From the Wolfson Unit for Prevention of Peripheral Vascular Diseases,
Department of Public Health Sciences, Edinburgh University Medical School
(A.J.L., P.I.M., F.G.R.F.); the University Department of Medicine, Royal
Infirmary, Glasgow (G.D.O.L., A.R.); and the Department of Radiology, The
Royal Infirmary of Edinburgh NHS Trust (P.L.A.), UK.
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
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.
In previous reports from the EAS, rheological factors have been
strongly associated both with asymptomatic
peripheral arterial disease and with the risk
of subsequent cardiovascular events (ischemic
heart disease or stroke).7 8 We have also noted
that men are more susceptible to the effects of rheological factors, in
particular plasma viscosity, and that this may contribute to the sex
differential in cardiovascular disease (Reference 1717 ,
and unpublished data, 1997). However, the mechanism behind the greater
susceptibility of men is unclear; in particular, it is not known
whether it is the thrombotic, ischemic, or atherogenic
component of cardiovascular disease that appears to be
more sensitive in men to changes in the rheological factors.
The present population-based study investigates the hypothesis that
hemostatic and rheological factors are associated with carotid
arterial wall thickness and that such effects are
independent of other "traditional" cardiovascular
risk factors. Results are analyzed on a sex-specific basis,
allowing us to identify any sex differences in the relationship between
a range of rheological and hemostatic factors and IMT.
Risk Factor Measurement
The blood samples were taken between 9:30 AM and 12:30
PM to minimize diurnal variation in the levels of
biochemical, hemostatic, and rheological factors. Fibrinogen was
measured in citrated plasma by a thrombin-clotting turbidometric method
in a centrifugal analyzer.20 tPA antigen
levels were estimated by an ELISA (Biopool).21
Fibrin D-dimer was measured with an ELISA
(AGEN).21 vWF was also assayed with an ELISA
(DAKO).22 Blood and plasma viscosities were
measured in K2EDTA blood (1.5 mg/mL) at high
shear rates (>300 s-1) in a Coulter-Harkness
viscometer at 37°C.20 23 Hematocrit was
measured with a Hawksley microcentrifuge and reader. Serum
total cholesterol was measured on a Cobas Bio-analyser
(Roche Products) with standard kits. The coefficients of variation
for each of the hemostatic and rheological factors were as follows:
fibrinogen, 2.1%; tPA, 9.8%; fibrin D-dimer, 15%; vWF,
7.7%; blood viscosity, 1.2%; plasma viscosity, 0.9%; and hematocrit,
0.6%.
Measurement of Carotid Atherosclerosis
The B-mode ultrasound scan was performed with the subject in the supine
position by use of an ATL UM9, HDI Duplex Scanner (Advanced Technology
Laboratories), with a 10-MHz transducer providing imaging at 10 MHz and
spectral Doppler at 7 MHz. The scanning protocol involved
examination of the carotid arteries in both transverse and longitudinal
planes. Measurement of IMT was made at the point on the far wall of the
common carotid artery, 2 cm proximal to the bifurcation, from the
longitudinal scan plane that showed the intima-media boundaries most
clearly with maximum image magnification. The distance between the two
cursors positioned on the boundaries of the intima and media was
recorded to the nearest 0.1 mm as the IMT. The procedure was
repeated for each side of the neck.
The higher of the values of IMT recorded for the right and left
sides of the neck was used as the measure of disease throughout all
subsequent analyses. IMT was recorded for only one side of
the neck in 27 participants (2.4%), and this value was used in the
analysis. The current analysis was repeated using the
mean of the left and right sides, and the results were almost identical
to those using the maximum.
Data Analysis
The distribution of IMT was positively skewed, and a logarithmic
transformation was used in all tests that assume approximate normality
of the dependent variable. Blood viscosity was corrected to a
standard hematocrit of 45% by the formula of Matrai et
al.29 Relative blood viscosity (corrected blood
viscosity/plasma viscosity) was calculated as a measure of red cell
deformability.30 The distributions of tPA and vWF
were positively skewed and required a square root transformation.
