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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:144-148.)
© 1996 American Heart Association, Inc.

Articles

Association Between Serum Fibrinogen Concentrations and HDL and LDL Subfraction Phenotypes in Healthy Men

Presented in part at the joint meeting of the 16th Congress of the European Society of Cardiology and the 12th World Congress of Cardiology, Berlin, Germany, September 10-14, 1994.

Martin Halle; Aloys Berg; Joseph Keul; Manfred W. Baumstark

From the Center for Internal Medicine, Department of Rehabilitation, Prevention and Sports Medicine, Freiburg University Hospital, Germany.

Correspondence to Dr Martin Halle, Medizinische Klinik, Abt. Rehabilitative und Präventive Sportmedizin, Hugstetter Strasse 55, D-79106 Freiburg, Germany. E-mail mh@msm1.ukl.uni-freiburg.de.

	Abstract

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Abstract Hyperfibrinogenemia and a dyslipoproteinemia characterized by reduced HDL₂ cholesterol and elevated levels of small, dense LDL particles are risk factors for coronary artery disease. However, the relationship between fibrinogen and lipoproteins, in particular LDL subfractions, is uncertain. We therefore measured serum fibrinogen levels and serum concentrations of cholesterol and apolipoproteins of VLDL, IDL, six LDL, and two HDL subfractions by using the technique of density-gradient ultracentrifugation in 132 nonsmoking men without evidence of coronary artery disease or infection. Dividing the individuals into quartiles according to their fibrinogen values showed that men within the highest fibrinogen quartile (fibrinogen 2.90 to 4.34 g/L) had significantly higher concentrations of small, dense LDL (d>1.044 g/mL) apolipoprotein B and cholesterol and lower concentrations of HDL₂ cholesterol than men within the lower fibrinogen quartiles (fibrinogen <2.55 g/L). Multivariate regression analysis revealed that the association between fibrinogen and small, dense LDL particles was independent of serum triglycerides, cholesterol, body mass index, and age. In contrast, the relationship between fibrinogen and HDL₂ cholesterol was primarily influenced by triglycerides and cholesterol and not independently influenced by fibrinogen. There were no significant differences between the quartiles in terms of insulin, glucose, insulin resistance, free fatty acids, lipoprotein(a), and blood pressure. This study showed that fibrinogen is associated with the expression of a more atherogenic LDL subfraction phenotype independent of body mass index, age, other serum lipids, and insulin resistance in a healthy male nonsmoking population. The reason for this association is uncertain. These findings reinforce the evidence that fibrinogen should be determined when assessing coronary risk.

Key Words: LDL subfractions • fibrinogen • coronary risk factors

	Introduction

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Low-density and high-density lipoproteins are a group of heterogeneous particles that differ in size, density, particle composition, and metabolic properties.^{1 2 3 4} Two main LDL phenotypes have been identified, one characterized by the predominance of large, buoyant LDL particles and the other by an excess of small, dense LDL particles. This latter profile is accompanied by elevated triglyceride levels and reduced HDL₂ CHOL and has been shown to be associated with premature CAD.^{5 6 7} Epidemiological studies indicate that elevated serum FIB levels are an important risk factor for CAD and coronary death, independent of other standard risk factors for ischemic heart disease.^{8 9 10 11 12 13} This has been explained by an increase in coagulability, platelet aggregability, blood viscosity, and fibrin deposition.¹⁴ However, FIB is also an acute-phase protein found to be elevated in states of acute and chronic infection or inflammation,¹⁵ such as arteriosclerosis, and in smokers.^{13 16 17}

To investigate whether FIB levels are associated with HDL and LDL subfraction phenotypes independent of signs of inflammation and smoking habits, we examined young, healthy nonsmoking men without evidence of acute infection or CAD and assessed their serum FIB concentrations and lipoprotein profiles. By measuring the CHOL and APO concentrations of VLDL, IDL, and subfractions of LDL and HDL and the concentrations of Lp(a), a detailed evaluation of the possible link between FIB and lipoproteins was possible.

