© 1995 American Heart Association, Inc.
Articles |
Fibrinogen and Silent Atherosclerosis in Subjects With Cardiovascular Risk Factors
From the Centre de Médecine Préventive Cardiovasculaire and INSERM U28, Broussais Hospital, Paris, France.
Correspondence to Jaime Levenson, MD, INSERM U28, Centre de Médecine Préventive Cardiovasculaire, Hôpital Broussais, 96 rue Didot, 75674 Paris Cedex 14, France.
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Abstract |
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Abstract Fibrinogen may play an active role in the development and progression of atherosclerotic plaques. We assessed the association between fibrinogen levels and atherosclerotic plaques over three different arterial sites in an asymptomatic never-treated male population with increased cardiovascular risk. We included 652 men aged 40 to 60 years old with at least one of the following cardiovascular risk factors: cholesterol >6.2 mmol/L and/or systolic blood pressure
160 mm Hg and/or
diastolic blood pressure 95 mm Hg, and/or because they
smoked. Carotid and femoral arteries and the abdominal aorta were
assessed by using ultrasonographic methods for the presence of plaque,
and subjects were categorized according to the presence (or absence)
and extent (one versus two or three sites) of plaque. Plasma fibrinogen
was measured according to the thrombin-time method of Clauss. While the
presence of atherosclerosis was significantly related
to age, current smoking, systolic pressure, LDL
cholesterol, and fibrinogen levels, the extent of
atherosclerosis was related to age and
triglyceride and fibrinogen levels. Multiple regression
analysis indicated independent associations between fibrinogen
and the presence and extent of atherosclerosis. Plaque
prevalence was significantly more pronounced with increasing tertile of
fibrinogen levels. The odds ratio of the upper to lower fibrinogen
tertiles for the presence of plaque was 1.6 (95% confidence interval,
1.4 to 1.8) and 1.4 (95% confidence interval, 1.2 to 1.7) for its
extent. Adjustment for other risk factors slightly reduced the
association between fibrinogen and atherosclerosis. In
conclusion, fibrinogen levels are related to
atherosclerosis, supporting the hypothesis that
increased fibrinogen may be one of the mechanisms linking
cardiovascular risk factors to formation and
progression of plaques.
Key Words: arterial plaques • hypercholesterolemia • hypertension • smoking • fibrin
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Introduction |
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The role of elevated fibrinogen levels as an independent risk factor for coronary, cerebral, and peripheral vascular disease is well established on the basis of clinical and epidemiological studies.1 2 3 4 5 6 7 Strong evidence implicating high fibrinogen levels in coronary heart disease and stroke has been reported in a meta-analysis of the cumulative data from six prospective epidemiological studies.8
In cardiovascular disease, fibrinogen has been mainly considered as being involved in thrombotic occlusion and hence in the final stage of atherothrombosis. However, a number of investigators have suggested that fibrinogen may play a more active role in the development and progression of atherosclerotic plaque. The simultaneous presence of fibrinogen, its degradation products, and LDL cholesterol (LDL-C) has been observed to influence atherogenesis in the arterial wall.9 10 11 Furthermore, smooth muscle cell proliferation and migration12 13 stimulated by fibrinogen and fibrin degradation products suggest that fibrinogen is involved in the earliest stages of plaque formation. Recent technological progress in noninvasive arterial investigation techniques based on high-resolution B-mode ultrasonography has made it possible to detect atherosclerosis early, before symptoms occur. The present study examines the association between fibrinogen levels and the presence and extent of atherosclerotic plaques over three different arterial sites (carotid and femoral arteries and the aorta) in an asymptomatic never-treated male population with increased cardiovascular risk (hypercholesterolemia, hypertension, and smoking).
