Interleukin-6 as a predictor of symptom resolution in psychological distress: a cohort study.

BACKGROUND: Elevated levels of interleukin-6 (IL-6) have been associated with the development of common mental disorders, such as depression, but its role in symptom resolution is unclear. METHOD: We examined the association between IL-6 and symptom resolution in a non-clinical sample of participants with psychological distress. RESULTS: Relative to high IL-6 levels, low levels at baseline were associated with symptom resolution at follow-up [age- and sex-adjusted risk ratio (RR) = 1.15, 95% confidence interval (CI) 1.06-1.25]. Further adjustment for covariates had little effect on the association. Symptomatic participants with repeated low IL-6 were more likely to be symptom-free at follow-up compared with those with repeated high IL-6 (RR = 1.21, 95% CI 1.03-1.41). Among the symptomatic participants with elevated IL-6 at baseline, IL-6 decreased along with symptom resolution. CONCLUSIONS: IL-6 is potentially related to the mechanisms underlying recovery from symptoms of mental ill health. Further studies are needed to examine these mechanisms and to confirm the findings in relation to clinical depression.

Hepatitis C infection and outcomes in the Scottish haemophilia population.

Patients with bleeding disorders previously frequently became infected with hepatitis C virus. We identified the number of patients infected in Scotland and assessed several aspects of the outcomes of HCV infection and its treatment comparing these with cohorts infected for other reasons. We calculated the number of individuals infected in Scotland (cohort A) starting with the total number of patients treated in Scottish haemophilia centres registered on the UKHCDO database between 1970 and 1989. Cases were then removed or added based on additional information from centre records. A second cohort B, consisted of 255 patients from cohort A and 47 patients HCV infected outside Scotland, but with follow-up data from Scottish centres around their HCV infection. We estimate that 455 patients with bleeding disorders became infected by coagulation factor provided by NHS Scotland. In 302 individuals with documented HCV infection, rates of natural clearance (17.4%), genotype spread (64% genotype 1) and responses to antiviral therapy (14.5% with monotherapy; 38.8% with combination therapy) were similar to those in other cohorts. Thirty-four liver biopsies were performed without adverse event and liver transplantation has been performed in 11 patients, seven for liver failure, four for hepatocellular carcinoma. Around 455 patients with bleeding disorders became HCV infected in Scotland before 1989. The natural history of HCV infection and responses to treatment are similar to those in other HCV-infected cohorts. Liver transplantation has been used successfully for the treatment of end-stage liver failure and hepatocellular carcinoma.

Do women exhibit greater differences in established and novel risk factors between diabetes and non-diabetes than men? The British Regional Heart Study and British Women's Heart Health Study.

AIMS/HYPOTHESIS: Type 2 diabetes is associated with greater relative risk of CHD in women than in men, which is not fully explained by conventional cardiovascular risk factors. We assessed whether cardiovascular risk factors including more novel factors such as markers of insulin resistance, inflammation, activated coagulation and endothelial dysfunction differ more between diabetic and non-diabetic women than between diabetic and non-diabetic men, and the role of insulin resistance. METHODS: A cross-sectional study of non-diabetic and diabetic men and women (n = 7,529) aged 60-79 years with no previous myocardial infarction who underwent an examination was conducted. Measurements of anthropometry, blood pressure and fasting measurements of lipids, insulin, glucose and haemostatic and inflammatory markers were taken. RESULTS: Non-diabetic women tended to have more favourable risk factors and were less insulin resistant than non-diabetic men, but this was diminished in the diabetic state. Levels of waist circumference, BMI, von Willebrand factor (VWF), WBC count, insulin resistance (HOMA-IR), diastolic blood pressure, HDL-cholesterol, tissue plasminogen activator (t-PA) and factor VIII differed more between diabetic and non-diabetic women than between diabetic and non-diabetic men (test for diabetes × sex interaction p < 0.05). The more adverse effect of diabetes on these risk markers in women was associated with, and thereby largely attenuated by, insulin resistance. CONCLUSIONS/INTERPRETATION: The greater adverse influence of diabetes per se on adiposity and HOMA-IR and downstream blood pressure, lipids, endothelial dysfunction and systemic inflammation in women compared with men may contribute to their greater relative risk of coronary heart disease.

