, even after adjusting for potential confounders (odds ratio: 1.77, 95% confidence interval: 1.05-2.99). When potential mediators were included in the model, the risk was substantially attenuated. Among the traditional risk factors, apolipoprotein B/apolipoprotein A-1 ratio seemed to be the largest mediator (26.0%), followed by body mass index (18.7%). The inflammatory and haemostatic markers similarly dampened the effect, with tissue plasminogen activator/plasminogen activator inhibitor-1 complex and IL-6 explaining 33.6 and 27.6% of MI risk, respectively. Combined, the potential mediators investigated seemed to explain 40.1% of MI risk related to car commuting.Overall, the traditional, inflammatory and haemostatic markers seemed to explain a substantial proportion of the reduction in MI risk related to active commuting in this study population. The predominant effect of the inflammatory and haemostatic markers supports the hypothesis that regular physical activity may work through additional biological mechanisms to reduce coronary risk beyond traditional risk factors. However, these findings need to be confirmed in larger studies.

OBJECTIVE To determine whether circulating levels of the inflammatory markers C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-α are associated with cognitive ability and estimated lifetime cognitive decline in an elderly population with type 2 diabetes. RESEARCH DESIGN AND METHODS A cross-sectional study of 1,066 men and women aged 60–75 years with type 2 diabetes and living in Lothian, Scotland (the Edinburgh Type 2 Diabetes Study), was performed. Seven cognitive tests were used to measure abilities in memory, nonverbal reasoning, information processing speed, executive function, and mental flexibility. The results were used to derive a general intelligence factor (g). A vocabulary–based test was administered as an estimate of peak prior cognitive ability. Results on the cognitive tests were assessed for statistical association with inflammatory markers measured in a venous blood sample at the time of cognitive testing. RESULTS Higher IL-6 and TNF-α levels were associated with poorer age- and sex-adjusted scores on the majority of the individual cognitive tests. They were also associated with g using standardized regression coefficients −0.074 to −0.173 (P < 0.05). After adjusting for vocabulary, education level, cardiovascular dysfunction, duration of diabetes, and glycemic control, IL-6 remained associated with three of the cognitive tests and with g. CONCLUSIONS In this representative population of people with type 2 diabetes, elevated circulating levels of inflammatory markers were associated with poorer cognitive ability. IL-6 levels were also associated with estimated lifetime cognitive decline.

It is unknown whether the relationship between raised inflammatory biomarker levels and late-life cognitive ability is causal. We explored this issue by testing the association between genetic regulators of plasma C-reactive protein (CRP) and cognition. Data were analysed from four cohorts based in central Scotland (Total N = 4,782). Associations were tested between variants in the CRP gene and both plasma CRP levels and a battery of neuropsychological tests, including a vocabulary-based estimate of peak prior cognitive ability and a general (summary) cognitive factor score, or 'g'. CRP levels were associated with a number of variants in the CRP gene (SNPs), including rs1205, rs1130864, rs1800947, and rs1417938 (P range 4.2e-06 to 0.041). Higher CRP levels were also associated with vocabulary-adjusted cognitive ability, used here to estimate lifetime cognitive change (P range 1.7e-04 to 0.038). After correction for multiple testing and adjustment for age and sex, no statistically significant associations were found between the SNPs and cognition. CRP is unlikely to be a causal determinant of late-life cognitive ability.