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Methods |
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Study subjects were obtained from an ongoing risk factor–screening program conducted at the worksite for employees of several companies within the Paris, France, area by a group of occupational health physicians (PCVMETRA Group: Prévention Cardiovasculaire en Médecine du Travail). After their consent was obtained, 2800 men were referred to the hospital between June 1989 and January 1993 because they had any of the following characteristics: hypercholesterolemia (plasma cholesterol >6.2 mmol/L [240 mg/L]) and/or hypertension (systolic blood pressure
160 mm Hg and/or diastolic
blood pressure 95 mm Hg) at the worksite, and/or because they
smoked. Exclusion criteria included treatment for hyperlipemia or
hypertension, secondary hypercholesterolemia or
hypertension, definite hypertriglyceridemia
(>5.6 mmol/L [5 g/L]), renal failure (creatinine >130
µmol/L [>1.5 mg/dL]), diabetes mellitus (fasting blood glucose
>7.7 mmol/L [>150 mg/dL]), or a history of myocardial infarction,
stroke, or intermittent claudication. From these subjects, those aged
40 to 60 years were analyzed, resulting in an initial study
sample of 1752 men. For logistic reasons, complete biological
investigation, including fibrinogen measurements, could be made only in
a random subsample of 1230 subjects. The ultrasonic evaluation of the
carotid and femoral arteries was made in 990 subjects, while those of
the aorta was made in 730. Only subjects with ultrasonic measurements
on the three different arterial sites were included,
leading to a final cross-sectional study sample of 652 men.
Cardiovascular Risk Factor Assessment
Cardiovascular risk indicators were measured
during the morning of a day-hospital visit after 12 hours' fasting.
Total blood cholesterol, HDL cholesterol
(HDL-C) after precipitation of LDL and VLDL by phosphotungstic
acid/magnesium chloride, and plasma triglyceride levels
were measured by using the classic enzymatic method on venous blood
samples that were drawn after the subjects had rested in the supine
position for 10 minutes.14 15 LDL-C was computed from the
Friedewald formula. Citrated platelet-poor plasma was used to
measure plasma fibrinogen according to the thrombin-time method
described by Clauss.16 Brachial systemic blood pressure
was determined as the mean of at least three consecutive measurements
by using the standard sphygmomanometric procedure after the subjects
had rested for at least 10 minutes in the supine position. Smoking was
carefully assessed by questioning the subjects, who were categorized
into current smokers, former smokers, and those who had never smoked.
Body mass index (BMI) (weight/height2) was used to
determine the presence or absence of excess weight.
Arterial Plaque Detection
Studies were performed with real-time B-mode ultrasound imagers
(Radius CF, General Electric, CGR France, and Ultramark 4, Advanced
Technology). Experienced sonographic physicians obtained bilateral
images of the common carotid artery, the carotid bifurcation, the
carotid bulb, and the internal carotid artery, and the common,
superficial, and deep femoral arteries in the upper part of the
thigh14 15 ; the proximal and distal sections of the
abdominal aorta were carefully assessed. Ultrasonic images were
magnified and projected in real time on a television monitor. Hard
copies of real-time images were made for longitudinal and axial
arterial sections. Nonstenotic plaque was
defined as a focal echogenic structure encroaching into the vessel
lumen having a distinct intimal plus medial thickness greater than 50%
thicker than neighboring sites. Intimal plus medial thickness was
evaluated after the sound beam was adjusted perpendicularly to the
arterial surface as the distance from the edge of the first
echogenic bright line, corresponding to the lumen-intima interface, to
the edge of the second echogenic line, corresponding to the
media-adventitia interface.17 Plaque was considered
"present" when one or more arterial plaques were
found regardless of their precise location or number.14 15
Because the aim of the study was to focus on the influence of
fibrinogen on early atherosclerosis, and thrombotic
complications are frequently associated with carotid or femoral artery
stenosis and/or aortic aneurysm, subjects with such
lesions were excluded from the study (n=22). No differences existed
between the two imagers used in this study for plaque detection at each
site examined.
Statistical Analysis
Values are expressed as mean±SD. Comparisons of risk factors
between groups were performed by ANOVA. As the distributions of
fibrinogen and triglyceride values were skewed, a
logarithmic transformation was applied. At each site plaque was
characterized as a dichotomous variable (absent or present),
and the extent of plaque was defined by three classes: one, two, or
three diseased sites (carotid and/or femoral artery and/or abdominal
aorta). Multivariate logistic analysis was
performed to assess the variables independently related to plaque.
A 
2 test was performed to assess trends in
qualitative variables when comparing groups with an increasing
number of diseased sites. The risk of the presence of plaque,
regardless of its site, and the extent of plaque (one diseased site
versus two or three diseased sites) were assessed as a function of
fibrinogen level tertile by using logistic regression analysis.
