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ABSTRACT: In England and Wales, approximately 20% extra deaths from coronary heart disease (CHD) occur between December and March, among older people. Circulating concentrations of tissue plasminogen activator (t-PA), von Willebrand factor (VWF) and fibrin D-dimer are associated with arterial disease, and tend to peak in winter. The potential contributions of these hemostatic activation measures to excess winter mortality are unknown.
To estimate contributions of hemostatic factors to excess winter mortality.
Seasonal patterns in t-PA, VWF and D-dimer were investigated in 4088 men aged 60-79 years from 24 British towns. Data on established coronary risk factors were collected by questionnaire, physical examination and blood sampling. The adjusted mean increase in hemostatic markers during winter months, after adjustment for a range of coronary risk factors, was combined with associations of each marker with CHD mortality obtained from 9 years' follow-up of participants, to predict degree of excess CHD winter mortality. Associations of hemostatic markers with CHD incidence from large meta-analyses were also used.
All three markers showed peaks in winter; the adjusted mean increases during winter months were 0.21, 0.15 and 0.12 standard deviations for t-PA, VWF and log(D-dimer), respectively. Predicted excess hazard ratios for winter CHD mortality were 3.0%, 2.4% and 3.1%, respectively, in combination, representing an 8.6% excess. This increased to 14% when applying meta-analysis estimates.
Seasonal patterns in three hemostatic markers predict at least 8.6% excess CHD mortality in winter in Great Britain, potentially accounting for over half the excess observed in recent years.
Journal of Thrombosis and Haemostasis 03/2012; 10(3):352-8. · 5.73 Impact Factor
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ABSTRACT: CD40 ligand(CD40L) is implicated in atherosclerotic plaque formation.
We investigated prospective associations between circulating soluble CD40L and myocardial infraction (MI) or stroke in an older general population cohort, accounting for established and novel cardiovascular risk factors.
Baseline serum CD40L (sCD40L) was measured in incident MI (n = 368) and stroke (n = 304) cases and two controls per case, 'nested' in prospective UK studies of 4252 men and 4286 women aged 60-79 years, sampled from general practices in Britain in 1998-2000, with 7-year follow-up for fatal and non-fatal MI and stroke.
sCD40L was higher in smokers and negatively associated with lung function and positively associated with total cholesterol and markers of inflammation, but not with other established cardiovascular disease (CVD) risk factors. Geometric mean sCD40L levels did not differ between MI cases and controls (5.94 ng mL(-1) vs. 5.82 ng mL(-1); P = 0.5) or between stroke cases and controls (5.61 ng mL(-1) vs. 5.28 ng mL(-1), P = 0.1). There was no strong evidence for elevated risk of MI or stroke in multivariable models comparing participants in the top to those in the bottom third of sCD40L. Age-adjusted odds ratios (ORs) were 1.39 [95% confidence interval (CI) 0.98, 1.96] for MI and 1.16 (0.78, 1.73) for stroke. These attenuated to 1.24 (95% CI 0.86, 1.79) and 1.18 (0.78, 1.78), respectively, after adjustment for established and novel CVD risk factors.
sCD40L is associated with other inflammatory markers but is not itself a strong independent risk marker for either stroke or MI.
Journal of Thrombosis and Haemostasis 06/2011; 9(8):1452-9. · 5.73 Impact Factor
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ABSTRACT: Hemostasis and thrombosis may be important contributors to cognitive decline and dementia. Certain blood markers may assist in diagnosis or management.
To collate evidence for the association of circulating hemostatic variables and dementia or cognitive impairment.
A systematic review of studies describing blood markers of hemostatic function and cognition/dementia. Abstracts were reviewed by two independent assessors and studies selected based on pre-specified criteria. We described methodological quality and performed meta-analyzes where data allowed.
From 7103 titles, 485 abstracts and included 21 studies (n = 32,773) were assessed. In two longitudinal studies, the incident of vascular dementia risk was greater for higher D-dimer [hazard ratio (HR): 1.50, 95% confidence interval (CI): 1.15-1.96]. For case-control data, we calculated standardized mean differences (SMD) and 95% CI. Higher levels of: factor (F)VII (SMD: 0.93; 95% CI: 0.60-1.26), fibrinogen (SMD: 1.53; 95% CI: 1.17-1.87), prothrombin fragment 1 and 2 (SMD: 0.64; 95% CI: 0.32-0.96), plasminogen activator inhibitor (SMD: 0.68; 95% CI: 0.26-1.10), D-dimer (SMD: 2.00; 95% CI: 1.59-2.40) and von Willebrand factor (VWF) (SMD: 1.68; 95% CI: 1.30-2.06) showed modest but significant associations with vascular dementia. For patients with any dementia diagnosis, associations were with higher D-dimer (SMD: 0.36; 95% CI: 0.15-0.56) and VWF (SMD: 0.31; 95% CI: 0.11-0.51). For specific cognitive domains, significant (P < 0.001) positive correlations were fibrinogen and speed of processing (0.76; 95% CI: 0.67-0.84), verbal memory (0.69; 95% CI: 0.59-0.79) and non-verbal reasoning (0.57; 95% CI: 0.49-0.65).