Introduction Inflammatory mechanisms may play a role in the pathogenesis of atherosclerosis and its complications. Interleukin-6 (IL-6) is an ‘upstream’ pro-inflammatory cytokine that stimulates hepatocytes to synthesize acute phase response proteins such as C-reactive protein (CRP) and fibrinogen. The purpose of this study was to determine whether IL-6 is associated with incident coronary heart disease (CHD) events independently of established risk factors and to examine its predictive ability for future CHD events. Methods Data from the British Women's Heart and Health Study, a prospective cohort of randomly sampled British women 60–79 years old at baseline was used. Three thousand five hundred and eighty-one women had no evidence of coronary heart disease at baseline and were followed up for a median of 4.6 years. Cox proportional hazard models were used to estimate the association of IL-6 with incident CHD. Results The age-adjusted association of IL-6 with the risk of CHD (hazard ratio, HR per doubling of IL-6 = 1.26, 95% CI 1.10, 1.43) was attenuated when adjusting for established CHD risk factors (HR per doubling of IL-6 = 1.13, 95% CI 0.97, 1.31). The main confounders of the association of IL-6 and CHD risk were smoking and forced expiratory volume (FEV 1 ). Further attenuation was observed when additional terms for components of the metabolic syndrome were added into the model (HR = 1.08, 95% CI 0.93, 1.27). Conclusions There was no strong evidence of an association between IL-6 and incident CHD in older British women after controlling for established CHD risk factors. Studies with measures of lung function and socio-economic position are needed to further investigate the role of IL-6 in CHD etiology.

Background Inflammation may play an important role in atherothrombosis and in promoting cerebral damage after stroke. We hypothesized that plasma adipocytokine concentrations would be associated with risk of stroke in older people. Methods Nested case-control study from the Prospective Study of Pravastatin in the Elderly ( PROSPER). Subjects were aged 70-82 years and followed up for a mean of 3.2 years: 266 incident stroke cases ( 179 confirmed as ischaemic) were compared with 532 controls matched for age, gender and treatment allocation ( pravastatin or placebo). Adipocytokines [ adiponectin, interleukin- (IL-)18 and tumour necrosis factor (TNF)alpha] were measured on stored baseline plasma samples. Results Elevated plasma adiponectin was associated with lower risk of ischaemic stroke on univariate analysis: odds ratio ( OR) 0.78 per 1 SD increase (95% CI 0.62-0.97). There were no associations of IL- 18 or TNF alpha with risk for ischaemic or total strokes. In multivariate models the independent predictors of ischaemic stroke were prior cerebrovascular accident ( OR 2.68, 95% CI 1.60-4.50), any alcohol use (1.98, 1.33-2.94), triglycerides (1.40, 1.11-1.77), Barthel score (0.75, 0.58-0.96) and known diabetes (1.72, 1.04-2.83); adiponectin, IL- 18 and TNFa did not contribute. A similar pattern of risk was seen for total stroke. Conclusions Reduced adiponectin may have a modest role in the aetiology of ischaemic stroke in older people, however IL- 18 and TNFa are unlikely to play any important part. These adipocytokines do not have clinical predictive utility; history of prior cerebrovascular accident, known diabetes mellitus, prior disability and higher alcohol intake explain much of the stroke risk.

We investigated the associations of circulating C-reactive protein (CRP) and interleukin-6 (IL-6) with cancer risk. We examined the associations of CRP and IL-6 with incident cancer in two prospective cohorts, the British Women’s Heart and Health Study (4,286 women aged 60–80) and the Caerphilly Cohort (2,398 men aged 45–59) using Cox regression and pooled our findings with previous prospective studies’ in fixed and random effects meta-analyses. CRP and IL-6 were associated with some incident cancers in our cohorts, but the numbers of cancer cases were small. In our meta-analyses elevated CRP was associated with an increased overall risk of cancer (random effects estimate (RE): 1.10, 95% CI: 1.02, 1.18) and lung cancer (RE: 1.32, 95% CI: 1.08, 1.61). Its associations with colorectal (RE: 1.09, 95% CI: 0.98, 1.21) and breast cancer risks (RE: 1.10, 95% CI: 0.97, 1.26) were weaker. CRP appeared unrelated to prostate cancer risk (RE: 1.00 0.88, 1.13). IL-6 was associated with increased lung and breast cancer risks and decreased prostate cancer risk, and was unrelated to colorectal cancer risk. Our findings suggest an etiological role for CRP and IL-6 in some cancers. Further large prospective and genetic studies would help to better understand this role.

