Haematological variables and risk of future venous thromboembolism in the British Regional Heart Study on men. Combined D-dimer and APTT as a predictive test for thromboembolism?

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.

Genetic associations for activated partial thromboplastin time and prothrombin time, their gene expression profiles, and risk of coronary artery disease.

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.

Plasma Biomarkers of Inflammation, Endothelial Function and Hemostasis in Cerebral Small Vessel Disease.

BACKGROUND: The cause of lacunar ischemic stroke, a clinical feature of cerebral small vessel disease (SVD), is largely unknown. Inflammation and endothelial dysfunction have been implicated. Plasma biomarkers could provide mechanistic insights but current data are conflicting. White matter hyperintensities (WMHs) are an important imaging biomarker of SVD. It is unknown if plasma biomarkers add predictive capacity beyond age and vascular risk factors in explaining WMH. METHODS: We prospectively recruited patients presenting with non-disabling ischemic stroke, classifying them clinically and with the help of MRI as lacunar or cortical. We measured biomarkers of inflammation, endothelial dysfunction and hemostasis for >1 month after stroke and compared biomarker levels between stroke subtypes. We quantitatively calculated WMH. We used multiple linear regression analysis to model WMH as a function of age, sex, hypertension and smoking (the baseline model). We fitted exploratory models using plasma biomarkers as predictor variables to assess model improvement over baseline. RESULTS: We recruited 125 patients. The lacunar group (n = 65) had lower tissue plasminogen activator (t-PA) levels in unadjusted (7.39 vs. 8.59 ng/ml, p = 0.029) and adjusted (p = 0.035) analyses compared with the cortical group (n = 60). There were no significant differences in the other plasma biomarkers. The results for t-PA were consistent with an updated meta-analysis, although the effect remains non-significant (standardized mean difference -0.08 (95% CI -0.25 to 0.09)). The baseline regression model explained 29% of the variance in quantitative WMH (R2 0.289). Inflammatory biomarkers showed minor improvement over baseline (R2 0.291), but the other plasma biomarkers did not improve the baseline model. CONCLUSION: Plasma t-PA levels appear to differ between lacunar and cortical stroke subtypes, late after stroke, independent of age, sex and vascular risk factors and may reflect endothelial dysfunction. Except for a minor additional predictive effect of inflammatory markers, plasma biomarkers do not relate to WMH severity in this small stroke population.

Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis.

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.

Direct comparisons of three alternative plasma fibrinogen assays with the von Clauss assay in prediction of cardiovascular disease and all-causes mortality: the Scottish Heart Health Extended Cohort.

There is strong evidence from meta-analyses of prospective epidemiological studies that increasing plasma fibrinogen levels are associated with an increasing risk of cardiovascular disease (CVD) and all-cause mortality. However, there are few published direct comparisons of the several different available fibrinogen assays in association with CVD or mortality. We therefore prospectively compared the standardized von Clauss assay of clottable fibrinogen with three other assays: prothrombin time (PT)-derived clottable fibrinogen, immunonephelometric fibrinogen, and heat precipitable fibrinogen in the Scottish Heart Health Extended Cohort. Hazard ratios (HRs) for a standard deviation increase in fibrinogen for risk of CVD, adjusted for age and sex, were 1.17 (95% confidence interval [CI] 1.14; 1.21) for the von Clauss assay; 1.19 (1.06; 1.33) for the heat precipitation assay; 1.16 (1.01; 1.35) for the PT-derived assay; and 1.28 (1.10; 1.51) for the immunonephelometric assay. HRs for all-cause mortality were 1.21 (1.18; 1.24); 1.13 (1.01; 1.26), 1.17 (1.00; 1.37) and 1.17 (0.99; 1.39), respectively. No significant differences were observed between the assays in such comparisons. We therefore conclude that the choice between plasma fibrinogen assays in routine clinical haematology and biochemistry laboratories should depend on practical factors, and not on expected differences in the strength of associations.

Prospective study of IL-18 and risk of MI and stroke in men and women aged 60-79 years: a nested case-control study.