Sex-specific time trends in first admission to hospital for peripheral artery disease in Scotland 1991-2007.

BACKGROUND: This study examined trends for all first hospital admissions for peripheral artery disease (PAD) in Scotland from 1991 to 2007 using the Scottish Morbidity Record. METHODS: First admissions to hospital for PAD were defined as an admission to hospital (inpatient and day-case) with a principal diagnosis of PAD, with no previous admission to hospital (principal or secondary diagnosis) for PAD in the previous 10 years. RESULTS: From 1991 to 2007, 41,593 individuals were admitted to hospital in Scotland for the first time for PAD. Some 23,016 (55.3 per cent) were men (mean(s.d.) age 65.7(11.7) years) and 18,577 were women (aged 70.4(12.8) years). For both sexes the population rate of first admissions to hospital for PAD declined over the study interval: from 66.7 per 100,000 in 1991-1993 to 39.7 per 100,000 in 2006-2007 among men, and from 43.5 to 29.1 per 100,000 respectively among women. After adjustment, the decline was estimated to be 42 per cent in men and 27 per cent in women (rate ratio for 2007 versus 1991: 0.58 (95 per cent confidence interval 0.55 to 0.62) in men and 0.73 (0.68 to 0.78) in women). The intervention rate fell from 80.8 to 74.4 per cent in men and from 77.9 to 64.9 per cent in women. The proportion of hospital admissions as an emergency or transfer increased, from 23.9 to 40.7 per cent among men and from 30.0 to 49.5 per cent among women. CONCLUSION: First hospital admission for PAD in Scotland declined steadily and substantially between 1991 and 2007, with an increase in the proportion that was unplanned.

Haemorheological predictors of cognitive decline: the Edinburgh Artery Study.

INTRODUCTION: vascular risk factors and diseases can negatively impact cognitive function. Determinants of blood flow are implicated in thrombogenesis and ischaemic events, yet little is known about their relationship with cognition. METHODS: blood rheology data were collected in 1987/88, and cognitive testing was performed in 1998/99 when the mean (+ or - standard deviation) age of the study sample was 73.1 years (+ or - 5.0). Follow-up assessment was performed 4 years later. Information was collected on verbal declarative memory, non-verbal reasoning, verbal fluency, information processing speed and a general cognitive factor representing the variance common to the individual test scores. RESULTS: after controlling for age, sex and cognitive performance in 1998/99, blood viscosity (BV) (P < 0.05) and fibrinogen (P < 0.05) predicted decline in non-verbal reasoning over 4 years. When estimated from pre-morbid level, decline in general cognition (P < 0.05), non-verbal reasoning (P < 0.05) and information processing speed (P < 0.01) was associated with BV levels. Haematocrit (HCT) had similar effects (P < 0.01 to P < 0.001). All associations persisted after control for multiple confounders. When examined together, HCT but not BV independently predicted cognitive decline. CONCLUSIONS: blood rheology is independently related to cognitive decline in older people. The value of strategies aimed at preserving cognition through influencing blood rheology needs investigation.

Early life growth and hemostatic factors: the Barry Caerphilly Growth study.