OBJECTIVE—The objective of this study was to assess the relationship between putative markers of endothelial dysfunction (tissue plasminogen activator [t-PA] antigen and von Willebrand factor [vWF] antigen) and development of type 2 diabetes, as well as the role of inflammation, adipokines, hepatic function, and insulin resistance in modifying these relationships. RESEARCH DESIGN AND METHODS—This was a prospective study of 3,562 nondiabetic men aged 60–79 years followed up for an average of 7 years during which there were 162 incident cases of type 2 diabetes. RESULTS—Elevated t-PA (top third) was associated with a near threefold increase in risk of diabetes compared with the risk in those in the bottom third after adjustment for lifestyle factors and waist circumference (relative risk [RR] 2.98 [95%CI 1.79–5.00]; Ptrend < 0.0001); weaker but significant (marginal) associations were seen with vWF (1.24 [0.83–1.85]; P = 0.05 for trend). Both biomarkers of endothelial dysfunction correlated significantly with markers of inflammation (interleukin-6 [IL-6] and C-reactive protein [CRP]), hepatic function (γ-glutamyl transferase [GGT]), and insulin resistance, with t-PA showing stronger associations with adiposity, hepatic function, and insulin resistance than vWF. t-PA was also significantly and inversely associated with adiponectin. Adjustment for IL-6, adiponectin, and GGT attenuated the association of incident diabetes with vWF (1.06 [0.71–1.60]), but the relationship seen with t-PA remained significant (adjusted RR 2.19 [1.29–3.70]). Subsequent adjustment for insulin attenuated the association further, but t-PA was still associated with a significant increase in risk (1.66 [0.96–2.85]; Ptrend = 0.02). CONCLUSION—t-PA antigen, but not vWF antigen, is independently associated with risk of type 2 diabetes.

The cumulative effects of socioeconomic position (SEP) on cardiovascular disease have been described, but the pathways are unclear. In this study, the authors examined the effects of life-course SEP on inflammatory and hemostatic markers: fibrinogen, C-reactive protein, von Willebrand factor antigen, and tissue plasminogen activator antigen. Data from the 1958 British birth cohort, including data on persons who underwent a biomedical followup in 2002–2004, were used. Social class was determined at three stages of respondents’ lives: childhood (birth), early adulthood (age 23 years), and midlife (age 42 years). A cumulative indicator score of SEP was calculated that ranged from 0 (always in the highest social class) to 9 (always in the lowest social class). In men and women, associations were observed between cumulative indicator score and fibrinogen (p < 0.001), C-reactive protein (p < 0.001), von Willebrand factor antigen (p � 0.05), and tissue plasminogen activator antigen (p < 0.001 only in women). The trends in fibrinogen and C-reactive protein remained after adjustment for body mass index, smoking, and physical activity. However, the trends became nonsignificant for von Willebrand factor antigen and tissue plasminogen activator antigen in women. Risk exposure related to SEP accumulates across the life course and contributes to raised levels of fibrinogen and C-reactive protein, while childhood SEP influences hemostatic markers more than does adult SEP. cohort studies; C-reactive protein; fibrinogen; hemostasis; inflammation; social class; tissue plasminogen activator; von Willebrand factor