AIM: IL-18 is hypothesized to destabilise atherosclerotic plaques, leading to thrombotic events and epidemiologic studies suggest that IL-18 may increase risk of CHD or CVD. We examined prospective associations between levels of serum IL-18 and new CHD and stroke events in older men and women from a general population. METHODS: A case-control study was nested within a prospective cohort of men and women aged 60-79 years recruited from general practices in 25 British towns in 1998-2000 and followed-up for 7.5 years for fatal and non-fatal MI and stroke. Baseline IL-18 was measured in stored serum samples of incident cases of MI (n=364) or stroke (n=300) and two controls per case. RESULTS: Geometric mean IL-18 levels were higher among the 364 MI cases than the 706 controls; 417.84 pg/mL (IQR 316.25, 537.44) compared to 386.90 pg/mL (IQR 296.54, 482.33), p(difference)=0.002. IL-18 was positively associated with adverse lipid and inflammatory profiles. Men and women in the top third of baseline IL-18 levels had an age and sex-adjusted odds ratio (OR) for MI of 1.31 (95%CI 0.92, 1.85) compared with those in the lowest third; this attenuated to 1.05 (95%CI 0.72, 1.53) after additional adjustment for established vascular and inflammatory risk factors. Each doubling of IL-18 level was associated with an increased OR for MI 1.34 (95%CI 1.04, 1.72), which was attenuated on adjustment for established vascular and inflammatory risk factors; 1.09 (95%CI 0.83, 1.44). Geometric mean IL-18 levels did not differ between stroke cases and controls. The OR for stroke associated with the highest compared to the lowest tertile of IL-18 was 1.24 (95%CI 0.84, 1.84). Results for MI and stroke did not differ by presence of pre-existing CVD, gender or age. CONCLUSIONS: Circulating IL-18 levels were strongly associated with a range of established and novel risk factors but were not independently associated with risk of MI or stroke in our study.

Inflammation and not cardiovascular risk factors is associated with short leukocyte telomere length in 13- to 16-year-old adolescents.

OBJECTIVE: Short leukocyte telomere length (LTL) is associated with cardiovascular (CV) disease in adulthood. However, the biological basis of this association remains unclear. We sought to define early determinants of the association between CV disease and LTL in an adolescent population. METHODS AND RESULTS: One thousand eighty adolescents, aged 13 to 16 years and participating in the Ten Towns Heart Health Study, provided blood samples for DNA extraction and measurement of a range of CV risk factors. LTL was measured by real-time polymerase chain reaction. LTL was inversely associated with age (P=0.04), longer in females than in males (P=0.03), and longer in South Asians than in white Europeans (P=0.01). No associations were found between LTL and traditional CV risk factors. There was a significant and inverse association between LTL and inflammatory markers, including C-reactive protein (P<0.001) and fibrinogen (P=0.001). The associations between LTL and inflammatory markers were not affected by multiple adjustments for behavioral and metabolic factors. CONCLUSIONS: High levels of inflammation are associated with shorter LTL from early adolescence; traditional CV risk factors have little association with LTL in adolescence. Inflammation in early life may play a causal role in the adult association between short LTL and CV disease.

Plasma viscosity, immunoglobulins and risk of cardiovascular disease and mortality: new data and meta-analyses.

AIMS: Associations of plasma viscosity and plasma Ig levels (a determinant of viscosity) with incident coronary heart disease (CHD) events; and with CHD, cardiovascular disease (CVD: CHD and stroke) and all-cause mortalities. METHODS: Meta-analysis of plasma viscosity levels from the MONitoring of trends and determinants of CArdiovascular (MONICA)/Cooperative Health Research in the Region of Augsburg, MONICA Glasgow and Speedwell Studies; and five other published studies. Meta-analysis of IgA, IgG and IgM levels from the Augsburg, Glasgow and Speedwell studies; and one other published study. RESULTS: Over median follow-up periods of 14-26 years, there were 2270 CHD events, and 4220 all cause deaths in 28 605 participants with baseline plasma viscosity measurements. After adjustment for major risk factors, (HRs; 95% CIs) for a 1 SD increase in viscosity were 1.14 (1.09 to 1.20) for CHD events; and 1.21 (1.17 to 1.25) for all-cause mortality. 821 CHD events and 2085 all-cause deaths occurred in 8218 participants with baseline Ig levels. For CHD events, adjusted HRs for 1 SD increases in IgA, IgG and IgM were, respectively, 0.97 (0.89 to 1.05); 0.95(0.76 to 1.17) and 0.90 (0.79 to 1.03). Corresponding adjusted HRs for all-cause mortality were 1.08 (95% CI 1.02 to 1.13), 1.03 (95% CI 0.94 to 1.14) and 1.01 (95% CI 0.96 to 1.06). CONCLUSIONS: After risk factor adjustment, plasma viscosity was significantly associated with risks of CHD events; and with CHD, CVD and all-cause mortalities. We found no significant association of IgA, IgG or IgM levels with incident CHD events or mortality, except for a borderline association of IgA with all-cause mortality.

