F. B. Smith

Hemostatic Factors as Predictors of Ischemic Heart Disease and Stroke in the Edinburgh Artery Study

Plasma fibrinogen is a consistent predictor of ischemic heart disease (IHD) in prospective studies, but there are fewer data relating other hemostatic variables to IHD and also to stroke. We therefore studied the relationships of plasma fibrinogen, von Willebrand factor antigen, tissue plasminogen activator (TPA) antigen, factor VII, and fibrin D-dimer to incidence of IHD and stroke and determined whether any associations could be explained by conventional risk factors and baseline heart disease. In the Edinburgh Artery study, 1592 men and women aged 55 to 74 years, randomly sampled from the general population, were followed prospectively over 5 years to detect fatal and nonfatal IHD and stroke events. During the 5 years, 268 new vascular events were identified. Baseline plasma fibrinogen was independently related to risk of stroke in multivariate analysis that adjusted for cigarette smoking, LDL-cholesterol, systolic blood pressure, and preexisting IHD (relative risk [RR] 1.52, 95% confidence interval [CI] 1.17, 1.98). TPA antigen, and fibrin D-dimer were also independently associated with risk of stroke (RR 1.69,95% CI 1.22,2.35 and RR 1.96, 95% CI 1.12,3.41, respectively). Significant relationships were found between TPA antigen and myocardial infarction (P < or = .05). In older men and women, increased coagulation activity and disturbed fibrinolysis are predictors of future vascular events (both IHD and stroke).

Improved Prediction of Fatal Myocardial Infarction Using the Ankle Brachial Index in Addition to Conventional Risk Factors The Edinburgh Artery Study

Background—Prediction of major cardiovascular and cerebrovascular events using conventional risk factor models is limited. Noninvasive measures of subclinical atherosclerosis such as the ankle brachial index (ABI) could improve risk prediction and provide more focused primary prevention strategies. We wished to determine the added value of a low ABI in the prediction of long-term risk of cardiovascular and cerebrovascular events and death. Methods and Results—In 1988, 1592 men and women 55 to 74 years of age were randomly selected from the age-sex registers of 11 general practices in Edinburgh, Scotland, and followed up over a period of 12 years for incident events. After adjustment for age and sex, an ABI ≤0.9 was predictive of an increased risk of fatal myocardial infarction (MI), cardiovascular death, all-cause death, combined fatal and nonfatal MI, and total cardiovascular events. After further adjustment for prevalent cardiovascular disease, diabetes, and conventional risk factors, a low ABI was independently predictive of the risk of fatal MI. Addition of the ABI significantly (P≤0.01) increased the predictive value of the model for fatal MI compared with a model containing risk factors alone. Comparison of areas under receiver operator characteristic curves confirmed that a model including the ABI discriminated marginally better than one without. Conclusions—Addition of the ABI significantly improved prediction of fatal MI over and above that of conventional risk factors. We recommend that the ABI be incorporated into routine cardiovascular screening and that the potential of its inclusion into cardiovascular scoring systems (with a view to improving their accuracy) now be examined.

Cognitive decline and markers of inflammation and hemostasis: The Edinburgh Artery Study

OBJECTIVES: To determine whether circulating markers of activated inflammation and hemostasis are associated with cognitive decline in older people.

Smoking, haemostatic factors and lipid peroxides in a population case control study of peripheral arterial disease

The aim of this study was to determine differences between cases of peripheral arterial disease and healthy controls in levels of haemostatic factors and lipid peroxides and the influence of cigarette smoking. The study groups were selected from the Edinburgh Artery Study which is a random sample survey of men and women aged 55-74 years. Mean levels of plasma fibrinogen, von Willebrand factor, beta-thromboglobulin, plasminogen activator inhibitor (type I), cross-linked fibrin degradation products and lipid peroxides were markedly elevated in 121 study cases compared with 126 age- and sex-matched controls. For example, cross-linked fibrin degradation products had a geometric mean of 106.8 ng/ml (95% confidence interval (CI) 95.3, 119.8) in study cases and 74.7 ng/ml (95% CI 67.0, 83.4) in controls (P < 0.001). Inclusion of smoking in logistic regressions of each factor on peripheral arterial disease significantly reduced the odds of disease for von Willebrand factor and for cross-linked fibrin degradation products, but had little effect on the increased odds associated with fibrinogen, beta-thromboglobulin, plasminogen activator inhibitor and lipid peroxides. We conclude that, in men and women in Edinburgh, peripheral atherosclerosis is associated with lipid peroxidation, endothelial disturbance, platelet activation, elevated fibrinogen, fibrin formation and increased inhibition of fibrinolysis. The most important effects of cigarette smoking in promoting atherosclerosis may be endothelial disturbance and fibrin formation.