	Methods

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Study Subjects
One hundred thirty-two healthy men were recruited for the study. The subjects were either volunteers from staff and students of the Freiburg University Medical School or were randomly selected from the outpatient clinic of the Department of Rehabilitation, Prevention and Sports Medicine, where they had presented for an elective cardiopulmonary assessment. All participants consumed a normal Western diet without daily or excessive intake of alcohol. Exclusion criteria were age >49 years; smoking; drug therapy of any kind; recent or current infection; chronic inflammatory disease; leukocyte count >9000 mm³; diabetes mellitus; a history of gastrointestinal, hepatic, or endocrine disease; symptoms of CAD; or an abnormal physical examination. In addition, no pathological findings were detected in a stepwise exercise stress test.

The study was approved by an institutional review committee, and all subjects gave informed consent for participation in the study.

Obesity Index and Ergometry
BMI (weight in kilograms divided by the square of the height in meters) was calculated for all participants in the study. A symptom-limited bicycle exercise stress test with a stepwise increment in workload of 50 W every 3 minutes was performed, with continuous ECG recording.

Density Gradient Ultracentrifugation
EDTA plasma was obtained after an overnight fast. VLDL (d<1.006 g/mL), IDL (d=1.006 to 1.019 g/mL), LDL (d=1.019 to 1.063 g/mL), and HDL (d=1.063 to 1.210 g/mL) were prepared by sequential flotation.^{4 18} Total LDL was separated into six and HDL into two density classes by equilibrium density-gradient centrifugation.⁴ The density ranges of LDL subfractions, as determined by precision refractometry¹⁸ of blank gradients, were LDL-1: 1.019 to 1.031 g/mL; LDL-2: 1.031 to 1.034 g/mL; LDL-3: 1.034 to 1.037 g/mL; LDL-4: 1.037 to 1.040 g/mL; LDL-5: 1.040 to 1.044 g/mL; LDL-6: 1.044 to 1.063 g/mL; HDL₂: 1.063 to 1.125 g/mL; and HDL₃: 1.125 to 1.210 g/mL. All centrifugation steps were performed at a temperature of 18°C using partially filled 6-mL polycarbonate bottles in a 50 Ti rotor (Beckman). The within-assay coefficient of variation for the determination of LDL subfraction concentrations was between 2.2% and 4.5% for CHOL and between 3.0% and 5.8% for APOB, depending on the subfraction.

Chemical Analysis
FIB was determined by end-point nephelometry to detect immune complexes of FIB and specific antibodies (Behring).

In all HDL and LDL subfractions, total CHOL was measured by automated (EPOS, Eppendorf) enzymatic methods (Boehringer Mannheim; bioMérieux). The APOA-I, APOB, and APOA-II were measured by end-point nephelometry (Behring).

Lp(a) was determined by a commercial ELISA with polyclonal anti-APO(a) antibodies (Immunozym Lp(a); Immuno GmbH).

Fasting INS concentrations were determined by an ELISA (Boehringer Mannheim), and FFA by an enzymatic colorimetric method (Wako Chemicals).

IR was calculated from fasting blood GLUC in mmol/L and serum INS concentrations by using a computer-solved homeostasis model assessment method^{19 20 21} : IR=fasting insulinxfasting glucose/22.5.

Statistical Analysis
An ANOVA was used to test the hypothesis that lipoprotein values were equal in all FIB quartiles. A conservative multiple comparison test (Scheffé's test) was chosen for pairwise comparisons of means between the FIB quartiles (Tables 1 through 3). All values for each FIB quartile are expressed as mean±SD if not otherwise indicated.

A univariate correlation analysis (Spearman's correlation) was performed between age, BMI, FIB, parameters of IR (GLUC, INS, and FFA), uric acid, BP, and lipoprotein subfractions (small, dense LDL [LDL-6] APOB and CHOL; HDL₂ CHOL and APOA-I). This analysis was followed by a stepwise multiple regression analysis, in which terms that were significantly associated with lipoprotein subfractions in the univariate correlation analysis were entered according to their level of significance, the APOs of LDL and HDL subfractions (LDL-6 APOB; HDL₂ APOA-I) being the dependent variable. For this procedure, all variables were logarithmically transformed to reduce the skew of the distribution.

Data were analyzed using the Statistical Package for the Social Sciences (SPSS/PC+, SPSS Inc). All values of P<.05 were considered to indicate statistical significance.