Body fat distribution in relation to smoking and exogenous hormones in British women.

OBJECTIVE: Both cigarette smoking and use of exogenous hormones are associated with changes in regional distribution of body fat, but their combined effects are less investigated. We examined the interrelation between smoking, exogenous hormones and fat distribution in premenopausal and postmenopausal women. METHOD: We used data from 20, 962 women without known cardiovascular disease (CVD) who were employees of a major department store in Britain. They completed a health questionnaire and attended a clinical examination that included waist and hip circumference measurements. The cross-sectional analyses were conducted using linear regression models. RESULTS: Cigarette smoking, particularly smoking ≥20 cigarettes/day, was associated with larger waist circumference and higher waist/hip ratio (WHR) in pre- and postmenopausal women after adjusting for potential confounding factors (all P < 0·001). Premenopausal women using combined oral contraceptive (COC) and postmenopausal women using oestrogen-only hormone replacement therapy (HRT) had lower WHR than non-hormone users in both smokers and nonsmokers. However, smokers had higher WHR than nonsmokers in both groups of hormone users and nonusers. There was no significant interaction between smoking and hormone use in premenopausal and postmenopausal women (P > 0·05). CONCLUSION: Although exogenous hormones use was related to a more favourable fat distribution in women, smoking was associated with greater abdominal fat accumulation.

Associations of Hemostatic Variables with Cardiovascular Disease and Total Mortality: The Glasgow MONICA Study.

The associations of plasma levels of hemostatic factors, other than fibrinogen, with risks of cardiovascular disease (CVD) and all-cause mortality are not well defined. In two phases of the Glasgow MONICA study, we assayed coagulation factors (VII, VIII, IX, and von Willebrand factor), coagulation inhibitors (antithrombin, protein C, protein S), coagulation activation markers (prothrombin fragment 1 + 2, thrombin-antithrombin complexes, D-dimer), and the fibrinolytic factors, tissue plasminogen activator (t-PA) antigen and plasminogen activator inhibitor type 1. Over 15 to 20 years, we followed up between 382 and 1,123 men and women aged 30 to 74 years, without baseline CVD, for risks of CVD and mortality. Age- and sex-adjusted hazard ratios (HRs) for CVD (top third vs bottom third) were significant only for factor VIII (1.30; 95% confidence interval [CI], 1.06-1.58) and factor IX (1.18; 95% CI, 1.01-1.39); these HRs were attenuated by further adjustment for CVD risk factors: 1.17 (95% CI, 0.94-1.46) and 1.07 (95% CI, 0.92-1.25), respectively. In contrast, factor VIII (HR, 1.63; 95% CI, 1.35-1.96), D-dimer (HR, 2.34; 95% CI, 1.26-4.35), and t-PA (HR, 2.81; 95% CI, 1.43-5.54) were strongly associated with mortality after full risk factor adjustment. Further studies, including meta-analyses, are required to assess the associations of these hemostatic factors with the risks of stroke and heart disease and causes of mortality.

Genetic associations between fibrinogen and cognitive performance in three Scottish cohorts.

There is increasing evidence to suggest that elevated plasma levels of fibrinogen are associated with late-life cognitive performance. This study tested the association of single nucleotide polymorphisms in the fibrinogen α (FGA) and ß (FGB) genes with cognitive performance. Data were analysed from three community-dwelling populations of older persons (>50 years) in central Scotland: the Aspirin for Asymptomatic Atherosclerosis (AAA) Trial (n = 2,091), the Edinburgh Type 2 Diabetes Study (ET2DS, n = 1,066), and the Lothian Birth Cohort 1936 (LBC1936, n = 1,091). Cognition was assessed using a battery of five, seven, and four psychometric tests, respectively. This information was used to derive a general cognitive factor. Weakly significant associations were found between the rs4220 (FGB), and rs2227412 (FGB) SNPs and a single test of cognitive performance in the AAA Trial (p < 0.05). These findings did not replicate in the LBC1936 or ET2DS cohorts, except for the rs2227412 SNP, which was significantly associated with the general cognitive factor in the ET2DS (p = 3.3 × 10(-4)). A summary term that combined results from all three studies suggested that the rs2227412 genotype associated with reduced cognitive ability also associated with higher plasma fibrinogen levels. These findings suggest a tentative role for fibrinogen as a determinant of late-life cognitive performance and justify further attempts at replication in older persons.

