© 1997 American Heart Association, Inc.
Articles |
Fibrinogen and Its Relations to Subclinical Extracoronary and Coronary Atherosclerosis in Hypercholesterolemic Men
the Centre de Medecine Preventive Cardiovasculaire, CRI (INSERM), Hopital Broussais, Paris, France.
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Abstract |
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The association between plasma fibrinogen and the presence of carotid, femoral, and aortic plaque (high-resolution B-mode ultrasonography) and coronary calcium deposit (ultrafast computed tomography scanner) was determined in 693 hypercholesterolemic, never-treated men free of previous or current clinical symptoms of cardiovascular disease. The number of subjects with extracoronary disease sites and coronary calcification deposits was significantly higher in the upper than in the lower tertile of fibrinogen. Plasma fibrinogen increased according to the number of diseased sites. The odds ratio of the upper to lower fibrinogen tertile for the presence of arterial lesions was 2.6 (1.7 to 4) for carotid, 2.2 (1.5 to 3.2) for aorta, 2.2 (1.5 to 3.1) for femoral, 1.8 (1.3 to 2.6) for coronary, and 3.6 (2.3 to 6.1) for one of four diseased sites. Adjustment for age, total cholesterol, HDL cholesterol, triglycerides, current smoking, and systolic pressure slightly reduced the association between fibrinogen and atherosclerosis. A synergistic effect between fibrinogen and total cholesterol/HDL cholesterol (TC/HDL) ratio seemed to be operating on atherosclerosis, because nearly all of the individuals (98%) had a diseased site when fibrinogen and TC/HDL tertiles were the highest. This result suggests that fibrinogen is involved in the subclinical phase of extracoronary and coronary atherosclerosis and may potentiate the atherogenic effect of hyperlipidemia.
Key Words: fibrinogen • B-mode ultrasonography • ultrafast computed tomography • extracoronary atherosclerosis • coronary atherosclerosis
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Introduction |
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Atherosclerosis is considered to be primarily a disorder of lipid and lipoprotein metabolism. Even in hypercholesterolemia, however, lipid levels should not be the sole risk factor to take into account in the development of atherosclerotic plaque, since extralipid risk factors may contribute to the localization and to the extension of atherosclerotic lesions on the arterial tree.1 Among these factors, the role of age, blood pressure, blood glucose, and smoking or a combination thereof should be mentioned. Plasma fibrinogen, which is frequently associated with hyperlipidemia, is another powerful risk factor for cardiovascular disease. Evidence has accumulated from several prospective studies that high plasma fibrinogen concentrations were associated with elevated risk of coronary, cerebral, and peripheral vascular disease.2 3 4 5 6 7 8 9 The relation between raised fibrinogen and myocardial infarction and stroke was at least as significant as for cholesterol.2 5 10
Although the thrombogenic potential of fibrinogen for cardiovascular events has been extensively investigated, relatively few studies have related the atherogenic association of fibrinogen to the clinical silent phase of atherosclerosis. Some of these studies used carotid intimal-medial wall thickness as a measure of subclinical atherosclerosis and a surrogate variable for coronary atherosclerosis.11 12 13 14 Other localizations most frequently involved in atherosclerosis, such as the abdominal aorta and the femoral arteries, which can be assessed by high-resolution B-mode ultrasonography, were less often reported.15 16
Ultrafast computed tomography was proposed recently for noninvasive quantification of coronary calcifications,17 18 19 20 21 and the use of this method to detect early coronary atherosclerosis was validated by angiographic and necropsy studies.21 22 23 24 We previously described associations of arterial1 25 26 27 and coronary lesions20 with other traditional risk factors and associations of arterial lesions with coronary calcifications.20
The purpose of this study was to examine plasma fibrinogen concentrations in hypercholesterolemic subjects free of previous or current clinical symptoms of cardiovascular disease to investigate the possible relation between fibrinogen and the presence of subclinical extracoronary and/or coronary atherosclerosis.
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Methods |
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Study Subjects
The 693 hypercholesterolemic men included in the study were selected from an ongoing cholesterol screening program in occupational medicine conducted in the Paris area.1 16 20 All the subjects had total cholesterol >5.2 mmol/L and had never been treated with lipid-lowering drugs. In each case, the presence of any history or symptom of cardiovascular disease, checked by complete clinical examination and careful questioning, resulted in exclusion from the study.