Background Associations of three markers of thrombotic tendency, von Willebrand factor, tissue plasminogen activator antigen and fibrin D-dimer, with coronary heart disease have been reported in meta-analyses. It is not known, however, whether findings are generalizable to older women. Design Prospective cohort of 3582 women aged 60-79 years randomly selected from 23 towns without evidence of cardiovascular disease at entry into the British Women's Heart and Health Study. Methods Women were followed for 4.7 years for incident coronary heart disease. Cox proportional hazard models were used to compare the hazard ratio of coronary heart disease per doubling for each thrombotic factor. Results In models adjusting for age and town only there was no association between von Willebrand factor or D-dimer and incidence of coronary heart disease, but there was a positive association of tissue plasminogen activator: coronary heart disease hazard ratio per doubling was 1.37 (95% confidence interval: 1.08-1.75). Adjustment for potential confounders (socio-economic position, smoking, lung function, physical activity, alcohol consumption, body mass index, waist-to-hip ratio) attenuated association to 1.20 (0.92-1.58). Further adjustment for risk factors that may be part of the same pathophysiological process linking tissue plasminogen activator to coronary heart disease (high density lipoprotein cholesterol, triglycerides, blood pressure, fasting glucose, insulin, C-reactive protein, fibrinogen) attenuated the hazard ratio to 1.05 (0.79-1.40). Conclusion In older women, tissue plasminogen activator was associated with incident coronary heart disease, but does not appear to be an independent risk factor for coronary heart disease as the association was attenuated by adjustment for confounding and other metabolic and vascular risk factors. Eur J Cardiovasc Prev Rehabil 14:638-645 © 2007 The European Society of Cardiology

Background: Inflammation is associated with worse prognosis and survival in many cancers. Our aim was to investigate the associations of circulating C-reactive protein (CRP) and interleukin-6 (IL-6) concentrations with all-cause mortality in cancer patients and to determine whether any associations were specific to malignancy. Method: We used data from the British Women's Heart and Health Study, a cohort of 4,286 women aged 60 to 79 years. We investigated the associations between CRP, IL-6, and survival in women with and without cancer using Cox regression and assessed the interaction between cancer status and these inflammatory markers to determine whether these associations differed according to cancer status. Results: Elevated CRP and IL-6 were associated with decreased survival in women with cancer [unadjusted hazard ratio per doubling of CRP, 1.22, 95% confidence interval (95% CI), 1.03, 1.46; and per doubling of IL-6, 1.52, 95% CI, 1.25, 1.86] and in women without cancer [CRP: 1.24 (1.12, 1.37); IL-6: 1.53 (1.35, 1.75)]. Adjustment for age, body mass index, physical activity level, socioeconomic position, HRT use, and tobacco smoking did not change these associations. After mutual adjustment, IL-6 but not CRP was independently associated with survival. We found no strong evidence that these associations differed between cancer patients and cancer-free women. Conclusions: Elevated CRP and IL-6 concentrations were similarly associated with an increased risk of death in elderly women with and without cancer. Thus, in this group, these markers are likely to be indicators of non-cancer comorbidities rather than related to the malignancy itself. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1155–9)

OBJECTIVES: To determine whether circulating markers of activated inflammation and hemostasis are associated with cognitive decline in older people. DESIGN: Prospective cohort study (Edinburgh Artery Study). SETTING: Eleven general practices in Edinburgh, Scotland. PARTICIPANTS: A sample of 452 men and women followed for 16 years. MEASUREMENTS: Biomarker data were collected in 1987/88, and cognitive assessment was first conducted in 1998/99, when the mean age of the sample +/- standard deviation was 73.1+/-5.0), and subsequently in 2002/03. Information was obtained on verbal declarative memory (Wechsler Logical Memory Test (LMT)), nonverbal reasoning (Raven's Standard Progressive Matrices), verbal fluency (Verbal Fluency Test), information processing speed (Wechsler Digit Symbol Test), and a general cognitive factor representing the variance common to the individual test scores. RESULTS: In age-adjusted analyses, plasma fibrinogen, interleukin-6 (IL-6), and intercellular adhesion molecule 1 (ICAM-1) were negatively associated with performance on all cognitive measures in 2002/03 except the LMT (correlation coefficients from -0.10 to -0.24). In multivariate analyses controlling for demographic characteristics, depression, and cardiovascular morbidity and risk factors, fibrinogen independently predicted 4-year decline in nonverbal reasoning (P