Fibrin D-dimer was more heavily skewed, and a logarithmic
transformation was necessary. Pack-years was calculated as a measure of
lifetime smoking history (years of smoking multiplied by the average
number of packs smoked per day). As expected, the distribution was
highly skewed, with a small number of very heavy smokers; a square root
transformation was used throughout the analysis.
Pearson correlation coefficients were calculated to examine the
relationship between each of the hemostatic and rheological factors and
three common risk factors (total cholesterol,
systolic blood pressure, and pack-years of smoking). These
three risk factors were chosen because they had previously been shown
to have an independent relationship with IMT in this population,
whereas other risk factors such as alcohol consumption and obesity
showed no independent effect.31 Least-squares
linear regression was used to assess the association between hemostatic
and rheological factors and IMT measured after adjustment for age.
Multivariate linear regression was then used to adjust
these effects for the three potential confounders: total
cholesterol, systolic blood pressure, and
pack-years of smoking. The population was divided into quartiles based
on the sex-specific distributions of IMT because there are large
differences in the distribution of IMT between men and
women.25 Mean values for each of the risk factors
were calculated across these quartiles. Finally, logistic regression
was used to calculate age-adjusted odds ratios of having a raised IMT
(above the upper quartile of its distribution) for every 1 SD increase
in each of the risk factors. The odds ratios were then adjusted further
for the potential confounding effects of pack-years, total
cholesterol, and systolic blood pressure.
The results of a linear regression analysis between the
hemorheological factors and carotid IMT are presented in Table 2
Table 3
Odds ratios of having a carotid IMT value above versus below the upper
quartile of its distribution for a unit (SD) increase in each of the
hemostatic and rheological factors are presented in Table 4
One important feature of the present study was that the hemostatic
and rheological factors were measured at baseline, 5 years before the
IMT measurement. Although this reduced the potential bias of studies in
which risk factors are measured retrospectively, it introduced two
other sources of bias. First, the risk factor levels may have changed
over the 5-year follow-up period; they may even have changed
differentially by level of IMT. Second, since a sizable proportion of
the cohort either died or did not attend the follow-up examination for
a variety of reasons, biased estimates of the risk factor–IMT
relationship may result. Both sources of bias are likely to reduce the
power of the statistical tests; they would not cause variables to
appear significant when they were unrelated to IMT, nor would they
reverse a true relationship.
The distribution of IMT in any population study is highly dependent on
how precisely it is measured and on the settings of the scanning
equipment. In the present study, a single measurement of IMT was
taken on each side of the neck. IMT was measured to the nearest
0.1 mm, which was a constraint imposed by the ultrasound scanner.
Given the somewhat narrow distribution of IMT in this population, the
authors accept that this may have led to a relatively large measurement
error and a subsequent loss of statistical power to detect significant
associations. Previous large population studies have used a variety of
techniques to measure IMT, and in contrast to the present study,
all have used multiple measurements of the carotid artery in their
calculation of IMT. The ARIC study32 used an
average of 11 measures spaced evenly over the far wall of the left
common carotid artery. In contrast, the Kuopio Ischemic Heart
Disease study13 used a mean of six values of IMT
(three measures on each side of the neck) and the
Cardiovascular Health Studies34
an average of two values. However, given these differences in
techniques of measurement, there is still some consistency
in the mean levels of IMT and its variation across the four population
studies. Needless to say, future epidemiological research involving
carotid IMT as a measure of early atherosclerosis would
benefit from standardization of both the scanning equipment and the
protocol for measurement.