Activation of hemostasis and decline in cognitive function in older people.

OBJECTIVE: To determine whether activation of hemostatic function (thrombosis and fibrinolysis) is associated with cognitive decline in older people. METHODS AND RESULTS: We studied 5804 people (age, 70-82 years) in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Mean follow-up was 3.2 years, including annual measurement of speed of information processing (letter, digit coding, and Stroop), verbal memory (picture-word naming), and basic and instrumental activities of daily living. Raised levels of markers of thrombin generation (d-dimer and prothrombin fragment 1+2) were associated independently with increased rate of cognitive decline (eg, Stroop increased by 4.44 s [SEM, 0.68] in bottom tertile of d-dimer compared to 5.46 [SEM, 0.71] in highest tertile; P<0.05) and deterioration in activities of daily living. This increased rate of decline was attenuated but not removed when subjects with incident nonfatal stroke were omitted from the analysis. It also persisted when adjustments were made for inflammation (C-reactive protein and IL-6). CONCLUSIONS: Older patients with increased markers of thrombin generation (d-dimer and prothrombin fragment 1+2) are at increased risk for cognitive decline and deterioration in ability to perform activities of daily living. This is likely attributable to increased risk of cerebral ischemic damage (including covert disease) associated with prothrombotic states.

Incident venous thromboembolic events in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER).

BACKGROUND: Venous thromboembolic events (VTE), including deep venous thrombosis and pulmonary embolism, are common in older age. It has been suggested that statins might reduce the risk of VTE however positive results from studies of middle aged subjects may not be generalisable to elderly people. We aimed to determine the effect of pravastatin on incident VTE in older people; we also studied the impact of clinical and plasma risk variables. METHODS: This study was an analysis of incident VTE using data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), a randomized, double-blind, placebo-controlled trial of pravastatin in men and women aged 70-82. Mean follow-up was 3.2 years. Risk for VTE was examined in non-warfarin treated pravastatin (n = 2834) and placebo (n = 2865) patients using a Cox's proportional hazard model, and the impact of other risk factors assessed in a multivariate forward stepwise regression analysis. Baseline clinical characteristics, blood biochemistry and hematology variables, plasma levels of lipids and lipoproteins, and plasma markers of inflammation and adiposity were compared. Plasma markers of thrombosis and hemostasis were assessed in a nested case (n = 48) control (n = 93) study where the cohort was those participants, not on warfarin, for whom data were available. RESULTS: There were 28 definite cases (1.0%) of incident VTE in the pravastatin group recipients and 20 cases (0.70%) in placebo recipients. Pravastatin did not reduce VTE in PROSPER compared to placebo [unadjusted hazard ratio (95% confidence interval) 1.42 (0.80, 2.52) p = 0.23]. Higher body mass index (BMI) [1.09 (1.02, 1.15) p = 0.0075], country [Scotland vs Netherlands 4.26 (1.00, 18.21) p = 0.050 and Ireland vs Netherlands 6.16 (1.46, 26.00) p = 0.013], lower systolic blood pressure [1.35 (1.03, 1.75) p = 0.027] and lower baseline Mini Mental State Examination (MMSE) score [1.19 (1.01, 1.41) p = 0.034] were associated with an increased risk of VTE, however only BMI, country and systolic blood pressure remained significant on multivariate analysis. In a nested case control study of definite VTE, plasma Factor VIII levels were associated with VTE [1.52 (1.01, 2.28), p = 0.044]. However no other measure of thrombosis and haemostasis was associated with increased risk of VTE. CONCLUSIONS: Pravastatin does not prevent VTE in elderly people at risk of vascular disease. Blood markers of haemostasis and inflammation are not strongly predictive of VTE in older age however BMI, country and lower systolic blood pressure are independently associated with VTE risk. TRIAL REGISTRATION: Not applicable when study undertaken.

Do inflammatory biomarkers add to the discrimination of cardiovascular disease after allowing for social deprivation? Results from a 10-year cohort study in Glasgow, Scotland.