None of the subjects had ever undergone coronary investigations. Nonlipid risk factor evaluation was made as follows: brachial systemic blood pressure was determined as the mean of at least three consecutive measurements by the standard sphygmomanometric procedure after at least 10 minutes in the supine position. Hypertension was defined by a systolic blood pressure of 
160 mm Hg and/or a diastolic blood pressure of 95 mm Hg (Korotkoff phase V).28 No subject had ever had any antihypertensive treatment. Patients with diabetes (fasting glucose >7.7 mmol/L) were excluded from the study. Body mass index (weight divided by height squared) was used to evaluate overweight. Lifelong smoking dose (pack-years) was assessed by questioning the subject. Smoking status was also categorized in subjects as current and former smokers and those who had never smoked. Current smokers were defined as having regularly smoked each day for the previous 3 months regardless of the amount smoked and former smokers as not having smoked for the preceding 3 months.
Blood Measurements
Venous blood was collected after the subject had fasted for 14 hours. Total blood cholesterol, HDL cholesterol (after precipitation of LDL and VLDL by phosphotungstic acid magnesium chloride), and plasma triglyceride levels were measured by the classic enzymatic method on venous blood samples withdrawn in the supine position after 10 minutes of rest.1
Citrated platelet-poor plasma was used to measure plasma fibrinogen according to the thrombin time method described by Clauss.29
Detection of Extracoronary Plaques and Coronary Artery Calcifications
Arterial investigations were performed with real-time B-mode ultrasonography (Ultramark 4, Advanced Technology Laboratories) with a 3-MHz probe for the abdominal aorta and a 7.5-MHz probe for the extracranial carotid and femoral arteries according to a careful procedure previously described in detail.1 20 At each of the three sites, data were classified into two categories: absence of any atherosclerotic plaque and presence of one or more arterial plaques, regardless of the precise location and number.
Coronary calcifications were detected as previously described by the use of an ultrafast computed tomography scanner (Imatron) with a 100-ms scan time, a 3-mm slice thickness, and electrocardiogram triggering. The threshold for a calcific lesion was set at a computed tomographic density of 130 Hounsfield units18 30 with an area of 1 mm2.18 The maximal computed tomographic density of each lesion was transformed into four classes in the following manner: 1, 130 to 199; 2, 200 to 299; 3, 300 to 399; and 4, 400 Hounsfield units.18 The total calcium score was defined as the sum of the lesion scores, calculated by multiplying the density number by the area of the lesions.18 The extent of atherosclerosis at different sites was defined by five classes: zero sites, one site, two sites, three sites, or four sites. A diseased site is an arterial site (carotid, aortic, femoral, or coronary) at which at least one arterial lesion was found, regardless of its precise location.
Statistical Analysis
Values are expressed as mean±SD. Comparisons of risk factors between groups defined by tertile of fibrinogen were made by ANOVA, and comparisons between first and third tertiles were made by the Tukey-Kramer test for continuous variables. Because the distributions of fibrinogen and triglyceride values were skewed, a logarithm transformation was applied for comparisons. For qualitative variables, a 
2 test was performed to compare proportions between first and third tertiles of fibrinogen. The presence of plaque at each site was characterized as a dichotomous variable (absence or presence), and the extent of plaque at the different sites investigated was defined by four classes: one, two, three, and four diseased sites. When fibrinogen levels of each group were compared with that of zero diseased sites, Dunnett's method was applied. To assess the strength of the association of arterial disease with the level of fibrinogen, for each arterial site and the extent of the disease, odds ratios with 95% CI were calculated by logistic analysis comparing low and high tertiles of fibrinogen and adjusting successively for the risk factors differing between the tertiles and for other atherosclerotic risk factors on which we obtained data. The statistical analysis was carried out on a computer (Apple Macintosh) with the use of JMP (SAS Institute) and Excel (Microsoft France) software.
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Results |
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Table 1
shows mean±SD of variables of the study population grouped under low, middle, and high tertiles of fibrinogen. Age, current smoking, lifelong smoking dose, and total cholesterol/HDL cholesterol ratio were higher for subjects in the upper than in the lower tertile of fibrinogen, whereas never smoking and HDL cholesterol were significantly lower.
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The number of subjects with extracoronary disease sites and coronary calcification deposit was significantly higher in the upper than in the lower tertile of fibrinogen (Table 2). Five hundred forty-six subjects (79% of the population) had atherosclerotic lesions in at least one of the four diseased sites. The prevalence for a carotid site was 25% (174 subjects); for an aortic site, 34% (239 subjects); for a femoral site, 51% (353 subjects); and for a coronary site, 57% (395 subjects).
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Fig 1 compares the values of fibrinogen according to the number of diseased sites. As the number of the diseased sites increased, plasma fibrinogen concentration increased significantly and was higher in the group with four (P<.001), three (P<.001), two (P<.01), and one (P<.05) than in the group with zero diseased sites.
