Paul L. Allan

Blood Viscosity and Elevated Carotid Intima-Media Thickness in Men and Women The Edinburgh Artery Study

BACKGROUND Several hemostatic and rheological factors have been associated with incident cardiovascular events. However, there have been no reports on the relationship of rheological factors with early atherosclerosis and very few on hemostatic factors. We therefore studied the relationship between these factors and carotid intima-media thickness (IMT). METHODS AND RESULTS The Edinburgh Artery Study measured fibrinogen, tissue plasminogen activator (tPA), fibrin D-dimer, von Willebrand factor (vWF), blood and plasma viscosities, and hematocrit as part of its baseline examination during 1988-1989. At the 5-year follow-up, valid measurements of IMT had been recorded in 1106 men and women 60 to 80 years old. In men, blood viscosity (P< or =.001) and its major determinants, plasma viscosity, fibrinogen (both P< or =.01), and hematocrit (P< or =.05), were all linearly related to IMT. Furthermore, blood viscosity, fibrinogen (both P< or =.01), and plasma viscosity (P< or =.05) remained significantly associated on multivariate analysis. Correcting blood viscosity to a standard hematocrit of 45% had little effect on its association. In men, there was a significantly increased risk of having an IMT above versus below the upper quartile of its distribution (1.05 mm) for SD increases in blood viscosity (P< or =.01), fibrinogen, corrected blood viscosity, and plasma viscosity (all P< or =.05). With the exception of plasma viscosity, these risks were unaffected by adjustment for other common cardiovascular risk factors. No significant associations were found between any of the hemorheological factors and IMT in women or for tPA, fibrin D-dimer, or vWF in either sex. CONCLUSIONS These findings suggest that in men, blood viscosity and its major determinants are associated not only with incident cardiovascular events but also with the early stages of atherosclerosis. This may be one explanation for the link between rheological factors and events.

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.

Accuracy and reproducibility of duplex ultrasonography in grading femoropopliteal stenoses

PURPOSE The aim of this study was to determine the accuracy of Doppler waveform characteristics in grading femoropopliteal stenoses and to determine the interobserver and intraobserver reproducibility of measuring the same waveform characteristics. METHODS Thirty patients with isolated areas of stenosis found by arteriography were evaluated by color duplex sonography. Each patient underwent scanning by two observers on two separate occasions. Each observer was blind to the others results. Doppler spectra were recorded in areas where color change suggested the highest velocity and also at the nearest normal proximal area. Peak systolic velocity, spectral broadening, and waveform configuration were measured at each site. RESULTS An increase in peak systolic velocity of more than 200% accurately predicted a 50% or greater reduction in luminal diameter on angiography (70% sensitivity, 96% specificity). The presence of spectral broadening and an abnormal waveform shape were found to correlate poorly with the degree of stenosis. Analysis of variance showed no significant difference between observers in velocity measurements (p = 0.78). CONCLUSIONS We conclude that although stenoses of greater than 50% can be distinguished from minor stenoses, more precise definition of the degree of narrowing is unlikely. The good repeatability of the velocity ratio makes it an excellent tool for monitoring major changes in the progression of disease.

EDINBURGH VEIN STUDY : METHODS AND RESPONSE IN A SURVEY OF VENOUS DISEASE IN THE GENERAL POPULATION

Objective: To describe the methods required to conduct a large epidemiological study of venous disease in the general population, and the resulting response. Design: Cross-sectional study. Setting: University of Edinburgh. Participants: Men and women aged 18–64 years, randomly selected from general practice registers. Methods: Subjects were invited for the following procedures: questionnaire, height and weight measurement, classification of varices and chronic venous insufficiency, duplex measurement of duration of venous reflux and venous blood sampling. A questionnaire survey of non-responders was carried out. Results of response: A total of 1566 subjects attended, a final response rate of 53.8%. The response rate increased with age. The distribution of ethnic origin and social class of attenders was similar to that of the general Edinburgh population. Study participants were generally older, from more affluent areas and more often female than non-responders (p ≤ 0.001). Conclusions: Large epidemiological studies of venous disease in the community are feasible but the level of response illustrates the importance of obtaining information on the disease status of non-responders.