Association strengths are represented as odds ratios with
95% confidence intervals. Statistical analysis was performed
on an Apple Macintosh computer by using JMP (SAS Institute)
and EXCEL (Microsoft) software.
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Results |
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Of this population, 35% had no plaque at any site, while 27% had carotid plaque, 39% had aortic plaque, and 50% had femoral plaque. Plaque was present in one, two, and three sites in 27%, 26%, and 13% of the population, respectively.
Table 1
shows the cardiovascular risk
characteristics in subjects with and without arterial
plaque. Subjects with arterial plaque were older
(P<.0003) and included a greater number of current smokers
(49% versus 31%, P=.001) and a smaller percentage of
subjects who had never smoked (23% versus 38%, P=.001).
Both groups had a similar percentage of former smokers. Although the
frequency of hypertension was similar in both groups, systolic and
diastolic pressure were slightly higher in subjects with
arterial plaque. Subjects with plaque had higher total and
LDL-C and triglyceride levels and lower HDL-C levels. BMI
and glucose levels did not differ between the two groups. Subjects with
arterial plaque had higher levels of plasma fibrinogen than
those without arterial plaque. The characteristics of
subjects according to the location of arterial plaque are
presented in Table 2. Similar results were
observed between risk factors and plaque locations to those described
in Table 1 between subjects with and without arterial
plaque. Table 3 compares cardiovascular
risk factors between groups with varying extents of silent
atherosclerosis. Subjects with one or two and three
sites of atherosclerosis were comparable regarding BMI,
smoking status, hypertension prevalence, and cholesterol
(total, LDL, and HDL) and glucose levels. In contrast, age and
triglyceride and fibrinogen levels increased with the
number of diseased sites. A multivariate logistic
regression analysis was performed to investigate risk factors
influencing the presence of plaques and the number of diseased sites
(Table 4). Only variables with a significance level
<.10 in univariate analysis were considered.
The presence of arterial plaque was associated with age
(P<.003), current smoking (P<.0001), systolic
pressure (P<.002), and LDL-C (P<.0001) and
fibrinogen (P<.009) levels. The extent of
atherosclerosis was associated with age
(P<.0001) and triglyceride
(P<.0004) and fibrinogen (P<.01) levels.
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Plaque prevalences in the lower, middle, and upper thirds of the
fibrinogen level distribution were 55%, 67%, and 74%, respectively
(Fig 1, top). Significant trends were found between
groups with increasing fibrinogen tertile for the presence or absence
of plaque (P<.04). Subjects with plaque belonging to the
lower, middle, and upper thirds of the fibrinogen level distribution
(Fig 1, bottom panel) had one site of arterial plaque in
51%, 42%, and 33% of cases, respectively, two sites in 34%, 40%,
and 42%, respectively, and three sites in 15%, 18%, and 25%,
respectively. Significant trends between groups with increasing
fibrinogen tertile were found for one site (P<.003) and
three sites (P<.04) but not for two diseased sites
(P<.19).
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The unadjusted odds ratios for the presence of arterial
plaque in the upper versus lower tertiles of plasma fibrinogen level
were 1.6 (95% confidence interval, 1.4 to 1.8) and 1.4 (95%
confidence interval, 1.2 to 1.7) for the extent of arterial
plaque (one site versus two and three sites). Adjustment for
differences in risk factors (age, current smoking, hypertension, LDL-C,
triglycerides) slightly reduced the magnitude of the
associations between fibrinogen and the presence and extent of
atherosclerosis without changing the direction of the
associations. Fig 2 shows the orderly progression of
subjects with arterial plaque with increasing fibrinogen
level according to smoking status. The percentage of subjects with
arterial plaque who had never smoked and were in the lower
fibrinogen tertile differed significantly from that with
arterial plaque who had never smoked and were in the upper
fibrinogen tertile (37% versus 65%; P<.01) and from that
with arterial plaque who were current smokers and in the
lower fibrinogen tertile (37% versus 67%, P<.01).
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Discussion |
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Our findings in this cross-sectional study of a male population at increased risk for cardiovascular disease provide evidence that plasma fibrinogen levels are associated with the presence and extent of silent atherosclerosis as assessed noninvasively in carotid and femoral arteries and the abdominal aorta.