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Table 3 shows the odds ratios for atherosclerosis at different arterial locations in subjects with fibrinogen levels in the upper tertile compared with the lower tertile. The unadjusted odds ratio for the carotid was 2.6 (95% CI, 1.7 to 4); for aorta, 2.2 (1.5 to 3.2); for femoral, 2.2 (1.5 to 3.1); for the coronary, 1.8 (1.3 to 2.6); and for one of the four diseased sites, 3.6 (2.3 to 6.1). Adjustment for age, current smoking, total cholesterol, HDL cholesterol, triglycerides, and systolic blood pressure slightly reduced the magnitude of the association between fibrinogen and atherosclerosis of the carotid, aortic, femoral, and one of the four diseased sites without changing the direction of the association.
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In a three-dimensional analysis, Fig 2 shows the number of subjects with atherosclerosis associated with increasing fibrinogen and total cholesterol/HDL cholesterol ratio separated into tertiles. Within the lowest and middle fibrinogen tertiles, there was no difference in percentage of diseased sites between those in the highest and lowest total cholesterol/HDL cholesterol ratio tertiles. By contrast, for fibrinogen the percentage of subjects with disease sites increased by 12% and 20% between the lowest and middle total cholesterol/HDL cholesterol tertiles, respectively. However, of the 87 patients in the top tertile for both variables, 85 had a diseased site, suggesting a synergistic effect.
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Discussion |
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In this study, hypercholesterolemic subjects never treated and free of any symptom of cardiovascular disease who were found to have extracoronary and coronary atherosclerosis had higher plasma fibrinogen concentration than did similar subjects without arterial lesions. The value of fibrinogen increases according to the number of diseased sites and suggests that such an increase may be a marker of the extent of arterial disease. Our results are consistent with the literature on fibrinogen as a risk factor for coronary, cerebral, and peripheral vascular disease2 3 4 5 6 7 8 9 and as a marker in the silent phase of extracoronary atherosclerosis,11 12 13 14 15 16 but they are the first to relate the high value of fibrinogen with coronary and extracoronary atherosclerosis in a selected population of hypercholesterolemic individuals. This result was also supported by the association of fibrinogen with a significantly higher number of subjects with carotid, aortic, femoral, and coronary arterial lesions when the upper tertile was compared with the lower tertile values of the fibrinogen distribution. The association between high fibrinogen and atherosclerosis observed in the present study is in accordance with previous cross-sectional studies that used carotid intimal-medial wall thickness or plaque status as a measure of atherosclerosis in general12 13 or in high-risk populations.14 16
Plasma fibrinogen had an unadjusted association with carotid, aortic, and femoral arterial lesions, and these associations were slightly attenuated by the adjustment for age, cigarette smoking, total cholesterol, triglycerides, HDL cholesterol, and systolic blood pressure, with no change in the direction of the association. These findings suggest that the association between plasma fibrinogen and atherosclerosis cannot be attributed to confounding by common cardiovascular risk factors and favors the hypothesis that arterial lesions are partially a direct consequence of increased fibrinogen, which in turn is related to similar risk factors. Several investigators detected the presence of fibrinogen, fibrin, and LDL cholesterol in atherosclerotic plaques, suggesting that a common mechanism may exist for fibrinogen and lipoprotein entry into the vessel wall.31 32 33 Other studies have found different molecular forms of fibrinogen in atherosclerotic plaques34 35 and a correlation between the levels of total fibrin(ogen)-related antigen and LDLs in the atherosclerotic plaques.36 The potential involvement of fibrinogen in the pathogenesis of atherosclerosis is supported by the demonstration that fibrin(ogen) induces endothelial cell disorganization and migration,37 38 stimulates smooth muscle proliferation,39 and enhances the release of endothelial cell–derived growth factors.40
To the best of our knowledge, there are no previous studies concerning the relation of plasma fibrinogen and subclinical coronary disease. The clinical value of this association is supported by the observation that atherosclerotic vessels, even with minimal obstruction, are a site of predilection for thrombosis.41 Several studies in patients with coronary artery disease showed that fibrinogen increased progressively with the extent of coronary atherosclerosis.42 43 44 A recent clinical study reported that plasma levels of fibrinogen may help to predict restenosis after coronary angioplasty and suggests that it can be a common risk factor for both spontaneous coronary atherosclerosis and postangioplasty restenosis, which is an accelerated form of atherosclerosis.45 The presence of asymptomatic coronary disease in subjects with a simultaneous increase of cholesterol and fibrinogen could greatly enhance the risk of complication when they operate together. In the present study, we detected coronary calcification noninvasively with ultrafast computed tomography according to a procedure previously used.20 Coronary artery calcification is both a sensitive and