AIMS: To assess the additional discriminative value of adding each of five inflammatory biomarkers to the ASSIGN risk score, which includes social deprivation. METHODS AND RESULTS: In this study, 1319 men and women aged 25-64 in the fourth Glasgow MONICA study were followed-up for cardiovascular endpoints. Baseline C-reactive protein, fibrinogen, IL-6, IL-18, and TNFα were related to risk of CVD. The discriminative value of adding each to the ASSIGN score was assessed using area under the receiver operating characteristic (AUC) and relative integrated percentage improvement in classification (RIDI). During a median of 10.5 years, 151 CVD events occurred. After adjusting for ASSIGN variables, each inflammatory marker except IL-18 had a significant (P < 0.05) association with CVD risk. The AUC using ASSIGN [0.799 (95% CI 0.790-0.809)] was improved by the inclusion of C-reactive protein and TNFα [0.805 (95% CI 0.795-0.815); P < 0.03], but not by other combinations. C-reactive protein and TNFα yielded a significant RIDI (IL-6 almost so). C-reactive protein and TNFα together improved the classification of risk by 11% (95% CI, 3-19%) when added to the ASSIGN variables. CONCLUSION: Some inflammatory biomarkers add moderate discriminative information to the ASSIGN CVD risk score. The clinical utility of this information, cost-effectiveness, and optimization should be assessed in future studies.

Venous thrombosis prevention - more than just guidelines.

Hospital-associated venous thromboembolism remains a major international cause of avoidable mortality and morbidity. Although the publication of national guidelines does increase the use of thromboprophylaxis, we present the results of a recent audit of thrombosis prevention in UK hospitals which, despite published guidelines, shows continuing significant variations in guideline implementation and practice. The results of this audit are paralleled with UK and international data on hospital-acquired thrombosis prevention and the potential solutions to these problems, particularly the lessons which can be learned from other areas of clinical practice, are discussed.

Genetic variants associated with altered plasma levels of C-reactive protein are not associated with late-life cognitive ability in four Scottish samples.

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.

Tissue plasminogen activator antigen predicts medium-term left ventricular end-systolic volume after acute myocardial infarction.

Von Willebrand factor (VWF) and tissue plasminogen activator (t-PA) predict adverse cardiovascular outcome following acute myocardial infarction (AMI) and are weakly associated with pre-discharge left ventricular ejection fraction (LVEF). We examined the relationships between VWF, t-PA antigen, matrix metalloproteinase (MMP)-2,-3, and -9, and B-type natriuretic peptide (BNP), and their predictive effect on serial change in LV volumes in a cohort of patients admitted with AMI. Plasma VWF, t-PA antigen, MMP-2,-3,-9, and BNP were measured at a mean 46 h after AMI in 100 patients (mean age 58.9 +/- 12 years, 77% male) with depressed LVEF. Cardiac magnetic resonance (CMR) imaging was then performed. Biomarker measurement and CMR were repeated at 12 and 24 weeks. Plasma concentrations of VWF, BNP and MMP-9 were elevated while t-PA antigen concentration was at the upper limits of normal; over 24 weeks VWF, t-PA antigen, MMP-9 and BNP decreased significantly. Baseline VWF correlated with BNP (r = 0.35, P < 0.001) and MMP-3 (r = 0.24, P = 0.019) as did t-PA antigen (r = 0.27, P = 0.007 for BNP; r = 0.40, P < 0.001 for MMP-3). t-PA antigen, VWF, MMP-3 and BNP were univariate predictors of LV end-systolic volume at 24 weeks; tPA antigen and BNP remained significant independent predictors on multivariate analysis. t-PA antigen and VWF are related to medium-term LV volumes after AMI, and to MMP-3. This novel link between the coagulation-fibrinolysis system and matrix turnover merits further study in understanding the pathophysiology of adverse ventricular remodeling after AMI.

Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial.