The present results suggest a modest association between hemostasis and vascular dementia including increased levels of thrombin generation markers (D-dimer and prothrombin fragment 1 + 2) and endothelial dysfunction (VWF and plasminogen activator inhibitor). Associations are weaker for specific cognitive tests and when all dementias are combined.
Journal of Thrombosis and Haemostasis 06/2011; 9(8):1475-82. · 5.73 Impact Factor
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ABSTRACT: Background Biomarkers might add to clinical measures of neurological impairment and age to predict poor outcome after stroke. Methods We recruited symptomatic patients <24 h after stroke or TIA from an emergency department. We drew blood for markers of inflammation, thrombosis, thrombolysis, cardiac dysfunction and cerebral damage. We measured outcome at 3 months with the modified Rankin Scale (mRS). We used logistic regression, calculated measures of discrimination and reclassification and adjusted for multiple comparisons. Results We drew blood from 285 patients (230 ischaemic strokes, 40 TIA, 15 haemorrhagic strokes) at a median of 7 h (IQR 3-19 h) after symptom onset and contacted 99% at 3 months: 160 (57%) had mRS 0-2 and 123 (43%) had mRS 3-6. After adjusting for neurological impairment and age, only IL-6 (OR 2.4 (95% CI 1.4 to 4.2), 75th to 25th centile) and Ln NT pro BNP (OR 2.2 (1.2 to 4.0)) were significantly associated with poor outcome. A clinical model containing the NIHSS score and age had an area under a receiver operator curve of 0.84 (95% CI 0.79 to 0.88); neither IL-6 nor Ln NT pro-BNP improved this significantly. There was no net reclassification improvement across clinically important boundaries after adding IL-6 or Ln NT pro-BNP to the clinical model. Conclusion It is unlikely that the biomarkers measured in this study improve the clinical prediction of death or disability when measured at a uniform and early point after stroke or TIA.
Journal of neurology, neurosurgery, and psychiatry 11/2010; 81(11):e70. · 4.87 Impact Factor
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B J Jefferis, G D O Lowe,
P Welsh,
A Rumley,
D A Lawlor,
S Ebrahim,
C Carson,
M Doig,
C Feyerabend,
L McMeekin,
S G Wannamethee,
D G Cook,
P H Whincup
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ABSTRACT: Secondhand smoke (SHS) exposure is associated with elevated CHD risks. Yet the pathways through which this may operate have not been investigated in epidemiologic studies with objective SHS exposure measures and a wide range of CHD risk factors associated with active smoking. Therefore we investigate associations between SHS exposure and CHD risk factors, to clarify how SHS exposure may raise risk of CHD.
Cross-sectional population-based study of 5029 men and women aged 59-80 years from primary care practices in Great Britain. Smoking, behavioural and demographic information was reported in questionnaires; nurses made physical measurements and took blood samples for analysis of serum cotinine and markers of inflammation, hemostasis and endothelial dysfunction.
Active cigarette smokers had lower albumin and higher triglycerides, CRP, IL-6, white cell count, fibrinogen, blood viscosity, factor VIII, VWF and t-PA than non-smokers. Among non-smokers, serum cotinine levels were independently positively associated with CRP, fibrinogen, factor VIII, VWF and t-PA and inversely associated with albumin, after adjustment for age, gender, social and behavioural factors. The differences in CRP, fibrinogen and albumin between cotinine < or =0.05 and >0.7 ng/ml were one-third to one half the size of differences between cotinine < or =0.05 ng/ml and current smokers, but were of similar magnitude for VWF and t-PA.
Endothelial, inflammatory and haemostatic markers related to CHD risk showed independent associations with SHS exposure in the same direction as those for active smoking. Results aid understanding of the associations between SHS exposure and elevated CHD risks.
Atherosclerosis 07/2009; 208(2):550-6. · 3.79 Impact Factor
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ABSTRACT: Matrix metalloproteinase-9 (MMP-9) has a potential role in arterial plaque rupture, but its relation to risk of coronary heart disease (CHD) is uncertain.