	Results

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The 132 men fulfilling all inclusion criteria were divided according to their serum FIB concentrations (mean, 2.6±0.51 g/L) into quartiles of 33 men each (Tables 1 through 3). Comparison of these FIB quartiles revealed that men within the highest FIB quartile (FIB 2.90 to 4.34 g/L) had significantly higher concentrations of serum CHOL, triglycerides, VLDL CHOL, and VLDL APOB than those within the two lowest FIB quartiles (FIB 1.78 to 2.54 g/L). No differences between FIB quartiles were observed with respect to IDL particles (Tables 1 and 2).

View this table: [in this window] [in a new window]   Table 1. Association Between Serum Fibrinogen and Lipoprotein Cholesterol Concentrations

View this table: [in this window] [in a new window]   Table 2. Association Between Serum Fibrinogen (g/L) and Apolipoprotein Concentrations (mg/dL)

Concentrations of CHOL and APOs of total LDL and total HDL did not vary between FIB quartiles (Tables 1 and 2). However, when dividing LDL and HDL into subfractions, it became evident that the FIB groups differed significantly in their CHOL and APO subfraction profiles. In particular, men with FIB >2.90 g/L had twofold higher concentrations of small, dense LDL particles (LDL-6 APOB) than men with FIB levels <2.55 g/L. They also had the lowest concentrations of HDL₂ CHOL and HDL₂ APOA-I (Tables 1 and 2).

In addition to the lipoprotein subfraction analysis, we determined other coronary risk factors such as age, BMI, GLUC, INS, FFA, IR, uric acid, Lp(a), and BP. Other than significant differences in age and body weight, no significant differences between FIB quartiles were found for all other parameters in this healthy population of nonsmoking men (Table 3).

View this table: [in this window] [in a new window]   Table 3. Association Between Fibrinogen Concentrations and Coronary Risk Factors

To investigate whether other risk factors were also predictors for a more atherogenic lipoprotein subfraction profile, namely an increased number of small, dense LDL particles (LDL-6 APOB) and reduced concentrations of HDL₂ CHOL, we performed a univariate correlation analysis between coronary risk factors and small, dense LDL APOB and HDL₂ CHOL particles. Serum triglycerides were the strongest predictor of small, dense LDL particles followed by CHOL, BMI, FIB, and age (Table 4). HDL₂ CHOL was also primarily determined by serum triglycerides (r=-.41; P<.001), BMI (r=-.34; P<.001), and FIB (r=-.12; P<.05), whereas age and CHOL had no effect. In this sample of healthy young nonsmoking men, the factors relating to IR (GLUC, INS, and FFA), as well as BP, were not associated with HDL and LDL subfraction distribution. In a multivariate stepwise regression analysis, only serum triglycerides on the first step (r=-.41, R²=.17, P<.001) and BMI (r=-.44, R²=.20, P<.05) on the second step independently influenced HDL₂ CHOL. FIB was not included in the multivariate regression equation. For the concentration of APOB in small, dense LDL, which corresponds with the number of circulating small, dense LDL particles, FIB was a significant and independent predictor (Table 4).

View this table: [in this window] [in a new window]   Table 4. Univariate Correlation and Multiple Regression Analysis

	Discussion

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Elevated levels of LDL CHOL and APOB and decreased levels of HDL CHOL and APOA-I are associated with an increased risk of CAD.^{22 23 24} Recently, the atherogenic lipoprotein profile has been better characterized, particularly the association between distinct LDL subfraction phenotypes and CAD.^{6 7 25} A pattern consisting of an increased concentration of small, dense LDL particles, an elevation of triglycerides, and a reduction in HDL₂ CHOL has been shown to increase the risk of ischemic cardiac events.^{5 6 26 27 28} Other risk factors for CAD, such as obesity, peripheral IR, and low physical activity, have been shown to be associated with a pattern of increased small, dense LDL particles and reduced HDL₂ CHOL,^{19 29 30} but the association between FIB and HDL and LDL subfractions is still uncertain. It is known, however, that elevated concentrations of FIB are found in a dyslipoproteinemia observed in diabetic, hypertensive, and obese patients.^{8 13 31 32} In particular, FIB correlates with elevated serum triglycerides, increased VLDL CHOL, and reduced HDL CHOL.³³ Additionally, FIB concentrations increase with age.^{13 16 34} In our study, we could show that elevated FIB concentrations of >2.90 g/L are associated with increased levels of circulating small, dense LDL particles and reduced HDL₂ CHOL (Tables 1 and 2). The association with small, dense LDL particles was even independent of other risk factors associated with hyperfibrinogenemia, such as BMI, age, IR, and serum lipid concentrations (Table 4). The relationship with HDL₂ CHOL was, however, primarily determined by serum triglycerides and BMI.