Subjects with arterial plaque had significantly higher levels of several well-established cardiovascular risk factors (age, total cholesterol, LDL-C, and blood pressure) and were more likely to be current smokers. The multivariate analysis of the present study failed to find any significant association between the presence of arterial plaque and BMI, hypertension prevalence, and triglyceride and glucose levels. The extent of atherosclerosis as defined by the number of diseased sites was significantly higher with increasing age and triglyceride levels but was not related to BMI, smoking status, hypertension, or glucose and cholesterol (total, LDL, and HDL) levels. Thus, the presence of plaque was associated with LDL-C levels, while the number of diseased sites was associated with triglyceride levels. LDL-C was significantly associated with atherosclerotic carotid plaque.14 15 17 18 More original was the association between the extent of atherosclerotic plaques and triglycerides levels. In univariate analysis the mean value of triglycerides was higher in subjects with than in those without arterial plaque and in subjects with extended atherosclerosis. However, multiple analysis showed that only the extent of plaque to two or three different arterial sites was associated with triglyceride levels, indicating that this relation was independent of other variables, in particular HDL-C. The majority of observational studies demonstrate a significant univariate relation of triglyceride levels and coronary heart disease.19 However, there is little information concerning the relation of triglycerides with early atherosclerosis. In a prospective 12-year study on the incidence of coronary heart disease, triglyceride level was the only risk factor to be an independent predictor of early onset of disease.20 We have shown that in asymptomatic hypercholesterolemic men triglyceride levels are related to coronary calcification.15 Prolonged exposure of arterial wall cells to triglycerides may enhance the atherogenic process (as assessed by wall-thickness imaging).21 These findings emphasize the importance of evaluating the influence of plasma triglycerides on the prevalence of early and late progression of atherosclerosis.
When the effect of these various cardiovascular risk factors was corrected by multivariate adjustment, plasma fibrinogen remained a statistically independent predictor of silent atherosclerosis. Age was the only other factor independently associated with both the presence and extent of arterial plaques. While age is known to have a consistent association with atherosclerotic lesions,14 15 the role of fibrinogen in early atherosclerosis is surprisingly less well documented at the clinical level. Studies have established an association between fibrinogen and a number of the major cardiovascular risk factors, including age,6 smoking,4 5 22 23 blood cholesterol and triglyceride levels,4 5 24 25 26 blood pressure,27 28 diabetes,5 and lower socioeconomic status.29 The subjects in the present study constituted a population of middle-aged male employees selected on the basis of increased cardiovascular risk, which is generally associated with high fibrinogen levels. Several prospective studies have revealed that fibrinogen has a strong predictive power for coronary heart disease and stroke.2 4 5 6 In these clinical outcomes, the role of fibrinogen is largely relegated thrombo-occlusion, the final consequence of atherosclerosis. Despite known associations between fibrinogen and other cardiovascular risk factors, few studies have considered fibrinogen as a factor potentially associated with the silent phase of atherosclerosis. Most of these studies use carotid intimal-medial wall thickness as a measure of atherosclerosis. In a Finnish study the association between carotid atherosclerosis and fibrinogen was explained mainly by age and smoking.18 A population-based study of the community of Bruneck reported that fibrinogen was highly indicative of carotid artery disease in elderly men and women.30 The ARIC study group revealed that fibrinogen is positively associated with asymptomatic early carotid atherosclerosis.31 A more recent study found significant association between fibrinogen and intimal-medial thickness as well as plaque status in the common carotid artery in a group at high risk for atherosclerotic disease.32 To date, however, the relation between fibrinogen and the presence and extent of asymptomatic early atherosclerosis in other sites than the carotid artery are not well documented in men. In a highly selected group with peripheral arterial occlusive disease, fibrinogen was associated with the severity of atherosclerosis as assessed by the ankle/brachial pressure index and duplex ultrasonography and/or angiography.33 An interesting new aspect of our results is the association of plasma fibrinogen concentration with the different locations investigated and the extent of atherosclerosis as defined by the number of diseased sites.