To determine whether circulating levels of serum MMP-9 are prospectively related to the risk of CHD in the general population.
We measured baseline MMP-9 levels in stored serum samples of subjects in a case-control study nested within a prospective study of 5661 men followed up for 16 years for CHD events (465 cases, 1076 controls).
MMP-9 values were associated with cigarette smoking, and with several inflammatory and haemostatic markers, but not with age, body mass index, blood pressure or lipid measurements. Men in the top third of baseline MMP-9 levels had an age-adjusted odds ratio (OR) for CHD of 1.37 (95% CI 1.04-1.82) compared with those in the bottom third. Adjustment for conventional risk factors (smoking in particular) reduced the odds ratio to borderline significance: OR 1.28 (95% CI 0.95-1.74), while additional adjustment for two markers of generalized inflammation, interleukin-6 and C-reactive protein, further attenuated the association: OR 1.13 (0.82-1.56).
Serum MMP-9 has a modest association with incident CHD in the general population, which is not independent of cigarette smoking exposure and circulating markers of generalized inflammation. MMP-9 is unlikely to be a clinically useful biomarker of CHD risk, but may still play a role in the pathogenesis of CHD.
QJM: monthly journal of the Association of Physicians 09/2008; 101(10):785-91. · 2.33 Impact Factor
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ABSTRACT: 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.
American journal of epidemiology 07/2008; 168(2):179-87. · 5.59 Impact Factor
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D Gimeno,
M Kivimäki,
E J Brunner,
M Elovainio,
R De Vogli,
A Steptoe,
M Kumari, G D O Lowe,
A Rumley,
M G Marmot,
J E Ferrie
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ABSTRACT: A lack of longitudinal studies has made it difficult to establish the direction of associations between circulating concentrations of low-grade chronic inflammatory markers, such as C-reactive protein and interleukin-6, and cognitive symptoms of depression. The present study sought to assess whether C-reactive protein and interleukin-6 predict cognitive symptoms of depression or whether these symptoms predict inflammatory markers.
In a prospective occupational cohort study of British white-collar civil servants (the Whitehall II study), serum C-reactive protein, interleukin-6 and cognitive symptoms of depression were measured at baseline in 1991-1993 and at follow-up in 2002-2004, an average follow-up of 11.8 years. Symptoms of depression were measured with four items describing cognitive symptoms of depression from the General Health Questionnaire. The number of participants varied between 3339 and 3070 (mean age 50 years, 30% women) depending on the analysis.
Baseline C-reactive protein (beta=0.046, p=0.004) and interleukin-6 (beta=0.046, p=0.005) predicted cognitive symptoms of depression at follow-up, while baseline symptoms of depression did not predict inflammatory markers at follow-up. After full adjustment for sociodemographic, behavioural and biological risk factors, health conditions, medication use and baseline cognitive systems of depression, baseline C-reactive protein (beta=0.038, p=0.036) and interleukin-6 (beta=0.041, p=0.018) remained predictive of cognitive symptoms of depression at follow-up.
These findings suggest that inflammation precedes depression at least with regard to the cognitive symptoms of depression.
Psychological Medicine 07/2008; 39(3):413-23. · 6.16 Impact Factor
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G D O Lowe
Journal of Thrombosis and Haemostasis 06/2008; 6(5):717-9. · 5.73 Impact Factor
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ABSTRACT: A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) may influence von Willebrand factor (VWF) levels and consequently the risk of myocardial infarction (MI). Moreover, ADAMTS-13 influences hemostatic plug formation in mouse models. We therefore studied their associations in the Glasgow MI Study (GLAMIS).
We measured ADAMTS-13 and VWF antigen levels by ELISAs in stored plasma from a case-control study of 466 MI cases and 484 age- and sex-matched controls from the same north Glasgow population. There was no correlation between ADAMTS-13 and VWF levels in cases or controls. ADAMTS-13 levels correlated positively with serum cholesterol and triglycerides and body mass index, and negatively with high-density lipoprotein-cholesterol. VWF levels correlated with age, fibrinogen and C-reactive protein. In multivariable analyses including risk factors, VWF correlated positively with risk of MI, and ADAMTS-13 correlated negatively with risk of MI. These associations were independent of each other. The association of ADAMTS-13 with risk of MI was observed only in multivariable analysis.
VWF and ADAMTS-13 levels were not associated in this study, and showed associations with MI risk in opposite directions but of similar strength. The association of ADAMTS-13 with MI is influenced by lipid levels, and consequently requires further investigation.