Cardiovascular Risk Factors for Early Carotid Atherosclerosis in the General Population: The Edinburgh Artery Study

Background Recent attempts to identify cardiovascular risk factors affecting early-stage carotid atherosclerosis, measured by ultrasonographically assessed intima-media thickness, have been inconclusive. Objective To study the relationship between traditional cardiovascular risk factors and intima-media thickness. Methods Ultrasonic evaluation of the intima-media thickness of the common carotid artery was included in the 5-year follow-up examination of participants of the Edinburgh Artery Study. We had valid readings of intima-media thickness for 1106 men and women aged 60-80 years. Information on a range of cardiovascular risk factors had been collected during the baseline examination. Results For men, in addition to age, lifetime smoking (measured in terms of pack years) was the only cardiovascular risk factor associated with increased intima-media thickness (P≤0.01) in the univariate analysis. Both systolic blood pressure (P≤0.001) and the high-density lipoprotein (HDL: Total cholesterol ratio (P≤0.01) were correlated with intima-media thickness for women. When all the variables had been included in a multivariate analysis, pack years of smoking and the HDL:total cholesterol ratio were associated with early atherosclerotic development in men. In an equivalent analysis for women, alcohol consumption, systolic blood pressure and the HDL:total cholesterol ratio were associated with intima-media thickness. Conclusion These data suggest that risk factors affecting intima-media thickness differ for men and women. Further sex-specific analyses of prospective population studies are required in order to clarify the role of ‘traditional’ cardiovascular risk factors in the early stages of carotid atherosclerosis. Common carotid artery intima-media thickness has been shown to be a valid and reliable marker of early atherosclerotic development. However, results from previous studies of cardiovascular risk factors for increased intima-media thickness have been inconclusive. We report the results of a sex-specific analysis of cardiovascular risk factors for early atherosclerotic development from a study of the general population. In addition to age, which was strongly associated with intima-media thickness for both sexes, lifetime smoking and the high-density lipoprotein: Total cholesterol ratio were related to early atherosclerosis in men, whereas systolic blood pressure, alcohol consumption and the high-density lipoprotein: Cholesterol ratio were significant risk factors for women.

Accuracy and reproducibility of duplex ultrasound imaging in a phantom model of femoral artery stenosis

PURPOSE The improvement of management strategies in patients with intermittent claudication might depend on a better understanding of the natural history of femoral atherosclerosis. The grading of stenoses, the monitoring of their progression, and the assessment of response to treatment are critically dependent on a methods accuracy and variability. Duplex ultrasound imaging provides a noninvasive way of measuring localized disease, but there has been relatively little objective evaluation of its accuracy and reproducibility. The aim of this study was to evaluate the accuracy and variability of duplex velocity ratio measurements of stenosis. METHODS In a laboratory flow model of the femoral artery, 14 concentric and eccentric stenoses were examined five times by three sonographers. Measurements were then repeated with a standardized technique in which Doppler angle and aperture position were fixed, giving a total of 420 measurements. RESULTS Velocity ratio showed good correlation with degree of stenosis, R2 = 0.996. Intraobserver variability was low, but interobserver variability was significant with more severe stenosis (p = 0.002, analysis of variance). Standardization of the technique did not improve accuracy or variability. The 95% confidence limit was +/- 20% for a single reading of velocity ratio for stenoses of > 50% diameter reduction. CONCLUSIONS We conclude that duplex ultrasound imaging can be used to accurately grade arterial stenosis in this range, and the potential exists for noninvasive monitoring of the progression of preocclusive femoral atherosclerosis and its response to treatment. In addition, repeated measurements of velocity ratio over time should be made by the same observer.

Incidence and Risk Factors for Venous Reflux in the General Population: Edinburgh Vein Study

OBJECTIVE/BACKGROUND Chronic venous disease (CVD) is common, but the incidence of venous reflux, a precursor to this condition, is unknown. This study measured the incidence of venous reflux and associated risk factors, and examined the association between venous reflux and the incidence of CVD. METHODS In the Edinburgh Vein Study, a random sample of 1566 men and women aged 18-64 years were examined at baseline. Eight hundred and eighty of these patients were followed up 13 years and underwent an examination comprising clinical classification of CVD and duplex scanning of the deep and superficial systems to measure venous reflux ≥0.5 s. RESULTS The 13-year incidence of reflux was 12.7% (95% confidence interval [CI] 9.2-17.2), equivalent to an annual incidence of 0.9% (95% CI 0.7-1.3). The 13-year incidence of isolated superficial, isolated deep, and combined deep and superficial reflux was 8.8% (95% CI 5.6-12.0), 2.6% (95% CI 1.2-5.0), and 1.3% (95% CI 0.4-3.2), respectively. The highest incidence was in the great saphenous vein in the lower thigh (8.1%, 95% CI 5.4-11.8). There were no age or sex differences (p > .050). The risk of developing reflux was associated with being overweight (odds ratio [OR] 2.1, 95% CI 1.0-4.4) and with history of deep vein thrombosis (OR 11.3, 95% CI 1.0-132.3). Venous reflux at baseline was associated with new varicose veins at follow up (p < .001): the age- and sex-adjusted OR was 4.4 (95% CI 1.8-10.8) in those with isolated superficial reflux and 7.3 (95% CI 2.6-22.5) in those with combined deep and superficial reflux. CONCLUSION For every year of follow-up, around 1% of this adult population developed venous reflux. In two thirds of cases, the superficial system was affected. Venous reflux increased the risk of developing varicose veins, especially when combined deep and superficial reflux was present.

