Amanda J. Lee

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).

RANDOMISED CONTROLLED TRIAL OF PERCUTANEOUS TRANSLUMINAL ANGIOPLASTY FOR INTERMITTENT CLAUDICATION

OBJECTIVESnTo determine differences between PTA and conventional medical treatment in treadmill distance until onset of claudication, treadmill maximum walking distance, patient reported maximum walking distance, ankle brachial pressure index (ABPI), quality of life (Nottingham Health Profile, NHP) and Duplex measured extent of occlusive disease.nnnDESIGNnRandomised controlled clinical trial.nnnMETHODSnSix hundred claudicants were screened. Fifty-one men and 11 women with intermittent claudication due to short femoral stenoses or occlusions (n = 47) and iliac stenoses (n = 15) were randomised to either PTA plus medical treatment (PTA group, n = 30) or to medical treatment alone (control group, n = 32). Medical treatment consisted of daily low dose aspirin and advice on smoking and exercise.nnnRESULTSnAt 6 month follow up: In the PTA group more patients reported no claudication (p < or = 0.05) and were asymptomatic on the treadmill (p < or = 0.01) compared to the control group. The ABPI was significantly higher in the PTA group. More of the PTA group reported lower NHP pain scores (p < or = 0.05). In the control group there were more occluded arteries (p < or = 0.001), and the stenosis velocity ratio of patient arteries was significantly higher (p < or = 0.001).nnnCONCLUSIONSnOnly 10% of claudicants had discrete lesions suitable for PTA. Treatment of these patients with PTA produces a greater short-term improvement in walking and quality of life than medical treatment alone and is associated with less progression of disease.

Lifestyle factors and the risk of varicose veins: Edinburgh Vein Study.

The objective of this study was to determine the inter-relationships between a range of lifestyle factors and risk of varicose veins to identify which factors may be implicated in the etiology. An age-stratified random sample of 1566 subjects (699 men and 867 women) aged 18 to 64 years was selected from 12 general practices throughout Edinburgh. A detailed self-administered questionnaire was completed, and a comprehensive physical examination determined the presence and severity of varicose veins. The slightly higher age-adjusted prevalence of varicose veins in men than in women (39.7% versus 32.2%) was not explained by adjustment for an extensive range of lifestyle risk factors (male odds ratio [OR] 2.11, 95% confidence interval [CI] 1.51-2.96). In both sexes, increasing height showed a significant relationship with varicose veins (male OR 1.50, 95% CI 1.18-1.93 and female OR 1.26, 95% CI 1.01-1.58). Among women, body mass index was associated with an increased risk of varicose veins (OR 1.26, 95% CI 1.02-1.54). The current study casts doubt as to whether varicose veins occur predominantly in women. In addition, no consistent relationship with any lifestyle factor was shown. Self-reported evidence suggested a familial susceptibility, thereby warranting future genetic studies.

Randomized controlled trial of gamma-linolenic acid and eicosapentaenoic acid in peripheral arterial disease.

BACKGROUND AND AIMSnepidemiological studies suggest polyunsaturated fatty acids protect against the development of atherosclerosis. The aim of this study was to perform a randomized controlled trial of gamma-linolenic and eicosapentaenoic acids in patients with lower limb atherosclerosis. Main outcome measures were: cholesterol and lipoprotein concentrations; haemostatic and rheological variables; the ankle brachial pressure index; walking distance; and cardiovascular events and death.nnnMETHODSn120 men and women with stable intermittent claudication were randomized to 2 years treatment with either a combination of gamma-linolenic and eicosapentaenoic acids, or placebo.nnnRESULTSn39 (65.0 cent) of those taking fatty acids and 36 (60.0 cent) of those taking placebo completed the trial. Lipid concentrations did not differ significantly during the trial. In those taking fatty acids, haematocrit was significantly higher than in the placebo group after 6 months (46.1 cent compared with 44.6 cent, P </= 0.01), and systolic blood pressure was significantly lower after 2 years (150|mmHg compared with 161.8|mmHg, </= 0.05). There was no difference in walking distance, but there was a small reduction in non-fatal coronary events in the fatty acid group (10 cent compared with 15 cent, P > 0.05).nnnCONCLUSIONSna combination of polyunsaturated fatty acids produced a statistically significant reduction in systolic blood pressure, but no other significant benefits on risk factors. The trend towards fewer coronary events in those taking fatty acids warrants further investigation.