Associations between early life growth trajectories and a range of adult (aged approximately 25 years) hemostatic factors were assessed in the Barry Caerphilly Growth study (N = 517) in South Wales, 1974-1999. Associations of birth weight, birth length, and weight and height velocities during three periods ("immediate": 0-<5 months, "infant": 5 months-<1 year 9 months, and "childhood": 1 year 9 months-5 years) with adult levels of hemostatic factors were assessed. Birth weight was inversely associated with fibrinogen (beta per 1-unit change in z score = -0.08, 95% confidence interval (CI): -0.15, -0.02). Immediate weight velocity was inversely associated with factor VII (beta = -1.88, 95% CI: -3.84, 0.09), factor VIII (beta = -2.58, 95% CI: -4.07, -0.45), and von Willebrand factor antigen (beta = -4.07, 95% CI: -7.25, -0.89). Birth length was inversely associated with fibrinogen (beta = -0.07, 95% CI: -0.14, -0.01). Evidence was weaker for an inverse association of immediate height velocity with factor VIII (beta = -2.16, 95% CI: -4.62, 0.29) and von Willebrand factor antigen (beta = -2.85, 95% CI: -6.52, 0.81). Childhood height velocity was positively associated with D-dimer (ratio of geometric means = 1.11, 95% CI: 1.01, 1.23). Results support the view that the immediate postnatal period may be particularly important, possibly through impaired liver development and/or infection in early life, in determining cardiovascular disease risk.

Inter-relationships of interleukin-6, cardiovascular risk factors and the metabolic syndrome among older men.

OBJECTIVES: Interleukin-6 (IL-6) has been implicated in the development of cardiovascular disease. We have examined the relationship between plasma IL-6 and insulin resistance, and metabolic, inflammatory and hemostatic markers. METHODS: We examined 3490 men aged 60-79 years who were drawn from general practices in 24 British towns. The men were not diabetic and were not taking warfarin. RESULTS: IL-6 was significantly associated with age, body mass index (BMI), waist circumference (WC), cigarette smoking, low physical activity, social class and alcohol intake (U-shaped). IL-6 showed no association with insulin resistance or its other components (blood glucose, triglycerides, blood pressure) except high-density lipoprotein-cholesterol (inversely), and no association with hematocrit, factor (F) VII or adiponectin after adjustment for age and WC. IL-6 was strongly associated with markers of inflammation (C-reactive protein, fibrinogen, white cell count); plasma viscosity; elevated markers of coagulation (fibrin D-dimer, FVIII, FIX); markers of endothelial dysfunction (von Willebrand factor, tissue plasminogen activator); and to a smaller extent with platelet count, APC ratio and gamma glutamyltransferase. Risk of the metabolic syndrome increased significantly with increasing IL-6 but was attenuated after adjustment for BMI. CONCLUSION: IL-6 may have a potential role as a mediator between cardiovascular risk factors and several biological mechanisms for cardiovascular disease.

Effects of older age on fibrin D-dimer, C-reactive protein, and other hemostatic and inflammatory variables in men aged 60-79 years.

BACKGROUND: Previous studies have suggested that several hemostatic and inflammatory variables, which are risk predictors for arterial or venous thrombosis, increase with age. However, there is a lack of data from large population studies for reliable estimates of reference ranges. OBJECTIVES: To establish reliable reference ranges of hemostatic and inflammatory variables for 5-year age groups in older men and their implications for pathogenesis and diagnosis. PATIENTS AND METHODS: A total of 3861 men aged 60-79 years at the 20 years follow-up of the British Regional Heart Study. RESULTS: Several variables increased with age. The greatest median increases between 60-64 and 75-79 years age groups were observed for fibrin D-dimer (91%) and C-reactive protein (CRP) (57%). Significant median increases were also observed for von Willebrand factor antigen (23%), tissue plasminogen activator antigen (11%), factor VIII (10%), and fibrinogen (8%). In contrast, levels of classical cardiovascular risk factors neither decreased nor increased substantially with age, with the exception of systolic blood pressure (median increase 10%). CONCLUSIONS: The exponential increases in risk of arterial and venous thrombotic events in men between age 60 and 79 years (when most such events occur) may be related in part to increasing activation of blood coagulation, fibrinolysis, and inflammation; possibly related to the increasing inflammatory burden of both atherosclerotic and non-vascular disease. These increases also have implications for diagnosis of suspected acute venous thromboembolism (D-dimer), and recently proposed screening for prediction of coronary heart disease risk and detection of occult disease (CRP).

Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study.