Background— The aim of our present study was to compare the association of a wide range of 17 biomarkers of inflammation, hemostasis, and blood rheology with incident heart disease and stroke after accounting for an indicator of subclinical atherosclerotic disease and traditional risk factors and also to determine their incremental predictive ability. Methods and Results— We used data from the Edinburgh Artery Study, a population cohort study started in 1987 that comprised 1592 men and women aged 55 to 74 years. Subjects were followed for a mean of 17 years, and 416 of them suffered at least 1 cardiovascular event. In analyses adjusted for cardiovascular risk factors and history of cardiovascular disease (CVD): C-reactive protein, interleukin-6, fibrinogen, fibrin D-dimer, tissue plasminogen activator (t-PA), leukocyte elastase, and lipoprotein(a) (all P P Conclusions— Several “novel” risk factors predicted CVD after adjustments for conventional risk factors and also for a measure of asymptomatic disease. However, their incremental predictive ability was modest and their clinical utility remains uncertain.

Elevated plasma interleukin-6 (IL-6) is associated with coronary heart disease (CHD), impaired glucose tolerance (IGT), and type 2 diabetes (T2DM). We and others have described an association between the human interleukin-6 -174G>C gene variant and body mass index (BMI). Within our previous sample of subjects with T2DM, we measured plasma IL-6 and grouped subjects by the WHO-defined metabolic syndrome, in order to study the association between the -174G>C gene variant, plasma IL-6 and the metabolic syndrome (and component parts). Genotype was obtained in 571 Caucasian subjects with plasma IL-6 measures. There was a significant association between genotype and plasma IL-6 (GG vs GC vs CC: 3.23+/-0.93 pg/ml vs 3.42+/-0.95 pg/ml vs 4.16+/-1.18 pg/ml, p=0.02; for GG/GC vs CC p=0.008). No interactions were observed between genotype and the individual components of the metabolic syndrome in determining plasma IL-6. Increased plasma IL-6 was also associated with the number of components (none vs 1 vs 2 vs > or =3: 2.67+/-0.71 pg/ml vs 2.97+/-0.94 pg/ml vs 4.07+/-1.13 pg/ml, p

Aims Recently, markers of inflammation, haemostasis, and blood rheology have received much attention as risk factors for coronary heart disease and stroke. However, their role in peripheral arterial disease (PAD) is not well established and some of them, including the pro-inflammatory cytokine interleukin-6 (IL-6), have not been examined before in prospective epidemiological studies. Methods and results In the Edinburgh Artery Study, we studied the development of PAD in the general population and evaluated 17 potential blood markers as predictors of incident PAD. At baseline (1987), 1519 men and women free of PAD aged 55–74 were recruited. After 17 years, 208 subjects had developed symptomatic PAD. In analysis adjusted for cardiovascular risk factors and baseline cardiovascular disease (CVD), only C-reactive protein, fibrinogen, lipoprotein (a), and haematocrit [hazard ratio (95% CI) corresponding to an increase equal to the inter-tertile range 1.30 (1.08, 1.56), 1.16 (1.05, 1.17), 1.22 (1.04, 1.44), 1.22 (1.08, 1.38)] were significantly ( P < 0.01) associated with PAD. However, these markers provided very little prognostic information for incident PAD to that obtained by cardiovascular risk factors and the ankle brachial index. Other markers including IL-6, intracellular adhesion molecule 1, d-dimer, tissue plasminogen activator antigen, and plasma and blood viscosities showed weak associations, which were considerably attenuated when CVD risk factors were accounted for. Conclusions Our prospective data showed that several inflammatory, haemostatic, and rheological markers are associated with incident PAD; however, their clinical utility is likely to be limited. Future research is necessary to validate the importance of these biomarkers explicitly on PAD and to address the causality of the reported associations.