Journal of Thrombosis and Haemostasis 05/2008; 6(4):583-8. · 5.73 Impact Factor
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G D O Lowe
Journal of Thrombosis and Haemostasis 03/2008; 6(2):256-8. · 5.73 Impact Factor
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ABSTRACT: Long-term increases in plasma fibrinogen levels of 1 g/liter are associated with an approximate doubling of risk of major cardiovascular disease outcomes, but causality remains uncertain. To quantify cross-sectional associations of fibrinogen levels with established risk factors and other characteristics, the investigators combined individual data on 154,211 apparently healthy adults from 31 prospective studies conducted between 1967 and 2003, using a linear mixed model that included random effects at the cohort level. Fibrinogen levels increased with age and showed continuous, approximately linear relations with several risk markers and slightly curvilinear associations with log triglycerides, albumin, and tobacco and alcohol consumption. Female sex, Black ethnicity, lower socioeconomic status, and alcohol abstinence were each associated with modestly higher fibrinogen levels. Approximately one third of the variation in fibrinogen levels was explained by cohort, age, and sex. An additional 7% was explained by established risk factors (notably, positive associations with smoking and body mass index and an inverse association with high density lipoprotein cholesterol), and a further 10% was explained by inflammatory markers (notably, a positive association with C-reactive protein). The association with body mass index was twice as strong in women as in men, whereas the association with smoking was much stronger in men. These findings substantially advance understanding of the correlates and possible determinants of fibrinogen levels.
American Journal of Epidemiology 11/2007; 166(8):867-79. · 5.22 Impact Factor
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ABSTRACT: 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.
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.
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.
IL-6 may have a potential role as a mediator between cardiovascular risk factors and several biological mechanisms for cardiovascular disease.
Journal of Thrombosis and Haemostasis 09/2007; 5(8):1637-43. · 5.73 Impact Factor
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G D O Lowe
Journal of Thrombosis and Haemostasis 07/2007; 5(6):1125-7. · 5.73 Impact Factor
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J Danesh,
S Erqou,
M Walker,
S G Thompson,
R Tipping,
C Ford,
S Pressel,
G Walldius,
I Jungner,
A R Folsom, [......],
L Pennells,
P Perry,
K Ray,
N Sarwar,
M Scherman,
A Thompson,
S Watson,
F Wensley,
I R White,
A M Wood
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ABSTRACT: Many long-term prospective studies have reported on associations of cardiovascular diseases with circulating lipid markers and/or inflammatory markers. Studies have not, however, generally been designed to provide reliable estimates under different circumstances and to correct for within-person variability. The Emerging Risk Factors Collaboration has established a central database on over 1.1 million participants from 104 prospective population-based studies, in which subsets have information on lipid and inflammatory markers, other characteristics, as well as major cardiovascular morbidity and cause-specific mortality. Information on repeat measurements on relevant characteristics has been collected in approximately 340,000 participants to enable estimation of and correction for within-person variability. Re-analysis of individual data will yield up to approximately 69,000 incident fatal or nonfatal first ever major cardiovascular outcomes recorded during about 11.7 million person years at risk. The primary analyses will involve age-specific regression models in people without known baseline cardiovascular disease in relation to fatal or nonfatal first ever coronary heart disease outcomes. This initiative will characterize more precisely and in greater detail than has previously been possible the shape and strength of the age- and sex-specific associations of several lipid and inflammatory markers with incident coronary heart disease outcomes (and, secondarily, with other incident cardiovascular outcomes) under a wide range of circumstances. It will, therefore, help to determine to what extent such associations are independent from possible confounding factors and to what extent such markers (separately and in combination) provide incremental predictive value.
European Journal of Epidemiology 02/2007; 22(12):839-69. · 4.71 Impact Factor
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G D O Lowe
Journal of Thrombosis and Haemostasis 10/2006; 4(9):1882-5. · 5.73 Impact Factor
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ABSTRACT: 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.
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.
A total of 3861 men aged 60-79 years at the 20 years follow-up of the British Regional Heart Study.
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%).
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).
Journal of Thrombosis and Haemostasis 06/2006; 4(5):982-7. · 5.73 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Scottish medical journal 12/2005; 50(4):166-9. · 0.40 Impact Factor
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G D O Lowe
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ABSTRACT: 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.
Journal of Thrombosis and Haemostasis 09/2005; 3(8):1618-27. · 5.73 Impact Factor
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G D O Lowe
Journal of Thrombosis and Haemostasis 05/2005; 3(4):635-7. · 5.73 Impact Factor