Plasma fibrinogen, haemostatic factors and prediction of peripheral arterial disease in the Edinburgh Artery Study.

&NA; The role of fibrinogen and other haemostatic factors in prediction of peripheral arterial disease (PAD) has not been established. We examined the associations of plasma fibrinogen, von Willebrand Factor (vWF), tissue plasminogen activator (t‐PA) antigen, fibrin D‐dimer, and factor VII with the development and clinical progression of PAD. In the Edinburgh Artery Study, 1592 men and women, aged between 55 and 74 years, were followed prospectively over 5 years to detect the onset of PAD, and the deterioration of established PAD. At baseline, 418 individuals had evidence of PAD and 60 (14.4%) subsequently deteriorated. 1080 subjects had no baseline disease, but 59 (5.5%) developed PAD during follow‐up. Median levels of fibrinogen and vWF were higher in the group developing disease compared with the group which did not (2.78 g/l versus 2.57 g/l, P ≤ 0.01; 116 IU/dl versus 104 IU/dl, P ≤ 0.05; respectively). After adjusting for age and sex, fibrinogen (P ≤ 0.01) and vWF (P ≤ 0.05) were significantly associated with the risk of developing PAD. The association between fibrinogen and development of disease remained after adjusting for cardiovascular risk factors and baseline ischaemic heart disease (relative risk, 1.35, 95% confidence interval, 1.05, 1.73; P ≤ 0.05). None of the haemostatic factors were significantly associated with progression of PAD. In conclusion, plasma fibrinogen levels are related to the future onset of PAD, providing further evidence of a possible role of elevated fibrinogen in the development of atherosclerotic disease.

Changes in ankle brachial index in symptomatic and asymptomatic subjects in the general population

OBJECTIVE To determine changes over time in the ankle brachial index (ABI) among subjects with and without intermittent claudication in the general population. DESIGN OF STUDY Population cohort study. SETTING General population in Edinburgh, Scotland. SUBJECTS A total of 1592 men and women aged 55 to 74 years selected at random from age-sex registers of 11 general practices and followed up over 12 years. Main outcome measures Changes in ABI for each leg recorded at baseline in 1988 and at subsequent 5-year and 12-year clinical examinations. RESULTS Overall, 695 subjects (348 men and 347 women) had valid ABI measurements on both legs at all three examinations. At baseline, the ABI was on average.03 higher in the right leg than the left (P < or =.001). Men had a mean ABI that was.07 higher than women (P < or =.001). Mean ABI in the worse leg showed little change over 12 years in both men and women. However, in the whole population, the ABI in the better leg showed a significant drop, 1.15 to 1.08 (P < or =.001). A total of 179 cases of intermittent claudication were identified during the 12-year follow-up. At baseline, ABI in the worse leg of the claudicants was significantly lower than in healthy subjects (.99 vs 1.08; P < or =.01). In claudicants, mean ABI in the worse leg fell by.04 over 5 years (P < or =.05) and in the better leg showed a highly significant drop of.09 (P < or =.001) to levels similar to those of the worse leg. CONCLUSIONS The mean ABI in the worse leg of study subjects showed little progression over 12 years. Individuals with intermittent claudication experienced a greater decline in both legs compared with those without claudication. Deterioration occurred more rapidly in the limb with a higher ABI at baseline, which possibly indicates a systemic tendency to atherosclerosis.

Cardiovascular Diseases and Decline in Cognitive Function in an Elderly Community Population: The Edinburgh Artery Study