Highlights • We analyzed mental stress, fibrinogen, and CVD within an integrated framework. • Fibrinogen is not a positive mediator between mental stress and CVD. • The higher the fibrinogen response to mental stress is, the lower the risk of CVD, assessed by detectable HS-CTnT levels., Summary Background Plasma fibrinogen is considered as a positive mediator between mental stress and cardiovascular disease because it is an acute-phase protein released in response to mental stress and a coagulation factor. However those three factors have never been studied together within a single integrated framework, using cardiac troponin T as a marker of cardiovascular risk. Methods 491 disease-free men and women aged 53–76 were tested for fibrinogen levels before, immediately after, and following recovery from standardized mental stress tasks. We measured plasma cardiac troponin T using a high-sensitivity assay (HS-CTnT) and coronary calcification using electron-beam dual-source computed tomography. Results The average fibrinogen concentration increased by 5.1% (s.d. = 7.3) in response to stress and then tended to return to baseline values. People with higher baseline fibrinogen values had smaller increases (blunted responses) following the stress task (P = 0.001), and people with higher stress responses showed better recovery (P

ObjectiveAbdominal aortic aneurysms often coexist with reduced lung function and chronic obstructive pulmonary disease (COPD). These conditions are each associated with cigarette smoking, cardiovascular disease, and evidence of increased inflammatory and hemostatic activity. The aim of this study was to determine if these factors accounted for the link between aneurysms and pulmonary disease.MethodsThe design was a case-control study comparing patients with an asymptomatic abdominal aortic aneurysm with population-based controls without an aneurysm. Aneurysms were diagnosed by ultrasound scan, and pulmonary function was measured by respiratory questionnaire and spirometry. Activation of inflammation and hemostasis was measured by assay of plasma interleukin-6 (IL-6), fibrinogen, von Willebrand factor (vWF), tissue plasminogen activator (tPA) antigen, fibrin D-dimer, and plasmin antiplasmin complexes.ResultsCases with an abdominal aortic aneurysm (n = 89) had more COPD and worse expiratory lung function as measured by forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) than controls (n = 98) (FEV1, 1.9 vs 2.2 L, P < .01; FEV1/FVC, 0.67 vs 0.75, P < .001) and did not differ in restrictive function (FVC, 2.9 vs 3.0 L, P = .33). Cases also had higher levels of lifetime cigarette smoking (30 vs 24 pack-years, P < 0.01), cardiovascular disease (35% vs 18%, P = .01), plasma fibrinogen (3.5 vs 3.1 g/L, P = .02), IL-6 (2.8 vs 1.8, pg/mL, P < .001), plasmin antiplasmin complexes (596 vs 384 μg/L, P = .01), and D-dimer (442 vs 93 ng/mL, P < .001). On multiple logistic regression analysis of lung function and COPD on the risk of aneurysm, both cigarette smoking and cardiovascular disease had little effect on the relationships. For the markers of activated inflammation and hemostasis, plasmin antiplasmin complexes and D-dimer had the most important confounding effect on the odds ratios. All markers combined had a substantial effect: odds ratio of aneurysm for a one standard deviation decrease in FEV1 fell from 2.3 (95% confidence interval [CI], 1.5 to 3.5) (P < .01) to 1.3 (95% CI, 0.55 to 2.4) (P ≥ .05).ConclusionThe association between reduced respiratory function and abdominal aortic aneurysm was not accounted for by cigarette smoking or cardiovascular disease. We hypothesize that activation of inflammation and hemostasis in response to injury may be an important explanation of the association between aneurysm formation and reduced respiratory function. Further studies are required to test this hypothesis.