Methylene tetrahydrofolate reductase (MTHFR) and nitric oxide synthase (ecNOS) genes and risks of peripheral arterial disease and coronary heart disease: Edinburgh artery study

Hyperhomocysteinaemia and reduced nitric oxide synthesis may each result in endothelial dysfunction predisposing to atherogenesis. Genetic variants of methylene tetrahydrofolate reductase (MTHFR) and endothelial nitric oxide synthase (ecNOS) influence homocysteine metabolism and nitric oxide synthesis, respectively and might thus be determinants of the risk of atherosclerotic disease. The aim of our study was to identify, in a general population sample, the risks of peripheral arterial disease and of coronary heart disease related to MTHFR (175;198) and ecNOS (4;5) polymorphisms. In the Edinburgh Artery Study, which is a population based cohort study, 940 men and women aged 60-79 years, who had previously been selected at random from the general population, had DNA extracted from a venous blood sample. Based on a clinical examination at baseline and follow up investigations, three groups of subjects were identified: those with peripheral arterial disease (n=80), those with coronary heart disease (n=137), and healthy controls who had no evidence of cardiovascular disease (n=300). The distributions of the ecNOS and MTHFR genotypes did not differ significantly between the groups with and without cardiovascular disease. However, the ecNOS-4 allele (frequency 0.13) was related to the occurrence of coronary heart disease in non smokers, OR=2.47 (95% CI [1.42, 4.34], P=0.02). No association was found with peripheral arterial disease. The MTHFR-175 allele (frequency 0.31) was not related to coronary heart disease, but was associated with a reduced risk of peripheral arterial disease, OR=0.54 (95% CI [0.32, 0.90], P=0.02). Neither the ecNOS-4 allele or MTHFR-175 allele was related to the ankle brachial pressure index in the whole study population. In conclusion, the ecNOS-4 allele was associated with a slightly increased risk of coronary heart disease in non-smokers, but otherwise the MTHFR and ecNOS genotypes appeared to have little influence on the risks of peripheral arterial disease and coronary heart disease in this older population.

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.

Haemostatic and rheological factors in intermittent claudication: the influence of smoking and extent of arterial disease

Patients with intermittent claudication have been reported to have disturbances in blood rheology and haemostasis. Whether these disturbances are a result of, or largely independent of, smoking history and arterial narrowing has not yet been established. The levels of whole blood and plasma viscosity, haematocrit, von Willebrand factor antigen, fibrin D‐dimer antigen and urinary fibrinopeptide A antigen were compared in 617 claudicants and 722 controls from two epidemiological studies in Edinburgh. After adjustment for age and sex, all factors, except whole blood viscosity and haematocrit, were significantly higher in the claudicants compared to controls (P≤0.001). The risk of intermittent claudication was significantly raised for unit change in each factor, except for whole blood viscosity and haematocrit. Adjustment for lifetime smoking had little effect on the odds ratios. After further adjustment for the ankle brachial pressure index (as a measure of the extent of peripheral arterial disease), haematocrit, von Willebrand factor and urinary fibrinopeptide A showed a significant independent relationship with the risk of intermittent claudication. We conclude that the association between selected rheological and haemostatic factors and leg ischaemia is largely independent of both smoking history and the extent of arterial narrowing, and may be directly related to microvascular ischaemia.

Lipoprotein (a) and development of intermittent claudication and major cardiovascular events in men and women: the Edinburgh Artery Study.