Additional trends and odds analyses in the present study strongly suggest that the association between fibrinogen and early atherosclerosis cannot be attributed to confounding cardiovascular risk factors and favors the hypothesis that these silent lesions are partly a direct consequence of plasma fibrinogen levels. Fibrinogen, fibrin, and LDL-C have been detected in atherosclerotic plaques, suggesting that a common mechanism may exist for fibrinogen and lipoprotein entry into the vessel wall.9 10 11 In addition, other studies have found different molecular forms of fibrinogen in atherosclerotic plaques34 35 and a correlation between total fibrin-related antigens and LDL-C in each group of atherosclerotic plaques.13 The potential involvement of fibrinogen in the pathogenesis of atherosclerosis is supported by the demonstration that fibrinogen degradation products stimulate smooth muscle proliferation and migration13 and enhance the release of endothelial cell–derived growth factors.36
Because silent atherosclerosis was investigated ultrasonographically in only the carotid and femoral arteries and abdominal aorta, we do not know whether fibrinogen is similarly involved in the early development of coronary artery plaque. However, we have demonstrated that the presence of plaque at two extracoronary sites has a powerful predictive value for the presence of coronary calcification.15 It is probable that high fibrinogen levels are also implicated in coronary artery atherosclerosis, as demonstrated in symptomatic patients in whom fibrinogen increased progressively with the extent of coronary atherosclerosis.37 38 39
The relation between fibrinogen and smoking should be considered when interpreting the prevalence of early atherosclerosis. Cigarette smoking and plasma fibrinogen concentration have been consistently found to be associated in the male population.4 5 22 23 Adjustment for smoking produced little change in the relative odds for silent atherosclerosis despite the fact that fibrinogen levels were higher in smokers than nonsmokers. Analysis of the combined influence of smoking status and fibrinogen on arterial plaques showed that the percentage of subjects in the lower fibrinogen tertile with plaques was higher among smokers that those who had never smoked. In these latter subjects, plaque prevalence increased with increasing fibrinogen tertile.
Fibrinogen is an acute-phase protein, and thus its high levels could simply be a reflection of underlying arterial plaque formation. The advanced lesions of atherosclerosis are considered the result of an excessive inflammatory fibroproliferative response to various insults to the arterial wall endothelium and smooth muscle cells.40 However, genetic control of fibrinogen plasma concentration seems to exist,41 42 43 and in addition, many other factors (eg, environmental8 or social29 risk factors for cardiovascular disease) may increase plasma fibrinogen levels, which could then play a role in the pathogenesis and course of arterial disease. High plasma fibrinogen levels may cause a hypercoagulable state, platelet aggregation, and important rheological alterations. Red blood cell aggregation and disaggregation shear stress are profoundly altered by the level of fibrinogen.28 Enhanced red blood cell aggregability leads to increased blood viscosity, which in turn might induce a further slowing of the circulation, which may play a role in the extent of arterial damage.
In conclusion, this cross-sectional study indicates that fibrinogen concentration is frequently elevated in subjects with silent atherosclerosis but particularly in those with several diseased arterial sites. This supports the hypothesis that increased fibrinogen may be one of the mechanisms linking cardiovascular risk factors to the formation and progression of atherothrombotic lesions.
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Acknowledgments |
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The authors are grateful to the staff of the PCVMETRA Group for their help: P. Segond (chairman), D. Badet, C. Baylac-Lebot, A. de Bonnières, A. Borie, M.R. Bourillon, J. Boursier, S. Bressler, M. Bru, M. Chenet, Ph. Corteel, C. Coulange, C. Delmotte-Devocelle, B. Demure, M.T. Douguet, M. Dubost, Th. Drumare, D. Esteve, M. Fragny, O. Galamand, A.M. Giard, R. Gitel, C. Guilbert, H. Hafe, F. Kiesgen, E. Lamothe, C. Lanoiselée, M.L. Leblanc, N. Le Chevanton, I. Leprince, A. Marty, D. Miara, B. Millet, J. Oziel, A. Parini, M.C. Pasteau, M. Picard, M.M. Pupponi, C. Quinio, F. Raulet, M.L. Rocca, F. Szabason, P. Taine, C. Tarin, A. Touati-Lumbroso, and L. Troudet. We would also like to thank Isabelle d'Argentré for secretarial assistance and Dr M. Day for help with the English version.
Received January 10, 1995; accepted May 23, 1995.
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