OBJECTIVES: To assess the risk of clinical complications associated with thrombophilia in three high-risk patient groups: women using oral oestrogen preparations, women during pregnancy and patients undergoing major orthopaedic surgery. To assess the effectiveness of prophylactic treatments in preventing venous thromboembolism (VTE) and adverse pregnancy outcomes in women with thrombophilia during pregnancy and VTE in patients with thrombophilia, undergoing major orthopaedic surgery. To evaluate the relative cost-effectiveness of universal and selective VTE history-based screening for thrombophilia compared with no screening in the three high-risk patient groups. DATA SOURCES: Electronic databases including MEDLINE, EMBASE, and four other major databases were searched up to June 2003. REVIEW METHODS: In order to assess the risk of clinical complications associated with thrombophilia, a systematic review of the literature on VTE and thrombophilia in women using oral oestrogen preparations and patients undergoing major orthopaedic surgery; and studies of VTE and adverse obstetric complications in women with thrombophilia during pregnancy was carried out. Meta-analysis was used to calculate pooled odds ratios (ORs) associated with individual clinical outcomes, stratified by thrombophilia type and were calculated for each patient group. To assess the effectiveness of prophylaxis, a systematic review was carried out on the use of prophylaxis in the prevention of VTE and pregnancy loss in pregnant women with thrombophilic defects and the use of thromboprophylaxis in the prevention of VTE in patients with thrombophilia undergoing major elective orthopaedic surgery. Relevant data were summarised according to the patient groups and stratified according to the types of prophylaxis. A narrative summary was provided; where appropriate, meta-analysis was conducted. An incremental cost-effectiveness analysis was then carried out, from the perspective of the NHS in the UK. A decision analytical model was developed to simulate the clinical consequences of four thrombophilia screening scenarios. Results from the meta-analyses, information from the literature and results of two Delphi studies of clinical management of VTE and adverse pregnancy complications were incorporated into the model. Only direct health service costs were measured and unit costs for all healthcare resources used were obtained from routinely collected data and the literature. Cost-effectiveness was expressed as incremental cost-effectiveness ratios (ICERs); an estimate of the cost per adverse clinical complication prevented, comparing screening with no screening, were calculated for each patient group. RESULTS: In the review of risk of clinical complications, 81 studies were included, nine for oral oestrogen preparations, 72 for pregnancy and eight for orthopaedic surgery. For oral contraceptive use, significant associations of the risk of VTE were found in women with factor V Leiden (FVL); deficiencies of antithrombin, protein C, or protein S, elevated levels of factor VIIIc; and FVL and prothrombin G20210A. For hormone replacement therapy (HRT), a significant association was found in women with FVL. The highest risk in pregnancy was found for FVL and VTE, in particular, homozygous carriers of this mutation are 34 times more likely to develop VTE in pregnancy than non-carriers. Significant risks for individual thrombophilic defects were also established for early, recurrent and late pregnancy loss; preeclampsia; placental abruption; and intrauterine growth restriction. Significant associations were found between FVL and high factor VIIIc and postoperative VTE following elective hip or knee replacement surgery. Prothrombin G20210A was significantly associated with postoperative pulmonary embolism. However, antithrombin deficiency, MTHFR and hyperhomocysteinaemia were not associated with increased risk of postoperative VTE. In the review of the effectiveness of prophylaxis, based on available data from eight studies, low-dose aspirin and heparin was found to be the most effective in preventing pregnancy loss in thrombophilic women during pregnancy, while aspirin alone was the most effective in preventing minor bleeding. All the studies on thrombophilia and major elective orthopaedic surgery included in the review of risk complications were also used in the review of the effectiveness of thromboprophylaxis. However, there were insufficient data to determine the relative effectiveness of different thromboprophylaxis in preventing VTE in this patient group. For the cost-effectiveness analysis, of all the patient groups evaluated, universal screening of women prior to prescribing HRT was the most cost-effective (ICER pound6824). In contrast, universal screening of women prior to prescribing combined oral contraceptives was the least cost-effective strategy (ICER pound202,402). Selective thrombophilia screening based on previous personal and/or family history of VTE was more cost-effective than universal screening in all the patient groups evaluated. CONCLUSIONS: Thrombophilia is associated with increased risks of VTE in women taking oral oestrogen preparations and patients undergoing major elective orthopaedic surgery, and of VTE and adverse pregnancy outcomes in women with thrombophilia during pregnancy. There is considerable difference in the magnitude of the risks among different patient groups with different thrombophilic defects. In women who are on combined oral contraceptives, the OR of VTE among those who are carriers of the FVL mutation was 15.62 (95% confidence interval 8.66 to 28.15). However, in view of the prevalence of thrombophilia and the low prevalence of VTE in non-users of combined oral contraceptives, the absolute risk remains low. Significant risks for VTE and adverse pregnancy outcomes have been established with individual thrombophilic defects. Thrombophilic defects including FVL, high plasma factor VIIIc levels and prothrombin G20210A are associated with the occurrence of postoperative VTE in elective hip or knee replacement therapy. These associations are observed in patients who were given preoperative thromboprophylaxis and are, therefore, of clinical significance. Universal thrombophilia screening in women prior to prescribing oral oestrogen preparations, in women during pregnancy and in patients undergoing major orthopaedic surgery is not supported by current evidence. The findings from this study show that selective screening based on prior VTE history is more cost-effective than universal screening. Large prospective studies should be undertaken to refine the risks and establish the associations of thrombophilias with VTE among hormone users and in patients undergoing orthopaedic surgery. The relative value of a thrombophilia screening programme to other healthcare programmes needs to be established.