Previous studies have shown that IMT, measured by B-mode ultrasound, is
a valid and accurate marker for the early, subclinical stages of
atherosclerosis.32 33 34 35 A strong
relationship between carotid IMT and the ankle-brachial pressure index,
a measure of peripheral occlusive arterial
disease, has already been demonstrated within this population,
suggesting that IMT is also a marker for generalized
atherosclerosis.25 Although a
number of epidemiological studies have considered the relationship
between hemostatic factors and the occurrence of
symptomatic cardiovascular
disease,1 2 3 4 5 6 7 8 9 few have studied the influence of
these variables on the early stages of atherosclerotic development
in large population samples.14 15 16 Others have
used small samples or selected patient
groups,36 37 38 39 and the results cannot be
extrapolated reliably to the general population. Analyses in
the present study have been performed on a sex-specific basis,
primarily because of large sex differences in the distribution of
IMT25 and also because there are substantial sex
differences in the relationships between IMT and traditional
cardiovascular risk
factors.31
Previous studies addressing the relationship of IMT to hematological
variables have focused primarily on plasma
fibrinogen.11 12 13 14 16 36 37 38 39 40 41 42 Fibrinogen may
promote atherosclerosis through various mechanisms,
including increases in platelet aggregation, fibrin formation, and
blood viscosity and decreased
fibrinolysis.10 Pathological
studies have suggested that fibrinogen may be particularly important in
early atherosclerotic development.43 Both the
ARIC Study14 and the
Cardiovascular Health Study16
reported significant associations between fibrinogen and IMT on
univariate analyses, but these relationships were
weakened after adjustment for other cardiovascular risk
factors, including smoking. However, as in the present study, ARIC
noted that the relationship remained significant after adjustment for
smoking in men.14 Results from other studies have
not provided conclusive evidence for the role of fibrinogen. Positive
correlations with IMT have been reported in population samples of
elderly subjects11 12 and in a smaller sample of
young people 10 to 19 years old.40 In contrast,
others, including the Kuopio Ischemic Heart Disease study, have
reported either very weak associations13 39 41 42
or no association37 between fibrinogen and IMT,
particularly on multivariate analyses.
Although epidemiological studies have demonstrated a relationship
between tPA antigen and cardiovascular disease or
events,7 21 44 45 46 47 only ARIC has reported its
association with IMT in a large population
study,15 which was significant on
univariate analysis but became nonsignificant after
multivariate adjustment. However, the present study
found no significant univariate relationship between tPA
and IMT in either sex. Similarly, fibrin D-dimer, a marker
of increased fibrin turnover, was not significantly associated with IMT
in the present study, confirming the findings from
ARIC.15 vWF, which like tPA antigen may be a
marker of endothelial disturbance,
activates aggregation of platelets and promotes their
adhesion to damaged subendothelium. Results from the
present analysis again confirm those from the ARIC
Study14 : there appears to be no
consistent relationship between vWF and IMT in either sex.
Hence, the associations of tPA, fibrin D-dimer, and vWF and
incident cardiovascular disease in the
EAS7 may not be mediated through association with
atherogenesis but rather through prothrombotic effects.
The most striking result from the present study was the strong,
independent relationship between blood viscosity and its major
determinants (hematocrit, plasma viscosity, and fibrinogen) and IMT in
men. Indeed, IMT was found to be more strongly associated with these
rheological factors than with a range of traditional
cardiovascular risk factors, which have already been
studied in this population.31 After adjustment
for three common cardiovascular risk factors, unit
increases in fibrinogen and blood viscosity were each associated with
significant increases in the risk in men of having an elevated IMT. The
association between blood viscosity and IMT remained significant after
correction to a standard hematocrit of 45% and also after adjustment
for fibrinogen. This suggests that the viscosity-IMT relationship is
not simply due to the contributions of these two major determinants of
blood viscosity. In contrast, the data suggested that no significant
relationship existed in women. This could have been partly a result of
the relatively smaller range of variation in the distribution of IMT in
women, although the finding is in agreement with that of a French
population study.37 With such a large sample
size, it could be argued that although the associations observed in men
were statistically significant, they may not be of biological
significance. However, an odds ratio of almost 1.4 for blood viscosity
would suggest that viscosity does have a real effect on early
atherosclerosis. Recently, Cortellaro and
coworkers42 reported that hematocrit was related
to 16-month progression of IMT in 64 patients with
peripheral arterial disease.