The interplay between inflammatory and hemostatic mechanisms may play a crucial role in the development and progression of atherosclerosis. The authors evaluated the separate and joint associations of hemostatic and inflammatory variables on peripheral atherosclerotic progression in the Edinburgh Artery Study, a population cohort study of 1,592 men and women aged 55-74 years that started in 1987. Levels of fibrinogen, fibrin D-dimer, von Willebrand factor, tissue plasminogen activator antigen, factor VII, prothrombin fragment 1 + 2, urinary fibrinopeptide A, C-reactive protein, and interleukin-6 were measured at baseline. Arm and ankle blood pressures were measured, and atherosclerotic progression was assessed by computing ankle brachial index (ABI) at baseline (1,582 participants) and after 12 years of follow-up (813 participants). Fibrinogen (p = 0.05) and D-dimer (p < or = 0.05) were significantly associated with ABI change independently of baseline ABI and cardiovascular disease risk factors. However, these associations were no longer significant when analyses were adjusted for either C-reactive protein or interleukin-6. Moreover, subjects with higher levels of both D-dimer and interleukin-6 at baseline had the greatest ABI decline. In conclusion, fibrinogen and D-dimer, but not other hemostatic factors, were associated with progressive peripheral atherosclerosis. Since D-dimer and fibrinogen are acute phase reactants, these data support the hypothesis that inflammation is more related to atherosclerosis than is hypercoagulation.

BACKGROUND: Circulating C-reactive protein (CRP) is associated with the metabolic syndrome and might be causally linked to it. Our aim was to generate estimates of the association between plasma CRP and metabolic syndrome phenotypes that were free from confounding and reverse causation, to assess the causal role of this protein. METHODS: We examined associations between serum CRP concentration and metabolic syndrome phenotypes in the British Women's Heart and Health Study. We then compared these estimates with those derived from a mendelian randomised framework with common CRP gene haplotypes to generate unconfounded and unbiased estimates of any causal associations. FINDINGS: In a sample of British women, body-mass index (BMI), systolic blood pressure, waist-to-hip ratio, serum concentrations of HDL cholesterol and triglycerides, and insulin resistance were all associated with plasma CRP concentration. CRP haplotypes were associated with plasma CRP concentration (p

Men with AS (ankylosing spondylitis) are at elevated risk for CHD (coronary heart disease) but information on risk factors is sparse. We compared a range of conventional and novel risk factors in men with AS in comparison with healthy controls and, in particular, determined the influence of systemic inflammation. Twenty-seven men with confirmed AS and 19 controls matched for age were recruited. None of the men was taking lipid-lowering therapy. Risk factors inclusive of plasma lipids, IL-6 (interleukin-6), CRP (C-reactive protein), vWF (von Willebrand factor), fibrin D-dimer, ICAM-1 (intercellular cell-adhesion molecule-1) and fibrinogen were measured, and blood pressure and BMI (body mass index) were determined by standard techniques. A high proportion (70%) of men with AS were smokers compared with 37% of controls (P=0.024). The AS patients also had a higher BMI. In analyses adjusted for BMI and smoking, men with AS had significantly higher IL-6 and CRP (approx. 9- and 6-fold elevated respectively; P

Aims: We have examined the cross-sectional relationship between insulin resistance, the metabolic syndrome and haemostatic and inflammatory markers.Methods and results: We carried out the study in 2722 non-diabetic men aged 60-79 years with no history of coronary heart disease or stroke and who were not on warfarin treatment, drawn from general practices in 24 British towns. Insulin resistance (HONIA) was significantly associated with increased inflammatory markers (C-reactive protein (CRP), white cell count), coagulation factors VII-IX, von Willebrand factor (VWF) and tissue plasminogen activator (t-PA) antigens (markers of endothelial dysfunction) and blood viscosity after adjustment for age, smoking, physical activity, alcohol intake and waist circumference. Relationships with fibrinogen and fibrin D-dimer were weak. The relationship between HOMA and CRP was abolished after adjustment for t-PA. The prevalence of the metabolic syndrome was similar using World Health Organization (WHO) and National Cholesterol Education Program definitions (26.7% and 27.0%) but associations between the metabolic syndrome and increased haemostatic markers, particularly for raised factor VIII and VWF were stronger using WHO criteria.Conclusion: Insulin resistance and the metabolic syndrome showed significant associations with markers of haemostasis and inflammation, which may be relevant to their associations with cardiovascular disease. (c) 2005 Elsevier Ireland Ltd. All rights reserved.