Fibrin D-dimer and coronary heart disease: prospective study and meta-analysis.

BACKGROUND: It is unknown whether modest increases of fibrin D-dimer, a circulating marker of fibrin turnover, are relevant to coronary heart disease (CHD) in the general population. METHODS AND RESULTS: We measured serum concentrations of D-dimer antigen in the stored baseline blood samples of 630 CHD cases and 1269 controls "nested" in a prospective cohort of 5661 men who were monitored for 16 years, and we conducted a meta-analysis of previous relevant studies to place our findings in context. In a comparison of men in the top third compared with those in the bottom third of baseline fibrin D-dimer values (tertile cutoffs, >94 versus <49 ng/mL), the odds ratio for CHD was 1.67 (95% CI, 1.31 to 2.13; P<0.0001) after adjustments for age and town. The odds ratio increased slightly after further adjustment for smoking, other classic risk factors, and indicators of socioeconomic status (1.79; 95% CI, 1.36 to 2.36). Strong correlations were observed of fibrin D-dimer values with circulating concentrations of C-reactive protein and serum amyloid A protein but not with smoking, blood lipids, blood pressure, and other risk factors. CONCLUSION: Although there may be an association between circulating D-dimer values and CHD, further studies are needed to determine the extent to which this is causal.

Adrenocortical, autonomic, and inflammatory causes of the metabolic syndrome: nested case-control study.

BACKGROUND: The causes of metabolic syndrome (MS), which may be a precursor of coronary disease, are uncertain. We hypothesize that disturbances in neuroendocrine and cardiac autonomic activity (CAA) contribute to development of MS. We examine reversibility and the power of psychosocial and behavioral factors to explain the neuroendocrine adaptations that accompany MS. METHODS AND RESULTS: This was a double-blind case-control study of working men aged 45 to 63 years drawn from the Whitehall II cohort. MS cases (n=30) were compared with healthy controls (n=153). Cortisol secretion, sensitivity, and 24-hour cortisol metabolite and catecholamine output were measured over 2 days. CAA was obtained from power spectral analysis of heart rate variability (HRV) recordings. Twenty-four-hour cortisol metabolite and normetanephrine (3-methoxynorepinephrine) outputs were higher among cases than controls (+ 0.49, +0.45 SD, respectively). HRV and total power were lower among cases (both -0.72 SD). Serum interleukin-6, plasma C-reactive protein, and viscosity were higher among cases (+0.89, +0.51, and +0.72 SD). Lower HRV was associated with higher normetanephrine output (r=-0.19; P=0.03). Among former cases (MS 5 years previously, n=23), cortisol output, heart rate, and interleukin-6 were at the level of controls. Psychosocial factors accounted for 37% of the link between MS and normetanephrine output, and 7% to 19% for CAA. Health-related behaviors accounted for 5% to 18% of neuroendocrine differences. CONCLUSIONS: Neuroendocrine stress axes are activated in MS. There is relative cardiac sympathetic predominance. The neuroendocrine changes may be reversible. This case-control study provides the first evidence that chronic stress may be a cause of MS. Confirmatory prospective studies are required.