Objective: To investigate cognitive performance and 4-year change in cognitive function in relation to different clinical manifestations of atherosclerotic disease in an elderly community population. Methods: The Edinburgh Artery Study is a population cohort study of men and women who were recruited to a baseline survey in 1987 and 1988. From the time of study entry, the participants have been invited to two follow-up clinical examinations and continuously monitored for major fatal and nonfatal vascular events. All alive and eligible subjects were invited for cognitive testing in two study years when the mean age of the sample was 73.1 (standard deviation = 5.0) years. A follow-up cognitive assessment was performed in 2002 and 2003 on 452 survivors. Results: In multivariate analyses controlling for demographic characteristics, depression, and major atherosclerotic risk factors, stroke was associated with a significantly worse performance on tests of verbal memory (p = .02) and letter fluency (p = .002). In addition, stroke was related to a significantly steeper 4-year decline in verbal memory performance (p = .04). Among the subjects who had not had an overt stroke, those with symptomatic peripheral arterial disease experienced a significantly greater 4-year decline in verbal memory functioning (p = .04). Conclusions: In older people, stroke is associated with both worse performance on cognitive tests and progressive verbal memory decline. Elderly individuals with vascular diseases other than stroke may also be vulnerable to a greater decline in verbal memory function. A relationship between vascular diseases and verbal memory decline may exist independently of depressed mood and major atherosclerotic risk factors. CVD = cardiovascular disease; PAD = peripheral arterial disease; IC = intermittent claudication; MI = myocardial infarction; WHO = World Health Organization; ECG = electrocardiogram; MRI = magnetic resonance imaging; LMT = logical memory test; RPM = Raven’s progressive matrices; VFT = verbal fluency test; DST = digit symbol test; NART = national adult reading test; GCF = general cognitive factor; SD = standard deviation; MMSE = mini-mental state examination; CHD = coronary heart disease; SBP = systolic blood pressure.

Tissue-plasminogen activator, plasminogen activator inhibitor and risk of peripheral arterial disease

In this population-based case-control study, we examined the relationship between the fibrinolytic variables tissue-plasminogen activator (t-PA) antigen and plasminogen activator inhibitor (PAI) activity, cardiovascular risk factors and peripheral arterial disease. Cases and controls were selected from the Edinburgh Artery Study, a random sample survey of men and women, aged 55-74 years. Mean levels of t-PA antigen and PAI activity were significantly elevated in 121 cases compared to 126 controls. The increased risks of peripheral arterial disease with increasing PAI activity and t-PA antigen levels were partly mediated by interactions with serum triglycerides, high density lipoprotein (HDL) cholesterol and cigarette smoking. For example, adjustment for triglycerides significantly reduced the odds of disease for PAI activity from 1.41 (95% confidence intervals 1.08, 1.86) to 1.24 (0.93, 1.65) and from 1.47 (1.09, 1.98) to 1.34 (0.99, 1.82) for t-PA antigen. We conclude that impaired fibrinolytic potential (raised PAI activity and t-PA antigen) is associated with peripheral atherosclerosis and that this relationship is partly influenced by lipids and cigarette smoking.

Smoking, hemorheologic factors, and progression of peripheral arterial disease in patients with claudication

PURPOSE The purpose of the current study was to determine whether hemostatic and rheologic factors are associated with the deterioration of peripheral arterial disease in patients with intermittent claudication and the influence of smoking and severity of underlying disease on these relationships. METHODS We conducted a prospective cohort study with a 6-year follow-up period of a consecutive series of 607 patients with uncomplicated intermittent claudication. The study setting was the Peripheral Vascular Clinic, Royal Infirmary of Edinburgh. The main outcome measures were peripheral vascular intervention or onset of severe chronic leg ischemia (rest pain, ulceration, gangrene). RESULTS A total of 210 patients died during follow-up. Two hundred three patients did not have a vascular event or deterioration of limb ischemia, 45 patients underwent a peripheral vascular intervention, and 64 progressed to severe chronic leg ischemia. Median levels (interquartile ranges) of whole blood viscosity were significantly higher in the vascular intervention group (3.75 mPa/sec; range, 3.38 to 4.13 mPa/sec) than in those who did not deteriorate 3.48 mPa/sec; range, 3.06 to 3.83 mPa/sec) (p < or = 0.05), and plasma von Willebrand factor was higher in those with severe chronic leg ischemia (154.0 IU/dl; range, 122.0 to 187.0 IU/dl) than in those who did not deteriorate (131.0 IU/dl; range, 106.0 to 165.0 IU/dl) (p < or = 0.01). After adjustment for age, sex, cigarette smoking, and ankle brachial pressure index, the levels of plasma fibrinogen and blood and plasma viscosities were each associated with an increased risk of vascular intervention (all p < or = 0.05). There were no significant associations between any of the hemorheologic factors and the risk of severe chronic leg ischemia on multivariate analyses. CONCLUSION Elevations in rheologic factors may have important effects on further reduction of blood flow in the legs of patients with claudication and promote worsening ischemia and clinical progression of symptoms.

Criteria for previously undiagnosed diabetes and risk of mortality: 15-year follow-up of the Edinburgh Artery Study cohort.

Aims  To compare risk of all‐cause and cardiovascular mortality associated with different criteria for undiagnosed diabetes and glucose tolerance.