© 1997 American Heart Association, Inc.
Articles |
Association of the Fatty Acid Composition of Serum Phospholipids With Hemostatic Factors
From the Department of Epidemiology and Health Promotion (V.V.S) and Department of Nutrition (I.S., A.A.), National Public Health Institute, and the Finnish Red Cross Blood Transfusion Service (V.R., E.V., G.M.), Helsinki, Finland.
Correspondence to Dr Veikko Salomaa, National Public Health Institute, Department of Epidemiology and Health Promotion, Mannerheimintie 166, FIN-00300 Helsinki, Finland.
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Abstract |
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Abstract It has been suggested that the fatty acid composition of serum phospholipids is an independent risk factor for cardiovascular disease. We examined the association of the fatty acid composition of serum phospholipids with fibrinogen, factor VII antigen (FVII:Ag), factor VII coagulant activity (FVII:C), plasminogen, and lipoprotein(a) [Lp(a)] in 338 men and 363 women 45 to 64 years old. Palmitic acid, the most abundant saturated fatty acid, was positively associated in univariate analyses with plasminogen, which explained 5.2% of its variance among men (P<.0001) and 5.8% among women (P<.0001). Linoleic acid, which is the most abundant polyunsaturated fatty acid, was negatively associated with plasminogen and fibrinogen. This explained 1.1% of the variance in fibrinogen among men (P=.04) and 3.2% among women (P=.0006) and 4.1% of the variance in plasminogen in both sexes (P<.0001). Dihomogammalinolenic acid was positively associated with FVII:Ag and explained 3.7% of its variance among men (P=.0003) and 4.6% among women (P<.0001). Furthermore, dihomogammalinolenic acid was positively and significantly associated with FVII:C, fibrinogen, and plasminogen among women but not among men. All these associations remained significant after adjustment for multiple potential confounding factors such as age, smoking, serum lipids, and body mass index. In conclusion, our findings suggest that linoleic acid, palmitic acid, and dihomogammalinoleic acid are significant independent determinants of hemostatic profile. It is not clear, however, to what extent these results reflect the effects of fatty acids on coagulation and to what extent they reflect the activity of inflammatory processes in the arteries.
Key Words: hemostasis • blood coagulation • coronary heart disease • fatty acids
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Introduction |
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Both prospective1 and cross-sectional2 3 studies have suggested that the fatty acid composition of serum phospholipids or cholesterol esters is an independent risk factor for CHD. The increased risk may be mediated by the effects of fatty acids on blood coagulation or fibrinolysis, but the mechanisms are insufficiently understood. Most of the research in this field has been based on small trials using carefully controlled special diets and focusing mainly on the effects of individual fatty acids on FVII, and the population-based data are scanty.4 5 6 7 8
A recent, population-based study by Folsom and coworkers8 found that FVII:C was positively associated with the percentage of fatty acids that was saturated and negatively with the linoleic acid percentage. In a controlled trial on the effects of two low-fat diets with different ratios of polyunsaturated to saturated fatty acids, Marckmann and coworkers9 found a significant decrease of FVII:C on both diets. A postprandial increase in FVII:C was independent of the dietary fat composition during the period of 7 days10 as well as after a single fatty meal.11 However, Mitropoulos and coworkers5 reported that dietary fat increases FVII:C through effects on plasma free stearic acid concentration, but Tholstrup and coworkers6 observed that fat high in stearic acid alters FVII:C favorably in comparison with fats high in palmitic or high in myristic and lauric acids. It has been suggested that the change in FVII:C is part of a general change in concentrations of vitamin K–dependent proteins,7 but the effects of fatty acids on other components of the coagulation cascade than FVII are not very well characterized.
Because the effects of fatty acid composition on CHD risk are independent of serum lipids,1 it is plausible that they are mediated in part by the effects of fatty acids on hemostasis. We therefore examined the associations of the fatty acid composition of serum phospholipids with fibrinogen, FVII:Ag, FVII:C, plasminogen, and Lp(a) in a large random sample of a Finnish population.