Elevated blood viscosity may promote atherosclerotic development by
increasing platelet adhesion to the subendothelium,
by increasing protein infiltration into the arterial wall,
and by altering local shear forces at sites of
atherogenesis.10 17 48 Through such effects,
blood viscosity may be one mechanism by which many other risk factors
promote atherogenesis.48 We have reported
elsewhere that the higher incidence of cardiovascular
events in men in the EAS may be partly explained by a sex difference in
susceptibility to rheological factors (Reference 1717 , and unpublished
data, 1997). The present analysis provides strong evidence
to suggest that in men, the atherogenic component of
cardiovascular disease may be more susceptible to
elevated blood viscosity and supports our previous findings of a sex
difference in susceptibility to peripheral
atherosclerosis with increases in
viscosity.17 Possible explanations for the
greater susceptibility of men to viscosity could relate to sex
differences in vascular geometry and wall shear
forces.49
Results from this population-based study provide strong evidence to
suggest that blood viscosity and its major determinants may be
important risk factors for the development of early
atherosclerosis in men. This relationship appears to be
independent of other common cardiovascular risk
factors. These findings need to be confirmed from other large
prospective studies, especially those that have estimated both
progression and regression of atherosclerosis.
Received October 8, 1997;
revision received December 8, 1997;
accepted December 12, 1997.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Blood Viscosity and Elevated Carotid Intima-Media Thickness in Men and Women
The Edinburgh Artery Study
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
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). 
.001) and its
major determinants, plasma viscosity, fibrinogen (both
P.01), and hematocrit (P.05), were
all linearly related to IMT. Furthermore, blood viscosity, fibrinogen
(both P.01), and plasma viscosity
(P.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.01), fibrinogen, corrected blood viscosity, and
plasma viscosity (all P.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.
Key Words: carotid arteries • blood flow • atherosclerosis • fibrinogen
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Epidemiological
studies have shown that certain hemostatic and rheological factors (eg,
fibrinogen, viscosity, hematocrit, vWF, tPA, fibrin
D-dimer) are associated with incident
cardiovascular events.1 2 3 4 5 6 7 8 9
Possible causal mechanisms include effects on thrombogenesis and
ischemia.10 However, these factors could
also be important in promoting the endothelial damage
and diffuse intimal thickening that constitute the prolonged,
asymptomatic phase of the atherosclerotic
process.10 Such early stages of disease can now
be assessed accurately by use of high-resolution B-mode ultrasound to
measure the IMT of the walls of the carotid arteries. However, only a
small number of population-based studies have considered the
association of hemostatic factors with IMT.11 12 13 14 15 16
Some of these have involved only
fibrinogen,11 12 13 and none have included
measurements of blood or plasma viscosity.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
The EAS is a prospective study of 1592 men and women whose age
at baseline ranged from 55 to 74 years. The population was selected at
random, in 5-year age bands, from 10 general practices spread
socioeconomically across the city. The response rate was 65%, and
follow-up of a random sample of 20% of the nonresponders showed no
substantial bias. Details of the study population and recruitment have
been reported previously.18 The study was
approved by the Lothian Health Board Ethics Committee, and informed
consent was obtained from each participant.
Assessment of all risk factors took place at baseline;
participants attended a university clinic, where a self-administered
questionnaire was checked and a comprehensive medical examination
carried out. The questionnaire included validated questions concerning
personal characteristics, smoking, and medical history (including the
World Health Organization angina and intermittent claudication
questionnaires19 ). The examination was conducted
by two pairs of specially trained nurses who took 20 mL of fasting
blood. Standing height and weight (without shoes) were measured, and
blood pressure was taken with a random-zero sphygmomanometer with the
subject in the supine position after a 10-minute rest.