Free radical activity and hemostatic factors in NIDDM patients with and without microalbuminuria.

In non-insulin-dependent diabetes mellitus (NIDDM) patients, microalbuminuria predicts early mortality, predominantly from cardiovascular disease. Increased free radical activity and abnormalities in hemostasis have been implicated in the development of vascular disease. Therefore, we measured markers of free radical activity (nonperoxide-conjugated diene isomer of linoleic acid [PL-9,11-LA'] and lipid peroxides expressed as malondialdehyde [MDA]) along with the hemostatic variables: fibrinogen, von Willebrand factor (vWf), plasminogen activator inhibitor (PAI-1), tissue plasminogen activator (t-PA), and plasmin activity (B beta 15-42) in 24 NIDDM patients (12 patients with microalbuminuria and 12 without microalbuminuria) and in 12 age-matched control subjects. There were no differences in linoleic acid (PL-9,12-LA) concentrations between the three groups. PL-9,11-LA' was elevated in the microalbuminuric patients compared with control subjects (P less than 0.05), but there was no difference between the two diabetic groups. MDA was elevated in the microalbuminuric diabetic patients compared with those patients without microalbuminuria (P less than 0.05) and control subjects (P less than 0.001). MDA was also increased in the patients without microalbuminuria compared with control subjects (P less than 0.01). Except for B beta 15-42, all the hemostatic variables were increased (P less than 0.05) in the diabetic patients compared with control subjects. The microalbuminuric diabetic patients had further increases in vWf (P less than 0.03) and t-PA (P less than 0.03) compared with patients with microalbuminuria. Our study suggests that there is an increase in free radical activity and abnormalities in hemostatic variables favoring a hypercoagulable state in NIDDM, especially in those with microalbuminuria.(ABSTRACT TRUNCATED AT 250 WORDS)

Circulating inflammatory markers and risks of cardiovascular and non-cardiovascular disease.

There is current interest in the associations of circulating inflammatory markers (C-reactive protein, fibrinogen, white cell count, albumin, erythrocyte sedimentation rate, the factor VIII:von Willebrand factor complex, the tissue plasminogen activator:plasminogen activator inhibitor type 1 complex, fibrin D-dimer) not only with prognosis in acute coronary syndromes and acute stroke, but also in prediction of cardiovascular events in the general population. Recent meta-analyses of long-term prospective studies have established their associations with coronary heart disease (CHD) events, which may be cause, consequence or coincidence. These markers are also associated in epidemiologic studies of general populations with many cardiovascular risk factors (which may confound their associations with CHD risk), and also with asymptomatic arterial disease (of which they be consequences: 'reverse causality'). The causality of their associations with cardiovascular events is questioned by their lack of specificity for risk of cardiovascular events; and by the lack of association of their functional genotypes with CHD in 'Mendelian randomized trials'. Hence, proof of causality awaits testing in randomized-controlled trials of long-term selective reduction by future agents. Markers are of little additional predictive value to current cardiovascular risk scores, and it is premature to advocate their use in screening for cardiovascular risk prior to careful evaluation of costs, risks, and benefits.

C-reactive protein, fibrin D-dimer, and incident ischemic heart disease in the Speedwell study: are inflammation and fibrin turnover linked in pathogenesis?