The reason for the independent association between FIB and concentrations of small, dense LDL particles is unclear. However, evidence for a direct metabolic link between serum lipids and FIB concentrations was reported almost 30 years ago. Animal and in vitro studies by Pilgeram and Pickart³⁵ demonstrated that plasma FFA exert significant control over the biosynthesis of FIB. They showed that the rate of synthesis of FIB by the liver is augmented by GLUC and FFA, particularly by palmitate. Thereby, they provided initial data connecting the metabolism of fatty acids, lipoproteins, and FIB. In our study population, FFA and GLUC levels were always within normal limits and did not differ significantly between FIB quartiles. Serum triglycerides and concentrations of triglyceride-rich lipoprotein particles (VLDL) were, however, higher in men with FIB >2.90 g/L than in men with FIB <2.55 g/L. Since elevated small, dense LDL particles are primarily found in hypertriglyceridemia,³⁶ and hypertriglyceridemia is in turn associated with hyperfibrinogenemia, it may be postulated that similar mechanisms lead to an elevated hepatic synthesis or secretion of VLDL and FIB. In the circulation, VLDL is then converted to small, dense LDL particles, thus explaining our observation that small, dense LDL particles are increased in hyperfibrinogenemia.

A few investigators have also hypothesized that LDL particles are synthesized and secreted directly by the liver.^{37 38} In hyperfibrinogenemia, metabolic states associated with elevated concentrations of FFA and triglycerides may stimulate the synthesis of both FIB and APOs simultaneously. Further research is necessary to resolve this matter.

Besides its effect on the progression of arteriosclerosis and acute cardiovascular events, FIB is also an acute-phase protein that is found in elevated concentrations in patients with inflammatory disease. Arteriosclerosis is itself an inflammatory process, and parameters of inflammation, such as a raised white blood cell count and ferritin concentrations, have also been observed to be elevated in patients with coronary artery disease and acute myocardial infarction.^{12 39} Other inflammatory mediators, such as interleukins, have been shown to influence the hepatic metabolism of lipoproteins and FIB in vitro.^{40 41} Via this mechanism, acute or chronic inflammation could influence FIB and serum lipoprotein concentrations. To exclude the effect of an acute or chronic infection or inflammation on the concentrations of FIB and lipoproteins in our study, we included only men without history of acute infection or chronic inflammatory disease or signs of acute infection (normal white blood cell count). Because smoking has also been shown to increase FIB levels,^{8 13} we also excluded smokers from the study. Therefore, the distinct association between concentrations of FIB and lipoprotein subfractions found in our study is not owing to underlying inflammatory processes or smoking.

Our study has shown that nonsmoking, clinically healthy men with serum FIB concentrations >2.90 g/L have a significantly unfavorable LDL subfraction profile that is independent of other coronary risk factors, such as BMI, age, IR, total CHOL, serum triglycerides, uric acid, and BP. This is in accordance with epidemiological studies showing that men with FIB levels >3.11 g/L have a significantly higher risk for CAD than subjects with lower levels.¹³ It may be proposed that in addition to its effect on coagulation, FIB influences atherogenesis by worsening the LDL subfraction profile. Because FIB is independently associated with the expression of a more atherogenic lipoprotein subfraction profile, it should be included in the assessment of coronary risk factors, particularly in patients with dyslipoproteinemia.

	Selected Abbreviations and Acronyms

 

APO = apolipoprotein BMI = body mass index BP = blood pressure CAD = coronary artery disease CHOL = cholesterol FFA = free fatty acids FIB = fibrinogen GLUC = glucose INS = insulin IR = insulin resistance Lp(a) = lipoprotein(a)

	Acknowledgments

 
Dr Halle is a scholar of the German Heart Foundation, Frankfurt/Main, Germany. The assistance of S. Jotterand and H. Zurmöhle in preparation and measurement of lipoproteins is greatly appreciated. We also wish to thank B. Spielberger and G. Zöllner for their technical help in completing the study and D. Grathwohl for his statistical advice.

Received August 11, 1995; accepted October 16, 1995.

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