CONTEXT: A low ankle brachial index (ABI) indicates atherosclerosis and an increased risk of cardiovascular and cerebrovascular events. Screening for a low ABI can identify an asymptomatic higher risk group potentially amenable to preventive treatments. OBJECTIVE: To determine the effectiveness of aspirin in preventing events in people with a low ABI identified on screening the general population. DESIGN, SETTING, AND PARTICIPANTS: The Aspirin for Asymptomatic Atherosclerosis trial was an intention-to-treat double-blind randomized controlled trial conducted from April 1998 to October 2008, involving 28,980 men and women aged 50 to 75 years living in central Scotland, free of clinical cardiovascular disease, recruited from a community health registry, and had an ABI screening test. Of those, 3350 with a low ABI (< or = 0.95) were entered into the trial, which was powered to detect a 25% proportional risk reduction in events. INTERVENTIONS: Once daily 100 mg aspirin (enteric coated) or placebo. MAIN OUTCOME MEASURES: The primary end point was a composite of initial fatal or nonfatal coronary event or stroke or revascularization. Two secondary end points were (1) all initial vascular events defined as a composite of a primary end point event or angina, intermittent claudication, or transient ischemic attack; and (2) all-cause mortality. RESULTS: After a mean (SD) follow-up of 8.2 (1.6) years, 357 participants had a primary end point event (13.5 per 1000 person-years, 95% confidence interval [CI], 12.2-15.0). No statistically significant difference was found between groups (13.7 events per 1000 person-years in the aspirin group vs 13.3 in the placebo group; hazard ratio [HR], 1.03; 95% CI, 0.84-1.27). A vascular event comprising the secondary end point occurred in 578 participants (22.8 per 1000 person-years; 95% CI, 21.0-24.8) and no statistically significant difference between groups (22.8 events per 1000 person-years in the aspirin group vs 22.9 in the placebo group; HR, 1.00; 95% CI, 0.85-1.17). There was no significant difference in all-cause mortality between groups (176 vs 186 deaths, respectively; HR, 0.95; 95% CI, 0.77-1.16). An initial event of major hemorrhage requiring admission to hospital occurred in 34 participants (2.5 per 1000 person-years) in the aspirin group and 20 (1.5 per 1000 person-years) in the placebo group (HR, 1.71; 95% CI, 0.99-2.97). CONCLUSION: Among participants without clinical cardiovascular disease, identified with a low ABI based on screening a general population, the administration of aspirin compared with placebo did not result in a significant reduction in vascular events. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN66587262.

Does fibrinogen add to prediction of cardiovascular disease? Results from the Scottish Heart Health Extended Cohort Study.

Plasma fibrinogen is an established risk factor for cardiovascular disease (CVD), but it has not been established whether it adds predictive value to risk scores. In the Scottish Heart Health Extended Cohort Study, we measured plasma fibrinogen in 13 060 men and women, aged 30-74 years, initially free of CVD. After follow-up for a median of 19.2 years, 2626 subjects had at least one CVD event. After adjusting for classical CVD risk factors and socio-economic status, the hazard ratios (95% confidence interval) for a one unit (g/l) increase in plasma fibrinogen were 1.09 (1.02, 1.16) for men and 1.10 (1.02, 1.19) for women. Although fibrinogen added significantly to the discrimination of the Framingham risk score for women, it failed to do so for men. Fibrinogen did not add significantly to the ASSIGN risk score. Fibrinogen added between 1.3% and 3.2% to the classification of CVD status by the existing risk scores. We conclude that the added value of fibrinogen to two currently used risk scores is low; hence population screening with fibrinogen for this purpose is unlikely to be clinically useful or cost-effective.

Gender differences in the cross-sectional relationships between sleep duration and markers of inflammation: Whitehall II study.

OBJECTIVE: To examine the relationships between sleep and inflammatory markers because these may be important in the development of cardiovascular disease. METHODS AND RESULTS: The relationship between self-reported sleep duration and interleukin-6 (IL-6) (n = 4642) and high-sensitivity C-reactive protein (hs-CRP) (n = 4677) was examined in individuals from the Whitehall II study. Following multiple adjustments, there were no overall linear or nonlinear trends between sleep duration and IL-6. However, in women but not men (interaction P < 0.05), levels of IL-6 tended to be lower in individuals who slept 8 hours (11% [95% confidence interval 4 to 17]) as compared to 7 hours. With hs-CRP, in the adjusted model, there was no association between hs-CRP and sleep duration in men. However, there was a significant nonlinear association in women, the level of hs-CRP being significantly higher in women short sleepers (5 hours or less) after multiple adjustments (P = 0.04) (interaction P < 0.05). CONCLUSIONS: No significant variation in inflammatory markers with sleep duration was observed in men. By contrast, both IL-6 and hs-CRP levels varied with sleep duration in women. The observed pattern of variation was different according to the inflammatory marker observed. Further longitudinal studies are required to fully investigate possible temporal relationships between short sleep and markers of inflammation.