B-mode ultrasound scanning was performed by four specially
trained staff members on the 1156 participants who attended their
5-year follow-up examinations between November 1992 and March 1994.
Complete details of the self-administered follow-up questionnaire and
the examination procedure,24 and in particular of
the scanning protocol,25 have been described
previously.
Information from the questionnaires and recording forms
was checked by the clinic staff and entered onto a DBASE IV database.
Data files were then transferred to the university mainframe computer
for analysis by the SPSS26 27 and
SAS28 statistical packages.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Of the 1592 subjects who were recruited at baseline, 1156 (72.6%)
attended the 5-year follow-up examination and completed the
questionnaire, 131 (8.2%) did not attend the examination but returned
their questionnaire, and there were 203 deaths (12.8%). Ultrasound
scans were of an acceptable quality for measurement of IMT in 1106
(95.7%) of the 1156 who attended the examination. There was no
significant difference (P>.05) in the distributions of sex
or social class between the baseline population and the subgroup who
attended the follow-up examination. In this population, men were found
to have significantly higher age-adjusted mean IMT values than women
(0.85 mm, with a 95% CI of 0.82 to 0.87, versus 0.79 mm,
with a 95% CI of 0.77 to 0.82). The correlations between the
hemorheological factors and total cholesterol,
systolic blood pressure, and pack-years are shown in Table 1
. Plasma viscosity showed the strongest
correlation with total cholesterol in both sexes. In men,
systolic blood pressure was most strongly correlated with tPA,
whereas blood pressure showed the strongest correlation with fibrin
D-dimer in women. As expected, the factor pack-years of
smoking was significantly correlated with most of the hemorheological
factors in men, whereas fibrinogen, tPA, and hematocrit were strongly
correlated with pack-years in women.
View this table:
[in a new window]
Table 1. Correlations Between Each of the Hemostatic and
Rheological Factors and Total Cholesterol, Systolic
Blood Pressure, and Pack-Years of Smoking in Men and Women . In men, fibrinogen, blood and plasma
viscosities, corrected blood viscosity (all P.01), and
hematocrit (P.05) were significantly associated with
carotid IMT after adjustment for age. When total
cholesterol, systolic blood pressure, and
pack-years were included in a multivariate model,
fibrinogen, blood viscosity, corrected blood viscosity (all
P.01), and plasma viscosity (P.05) each
maintained a statistically significant relationship to IMT. In
contrast, Table 2 shows that none of these rheological factors were
significantly related to carotid IMT in women (P>.05). No
significant association was observed between tPA, fibrin
D-dimer, or vWF and IMT in either sex.
View this table:
[in a new window]
Table 2. Age-Adjusted and
Multivariate-Adjusted Linear Associations Between
Hemostatic and Rheological Factors and IMT (mm) in Men and Women gives the age-adjusted mean
levels of the hemostatic and rheological factors by quartile of IMT in
men and women. As expected from the analyses in Table 2
, in
men, significant linear trends across quartiles of IMT were noted for
fibrinogen, blood and plasma viscosities, and corrected blood viscosity
(all P.01), with hematocrit just failing to reach
statistical significance (P=.067). No significant linear
trends were seen for any of the hemorheological factors across
quartiles of IMT in women or for tPA, fibrin D-dimer, or
vWF in either sex.
View this table:
[in a new window]
Table 3. Sex-Specific, Age-Adjusted Mean Levels of Hemostatic
and Rheological Factors by Quartiles of IMT . In men, after adjustment for age,
standard unit increases in fibrinogen (P.05), blood
viscosity (P.01), corrected blood viscosity
(P.05), and plasma viscosity (P.05)
significantly raised the likelihood of having an elevated IMT.