Plasma levels of C-reactive protein (CRP, a marker of the reactant plasma protein component of the inflammatory response) and of fibrin D-dimer (a marker of cross-linked fibrin turnover) have each been associated in recent studies with the risk of future ischemic heart disease (IHD). Previous experimental studies have shown that fibrin degradation products, including D-dimer, have effects on inflammatory processes and acute-phase protein responses. In the Speedwell Prospective Study, we therefore measured CRP and D-dimer levels in stored plasma samples from 1690 men aged 49 to 67 years who were followed-up for incident IHD for an average of 75+/-4 months (mean+/-SD) and studied their associations with each other, with baseline and incident IHD, and with IHD risk factors. CRP and D-dimer levels were each associated with age, plasma fibrinogen, smoking habit, and baseline evidence of IHD. CRP was associated with D-dimer (r=0.21, P<0.00001). On univariate analyses, both CRP and D-dimer were associated with incident IHD. The incidence of IHD increased with CRP independently of the level of D-dimer (P=0.0002) and also increased with D-dimer independently of the level of CRP (P=0.048). In multivariate analyses, inclusion of D-dimer and conventional risk factors reduced the strength of the association between CRP and incident IHD; likewise, inclusion of CRP and conventional risk factors reduced the strength of the association between D-dimer and incident IHD. We conclude that although these respective markers of inflammation and fibrin turnover show modest association with each other in middle-aged men, they may have additive associations with risk of incident IHD. Further larger studies are required to test this hypothesis.

C-reactive protein, fibrin D-dimer, and risk of ischemic heart disease: the Caerphilly and Speedwell studies.

BACKGROUND: There is increasing interest in the predictive value of C-reactive protein (CRP) and fibrin D-dimer in the prediction of ischemic heart disease (IHD). We assessed their joint and independent associations with IHD in a large combined analysis of 2 population cohorts. METHODS AND RESULTS: Men aged 49 to 66 years from the general populations of Caerphilly and Speedwell were studied between 1982 and 1988 and re-examined for new IHD events at fixed intervals of approximately 105 months (Caerphilly) and 75 months (Speedwell). 3213 men had CRP and D-dimer measured at baseline and 351 (11%) had a new IHD event. Mean levels of CRP and D-dimer were significantly higher among men in whom IHD developed. The relative odds of IHD in men in the top 20% of the distribution of CRP was 2.97 (95% CI, 2.04, 4.32) and for D-dimer was 2.40 (95% CI, 1.69, 3.40); CRP and D-dimer had additive effects on risk of IHD. Multivariate analysis reduced the size of the relative odds, which remained significant for D-dimer. CONCLUSIONS: Both inflammatory and thrombogenic markers are important (and potentially additive) predictors of coronary risk.

Interleukin-6 gene -174g>c and -572g>c promoter polymorphisms are strong predictors of plasma interleukin-6 levels after coronary artery bypass surgery.

Interleukin-6 (IL-6) synthesized in response to diverse stimuli may play an important role in bridging the inflammatory and atherosclerotic processes. The acute-phase response after coronary artery bypass graft surgery (CABG) is associated with the induction and release of cytokines, such as IL-6. We have examined the effect of common polymorphisms in the IL-6 gene promoter (-174G>C, -572G>C, and -597G>A) on IL-6 levels after elective CABG. DNA extracted from the peripheral blood of 127 patients was amplified by polymerase chain reaction. IL-6 genotypes were resolved by gel electrophoresis after restriction enzyme digestion. Serum IL-6 was measured before surgery and in serial samples at 6, 24, 48, and 72 hours after CABG. Genotype distribution was as expected for a population in Hardy-Weinberg equilibrium for all polymorphisms. Rare allele frequencies (+/-95% CIs) were similar to those reported previously: -597A 0.36 (0.30 to 0.42), -572C 0.07 (0.04 to 0.10), and -174C 0.37 (0.31 to 0.43). The -174G>C and -597G>A genotypes were in strong allelic association (Delta=0.97, P<0.001). Baseline IL-6 levels did not significantly differ between patients with different genotypes for any polymorphism. However, 6 hours after CABG, peak IL-6 levels were significantly higher (P=0.03) in carriers of the -572C allele than in those of the -572GG genotype (355+/-67 versus 216+/-13 pg/mL, respectively) and in those with genotype -174CC compared with -174G allele carriers (287+/-31 versus 227+/-15 pg/mL, respectively; P=0.04). These effects remained statistically significant after adjusting for possible confounders, including age, sex, smoking, duration of cardiopulmonary bypass, aortic cross-clamp time, and total duration of surgery. These data demonstrate that IL-6 promoter polymorphisms influence peak IL-6 production after CABG, suggesting that these polymorphisms, which are functional in vitro, are also functional in vivo, suggesting a genetic influence on IL-6 levels after acute severe injury.