specific marker for the presence of coronary atherosclerosis.18 19 20 21 22 23 24 We reported that coronary artery calcifications determined by ultrafast CT are closely related to the presence and extent of extracoronary atherosclerosis in individuals with hypercholesterolemia and no symptoms.20 More recently, we demonstrated that total coronary calcification deposit may predict the risk of coronary events on the basis of traditional risk factors.46 The relatively high prevalence (57%) of coronary calcification in our population agrees with our previous observations.20 The association of plasma fibrinogen and coronary calcification was lower than that observed with extracoronary arteries. In addition, this association was weakened by smoking status, as shown by the lower odds ratio between the higher and lower tertiles of fibrinogen after cigarette smoking adjustment. The association between fibrinogen and coronary calcification deposit may be weaker because arterial calcification is a less subtle marker of atherosclerosis than arterial plaque as detected by B-mode ultrasonography in peripheral arteries. Indeed, atherosclerotic plaque in coronary vessels as well as in extracoronary vessels is not invariably associated with calcium.47 48 Therefore, subjects without coronary calcification may be carriers of early, noncalcified atherosclerotic coronary lesions. An alternative explanation is that fibrinogen is more closely related to extracoronary artery events. According to epidemiological studies, stroke is more closely related to fibrinogen level than myocardial infarction.2 49
A final interesting feature of our results is the possibility of individualizing hypercholesterolemic subjects with asymptomatic arterial plaque from the simultaneous measurements of total cholesterol, HDL cholesterol, and fibrinogen. It was found in two general populations as well as in a population of high-risk men that the total cholesterol/HDL ratio was superior to either the total cholesterol or the LDL cholesterol level for identifying people at greater risk for developing subsequent coronary heart disease events.50 In the present study, we tested the use of the total cholesterol/HDL ratio and fibrinogen as combined potential markers for the presence of atherosclerosis. We found that the presence of subclinical artery disease is increased more than additively when both total cholesterol/HDL ratio and fibrinogen are high. Indeed, nearly all of the subjects with values of total cholesterol/HDL ratio >5.98 and values of fibrinogen >3.36 g/L presented a diseased arterial site. It is surprising that atherosclerosis does not increase at increasing tertiles of total cholesterol/HDL cholesterol ratio except in subjects in the upper fibrinogen tertile. Similarly, low fibrinogen concentrations in patients with angina pectoris characterize subjects at low risk for coronary events despite increased serum cholesterol levels.51 Mechanisms involved in the synergistic effect of fibrinogen and total cholesterol/HDL cholesterol are not known. The lower values of HDL cholesterol observed in subjects with the upper tertile of fibrinogen may account for the higher prevalence of atherosclerosis. Several studies have observed a negative correlation between fibrinogen and HDL cholesterol52 53 54 55 (r=-.16, P<.0001 in the present study). Erythrocyte aggregation induced by fibrinogen may be modified by increased HDL subfractions in hypercholesterolemic subjects.52 56 In addition to the protective effect of HDL cholesterol related to reverse cholesterol transport, a recent study reported that physiological concentrations of HDL cholesterol are able to inhibit the cytokine activation of adhesion molecules participating in the inflammatory initiation and progression of atherosclerosis.57 In view of their central importance for atherogenesis, further studies on the interrelationships between lipoproteins and fibrinogen in hypercholesterolemic subjects are therefore indicated.
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Acknowledgments |
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We thank the Banque Nationale de Paris, l'Oreal SA, Matra SA, Procter & Gamble France, and the Automobiles Peugeot for sponsoring the Groupe de Prevention Cardio-Vasculaire en Medecine du Travail (PCV METRA). We thank the PCV METRA Group, including the following persons: P. Segond (Chairman), D. Badet, C. Baylac-Lebot, P. Bonneau, A. de Bonnieres, A. Borie, M.F. Bourillon, J. Boursier, S. Bressler, M. Brun, N.P. Chau, M. Chenet,
S. Consoli, P. Corteel, C. Coulange, L. Darbon, C. Delmotte-Devocelle, B. Demure, T. Desse, M.T. Douguet, T. Drumare, M. Dubost, D. Esteve, M. Fragny, O. Galamand, A.M. Giard, R. Gitel, C. Guilbert, H. Hage, F. Kiesgen, E. Lamothe, C. Lanoiselee, G. Latscha, D. Laurier, M.L. Leblanc, N. Le Chevanton, I. Leprince, A. Marty, D. Miara, B. Millet, J. Oziel, A. Parini, M.C. Pasteau, M. Picard, M.C. Plainfosse, M.M. Pupponi, C. Quinio, F. Raulet, M.L. Rocca, F. Szabason, P. Taine, M.C. Tardieu, C. Tarin, A. Touati-Lumbroso, and L. Troudet (deceased). We thank Isabelle d'Argentre for her excellent secretarial assistance and for her invaluable assistance in ultrafast computed tomographic data entry. |
Footnotes |
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Reprint requests to Docteur Jaime Levenson, Centre de Medecine Preventive Cardiovasculaire, Hopital Broussais, 96 rue Didot, 75674 Paris Cedex 14, France. E-mail levenso@world-net.sec.fr.
Received November 7, 1995;
revision received May 8, 1996;
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