Adjustment for pack-years, total cholesterol, and
systolic blood pressure had very little effect on the magnitude
of these odds ratios, with the exception of plasma viscosity, which was
reduced to marginal nonsignificance (P=.07). The odds ratios
for each of the viscosity measurements were then further adjusted for
plasma fibrinogen level, and there was little change in their
significance levels (data not shown). Table 4 shows that none of the
hemorheological factors were associated with an increased IMT in women.
Again, tPA, fibrin D-dimer, and vWF showed no relationship
to IMT in either sex.
View this table:
[in a new window]
Table 4. Odds Ratios of IMT >1.05 mm (Men) and
>0.95 mm (Women) for a 1 SD Increase in Each of the Hemostatic
and Rheological Factors
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The relationships between a range of hemostatic and rheological
factors and carotid IMT, a measure of early
atherosclerosis, have been studied in a large
representative sample of the general population. To the
best of our knowledge, this is the first epidemiological study of the
association between rheological factors and IMT. Blood viscosity and
its major determinants (hematocrit and plasma viscosity) and
fibrinogen, which is an important determinant of plasma viscosity, were
strongly associated with IMT in men. Importantly, these relationships
were independent of three major traditional
cardiovascular risk factors: total
cholesterol, blood pressure, and lifetime smoking history.
Furthermore, for men, unit increases in the levels of fibrinogen, blood
and plasma viscosities, and corrected blood viscosity significantly
increased the risk of having an elevated IMT (above the upper quartile
of its distribution). In contrast, none of these rheological
variables showed any significant association with carotid IMT in
women. Our results support the hypothesis that rheological factors may
have a significant and independent effect on early carotid
atherogenesis in men. This relationship may be one mechanism for the
association of these factors with incident stroke and IHD events in men
in this cohort.8
Selected Abbreviations and Acronyms
ARIC
=
Atherosclerosis Risk in Communities
EAS
=
Edinburgh Artery Study
IMT
=
intima-media thickness
tPA
=
tissue plasminogen activator
vWF
=
von Willebrand factor
Acknowledgments
We would like to thank the British Heart Foundation for program
grant support.
Footnotes
Reprint requests to Dr Amanda J. Lee, Wolfson Unit for Prevention of Peripheral Vascular Diseases, Department of Public Health Sciences, Edinburgh University Medical School, Teviot Place, Edinburgh EH8 9AG, UK.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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A. Sramek, J.H.C. Reiber, W.B.J. Gerrits, and F.R. Rosendaal Decreased Coagulability Has No Clinically Relevant Effect on Atherogenesis: Observations in Individuals With a Hereditary Bleeding Tendency Circulation, August 14, 2001; 104(7): 762 - 767. [Abstract] [Full Text] [PDF]
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H. Tanaka, F. A. Dinenno, K. D. Monahan, C. A. DeSouza, and D. R. Seals Carotid Artery Wall Hypertrophy With Age Is Related to Local Systolic Blood Pressure in Healthy Men Arterioscler. Thromb. Vasc. Biol., January 1, 2001; 21(1): 82 - 87. [Abstract] [Full Text] [PDF]
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J. Willeit, S. Kiechl, F. Oberhollenzer, G. Rungger, G. Egger, E. Bonora, M. Mitterer, and M. Muggeo Distinct Risk Profiles of Early and Advanced Atherosclerosis : Prospective Results From the Bruneck Study Arterioscler. Thromb. Vasc. Biol., February 1, 2000; 20(2): 529 - 537. [Abstract] [Full Text] [PDF]
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S. Ebrahim, O. Papacosta, P. Whincup, G. Wannamethee, M. Walker, A. N. Nicolaides, S. Dhanjil, M. Griffin, G. Belcaro, A. Rumley, et al. Carotid Plaque, Intima Media Thickness, Cardiovascular Risk Factors, and Prevalent Cardiovascular Disease in Men and Women : The British Regional Heart Study Stroke, April 1, 1999; 30(4): 841 - 850. [Abstract] [Full Text] [PDF]
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