Lipoprotein (a) may be an important risk factor for atherosclerosis. It is widely accepted that lipoprotein (a) levels are raised in patients with coronary heart disease, but there is some doubt about the causality of the relationship. In addition, little is known about the relationship between lipoprotein (a) and either stroke or peripheral arterial disease, nor about the role of lipoprotein (a) in women. Subjects aged 55-74 years (n=1592) were selected at random from 11 general practices in Edinburgh, Scotland and followed up for 5 years. The incidences of myocardial infarction, intermittent claudication and stroke were 13.4, 9.4 and 3.7%, respectively. Raised lipoprotein (a) levels at baseline were associated with an increased risk (95% confidence interval) of myocardial infarction RR 1.15 (1.00, 1.32), intermittent claudication RR 1.32 (1.10, 1.57) but not significantly for stroke RR 1.24 (0.93, 1.64). This increased risk persisted for intermittent claudication after adjustment for baseline cardiovascular disease and other risk factors RR 1.20 (1.00, 1.43), but for myocardial infarction became non-significant RR 1.06 (0.91, 1.23). The risk of disease associated with raised lipoprotein (a) was slightly higher in women than in men, especially for intermittent claudication (men RR 1.09 (0.87, 1.36) compared to women RR 1.37 (1.01, 1.87)). In conclusion, we found that lipoprotein (a) was an independent predictor of cardiovascular events in both sexes. The association between lipoprotein (a) and cardiovascular events may have been stronger in women than in men, and for peripheral arterial disease than myocardial infarction and stroke.

Prognostic scoring in ruptured abdominal aortic aneurysm: A prospective evaluation

BACKGROUNDnProspective validation of prognostic scoring systems for ruptured abdominal aortic aneurysm (AAA) is lacking. This study assesses the validity of three established risk scores and a new prognostic index.nnnMETHODnPatients admitted with ruptured AAA during a 26-month period (August 2002-December 2004) were recruited prospectively. The Glasgow Aneurysm Score (GAS), Hardman Index, Physiological and Operative Severity Score for enUmeration of Mortality and Morbidity (POSSUM) scores, and the Edinburgh Ruptured Aneurysm Score (ERAS) were recorded and related to outcome.nnnRESULTSnDuring the study period, 111 patients were admitted with ruptured AAA. Of these, 84 (76%) underwent attempted operative repair and were included in the study; 37 (44%) died after operation. The GAS, Hardman Index, and the ERAS were statistically related to mortality. However, analysis by receiver-operator characteristic curve revealed the ERAS to have an area under the curve (AUC) of 0.72 (95% confidence interval [CI], 0.61-0.83). The vascular (V)-POSSUM and ruptured AAA (RAAA)-POSSUM models had an AUC of 0.70 (95% CI, 0.59-0.82). The Hardman Index and GAS had an AUC of 0.69 (95% CI, 0.57-0.80) and 0.64 (95% CI, 0.52-0.76), respectively. Although the V-POSSUM equation predicted mortality effectively (P = .086), the RAAA-POSSUM derivative demonstrated a significant lack of fit (P = .009).nnnCONCLUSIONnProspective validation shows that the Hardman Index, GAS, and V-POSSUM and RAAA-POSSUM scores do not perform well as predictors for death after ruptured AAA. The ERAS accurately stratifies perioperative risk but requires further validation.

The role of haematological factors in diabetic peripheral arterial disease: the Edinburgh Artery Study

The relationship between haematological factors and peripheral arterial disease (PAD) among diabetics has not been widely examined. 1592 men and women aged 55–74 years were selected from the general population. They underwent an assessment for PAD and a glucose tolerance test. 288 subjects (18.7%) were identified as having diabetes or impaired glucose tolerance (IGT). Among the diabetes/IGT group, median levels of fibrinogen, von Willebrand factor (VWF), tissue plasminogen activator (t‐PA), fibrin D‐dimer and plasma viscosity were higher in subjects with PAD than those without PAD (Pu2003≤u20030.05). The prevalence of PAD was higher in those with diabetes/IGT (20.6%) compared to those with normal glucose tolerance (12.5%) (odds ratio 1.64; 95% CI 1.17, 2.31). After separate adjustment for fibrinogen, VWF, t‐PA, fibrin D‐dimer, leucocyte elastase, plasma viscosity and haematocrit, those with diabetes/IGT no longer had a significantly higher risk of PAD compared to those with a normal glucose tolerance test. Simultaneous adjustment for the first four of these haematological factors reduced the risk of PAD among subjects with diabetes/IGT to 1.11 (95% CI 0.76, 1.63). Increased levels of haemostatic factors may partly explain the higher prevalence of PAD in diabetic/IGT subjects compared to normal glucose‐tolerant subjects. Future randomized controlled trials involving the indirect lowering of levels of haematological factors should help to explain whether the associations reported here are of causal significance.