A study of genetic linkage heterogeneity in 35 adult-onset polycystic kidney disease families

A genetic heterogeneity analysis of 35 kindreds with adult-onset polycystic kidney disease (ADPKD) was carried out using the D16S85, D16S84, D16S125 and D16S94 loci that are closely linked to the PKD1 locus on chromosome 16. The results show that the likelihood of two ADPKD loci is 2,514.9 times greater than for a single locus (P < 0.0001). The maximum likelihood lod score is 27.38 under heterogeneity with PKD1 lying 4.9 cM proximal to D16S85 (in males). At least 3% of kindreds are unlinked to PKD1, since the 95% confidence limits of alpha, the proportion of families linked to PKD1, are 0.54–0.97. Only 2 out of 35 kindreds (5.7%) show statistically significant evidence of non-linkage to PKD1, with conditional probabilities of 0.987 and 0.993 that the disease locus is unlinked. This confirms the existence of a small subgroup of ADPKD kindreds that are unlinked to PKD1 and provides a firm basis for genetic counselling of this population on the basis of DNA probes.

Validity of duplex scanning in the detection of peripheral arterial disease in the general population

Duplex scanning has the potential to identify asymptomatic atherosclerosis of the lower limbs in the general population. The aim of this study was to assess the validity of scanning in a group of men and women aged 55-74, sampled from a population survey. Disease was measured using the WHO questionnaire on claudication, the ankle brachial pressure index, and a reactive hyperaemia test. In 73 cases of peripheral arterial disease and 91 controls, a duplex scan was conducted on both legs from the inguinal ligament to the lower popliteal region. The two radiologists performing the scans were blind to the arterial status of the subjects. Interpretation of the image, waveform and peak systolic velocity resulted in a sensitivity of 78%, specificity of 65% and positive predictive value of only 19%. The image alone had the best positive predictive value (62%) and specificity (97%). These results suggest that duplex scanning may currently be of limited use as a diagnostic screening test in the general population. Interpretation of the image alone, however, may be useful in some settings in identifying healthy subjects free of disease.

Telangiectasia in the Edinburgh Vein Study : Epidemiology and Association with Trunk Varices and Symptoms

OBJECTIVE Little research has been devoted to telangiectasia. The purpose of this study was to analyse the data in the Edinburgh Vein Study to determine the prevalence of telangiectasia in the general population, to analyse the demographic characteristics and association with symptoms and to compare the findings to those relating to varices of the saphenous systems. DESIGN Cross-sectional population study. SETTING Twelve general practices with catchment areas geographically and socioeconomically distributed throughout Edinburgh. PARTICIPANTS An age stratified random sample of 1566 people (699 men and 867 women) aged 16-64 selected from computerised age-sex registers of participating practices. METHODS Included in the population screening was a clinical examination, photography and duplex ultrasonography of the superficial veins and the deep veins down to popliteal level. Telangiectases and varicose veins were graded 1-3 according to severity. RESULTS A total of 1322 (84%) of the population were classified as having telangiectasias in their right legs; 555 (79%) of men and 767 (88%) of women; 1226 (92%) as grade 1 and 96 (8%) as grades 2 and 3. There were no significant differences between left and right legs (p=0.144). The commonest locations for telangiectases were the postero-medial aspects of the thigh, popliteal fossa and upper one third of calf. There was a highly significant association between the degree of severity of varicose veins and the grade of telangiectasia (p<0.001). Less than 1% of subjects with grades 2-3 trunk varices were free of telangiectasia, but 51% of subjects with grades 2-3 telangiectasia had no clinical evidence of varicose veins. There was a significant linear trend in the proportion of subjects reporting heaviness, swelling, aching and cramps being highest among those with neither telangiectasia nor varicose veins, lower in those with telangiectasia or varicose veins only and lowest in subjects having both. The highest frequency of most symptoms was found in subjects with both telangiectasia and varicose veins. CONCLUSIONS Telangiectasia is so common in the general population, especially in women, as to represent the norm. The anatomical distribution is entirely different from the distribution of the skin and subcutaneous manifestations of chronic venous insufficiency. Our confirmation of a strong association between trunk varices and grades 2-3 telangiectasia suggests the need for controlled studies into which condition should be treated. We found no evidence that telangiectasia per se was entirely responsible for leg symptoms.