Human CRP gene polymorphism influences CRP levels: implications for the prediction and pathogenesis of coronary heart disease.

OBJECTIVE: C-reactive protein (CRP) concentrations are predictive of cardiovascular disease, and levels are heritable, in part. We identified novel polymorphisms in the CRP gene and assessed their influence on CRP level. METHODS AND RESULTS: CRP was measured in 250 male army recruits before and after strenuous exercise and perioperatively in 193 coronary artery bypass graft (CABG) patients. Two novel polymorphisms were identified in the CRP gene, -717G>A in the promoter and +1444C>T in the 3'UTR. Among army recruits, CRP was higher in +1444TT homozygotes than +1444 C-allele carriers at baseline (1.04+/-0.38 versus 0.55+/-0.06, P=0.014) and at all time points after exercise (2.35+/-0.68 versus 1.07+/-0.12, 2.11+/-0.53 versus 0.88+/-0.09, and 1.77+/-0.44 versus 0.71+/-0.09, P=0.034, P=0.007, and P=0.013, at 2, 48, and 96 hours after exercise, respectively). In the CABG patients, mean CRP (mg/L) rose from 1.97+/-0.36 at baseline to 167.2+/-5.0 72 hours postoperatively. Genotype did not influence CRP at baseline; however, peak post-CABG CRP levels were higher in +1444TT homozygotes compared with +1444C-allele carriers (198+/-17 versus 164+/-5, P=0.03). CONCLUSIONS: The CRP gene +1444C>T variant influences basal and stimulated CRP level. These findings have implications both for the prediction and pathogenesis of coronary heart disease.

Bronchial carcinoma in von Willebrand's disease. Successful removal after hemostasis with lyophilized cryoprecipitate.

A man with severe von Willebrand's disease who had hemoptysis was followed-up for 2 1/2 years for continued hemoptysis and was discovered to have a bronchial carcinoma. Under close hematological surveillance, an uncomplicated pneumonectomy was performed, using a new factor VIII product--freeze-dried cryoprecipitate. This case illustrates that hemoptysis in von Willebrand's disease cannot always be attributed to the disease itself: that continued hemoptysis requires regular bronchoscopy and that major surgery can be performed in von Willebrand's disease with effective correction of the coagulation defect using freeze-dried cryoprecipitate.

Are atrial fibrillation guidelines altering management? A community based study.

BACKGROUND AND AIMS: We wanted to determine the prevalence of atrial fibrillation (AF) in a community based cross sectional study in greater Glasgow and how current anti-thrombotic management compares to published guidelines. METHODS: 1466 patients with AF were identified in General Practices in our community and 1008 consented to take part. Their demographic details and medical history were recorded. RESULTS: 1466 patients (mean age 73.4; 55% female) with AF were identified, in our community, giving a prevalence of 1%. 53% of patients were on warfarin therapy. Of those not receiving warfarin, only one third had a putative contra-indication. The proportion ofAF patients on warfarin increased with increasing stroke risk, and over the period of the study. CONCLUSIONS: Prevalence of AF was in keeping with previous estimates. The proportion of patients with AF receiving warfarin therapy appears to be increasing. In the moderate risk group, there was a tendency to use more warfarin in the younger age groups compared to the elderly. It was in the moderate and low risk groups that there was still evidence of deviation from published guidelines.