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Methods |
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Participants
The subjects consisted of 338 men and 363 women 45 to 64 years old. They were a subsample of participants of the FINRISK Hemostasis Study, which has been described in detail elsewhere.12 13 In brief, a random sample of 3000 individuals was drawn from the population registers of three geographic areas in Finland. Altogether, 79.6% of the invited persons participated. Of these, persons born on days 1 through 11 of each month took part in a simultaneous nutritional survey, and the fatty acid composition of their serum phospholipids was determined. As described previously,12 a small number of samples were deemed unsuitable for analyses in the hemostasis laboratory or did not produce consistent results in duplicate analyses. Therefore, the final numbers of samples varied between 326 and 333 among men and between 348 and 357 among women, depending on hemostatic parameter.
The participants were examined between 11 AM and 6 PM. They were advised to fast totally for at least 4 hours before the examination and to avoid fatty meals earlier during the day; a low-fat breakfast was allowed, however. The time of blood sampling, the duration of the fast, and the nature of the preceding meal were recorded. The effect of these factors on the levels of hemostatic factors was assessed and found to be negligible, indicating good compliance with the instructions.
Blood Collection
Blood samples were drawn with minimum stasis and a 20-gauge needle into citrate vacuum tubes from an antecubital vein with the participant in a sitting position. The second and third tubes were used for the coagulation assays. The tubes were centrifuged at room temperature at 1400g for 30 minutes. Plasma was then collected with a plastic Pasteur pipette and divided into 0.5-mL aliquots for freezing and storage. The plasma samples were snap-frozen within 2 hours of venipuncture in a mixture of dry ice and alcohol. They were stored at -70°C until analyzed (within 8 months of sampling).
Laboratory Methods
Determination of hemostatic factors was carried out in the Department of Hemostasis of the Finnish Red Cross Blood Transfusion Service, Helsinki. Fibrinogen was measured with an ACL 300 R coagulometer (Instrumentation Laboratory) from the light scattered by the clot during the prothrombin time assay (PT-Fibrinogen, Instrumentation Laboratory).14 The intra-assay precision was 3.6% and interassay precision, 2.3%. The samples were measured in duplicate and had to lie within 10%, or the analysis was repeated using a split sample.
FVII:C was measured with the one-stage method15 using rabbit brain thromboplastin (Thromboplastin-IS, Baxter Dade) and human immunodepleted FVII-deficient plasma (Behring). The assays were carried out with an ACL 300 R coagulometer. A lyophilized plasma pool was used as a standard. It was calibrated with a frozen plasma pool from 44 normal donors and taken as 100%. The intra-assay precision was 2.4% and the interassay precision, 3.9%. FVII:Ag was measured with an ELISA technique using an Asserachrom FVII:Ag kit (Diagnostica Stago) according to the manufacturer. A frozen plasma pool, as for FVII:C, was used as a standard and taken as 100%. The intra-assay precision was 5.0% and the interassay precision, 10.9%. The samples were determined in duplicate and had to remain within 16%, or the analysis was repeated using a split sample.
Plasminogen was measured with a Coamate Plasminogen kit (Chromogenix AB) according to the manufacturer's instructions. This method was found to be independent of the fibrinogen concentration of the sample at the usual fibrinogen levels. The intra-assay precision was 3.2% and the interassay precision, 2.9%.
The fatty acid methyl ester composition of serum phospholipids was determined with gas chromatography after a thin-layer chromatography separation of phospholipids from serum fat extract16 and interesterification to methyl esters.17 The gas chromatograph was equipped with a 25-m-long silica column, ID 0.32 mm, phase layer 0.20 µm (NB 351, HNU-Nordion), and a split injection system. Helium was used as a carrier gas. The interassay precision varied from 2% to 10%, depending on the peak size.
Serum lipids and Lp(a) were determined in the Department of Biochemistry, National Public Health Institute, Helsinki. Lp(a) was determined with an immunoradiometric assay (IRMA; Pharmacia Diagnostics) as described.18 Total cholesterol and triglycerides were determined with enzymatic assays (Boehringer Mannheim, GmbH Diagnostics). HDL cholesterol was determined after precipitation of apo B–containing lipoproteins with dextran sulfate and MgCl2.
Statistical Methods
Univariate associations between the proportions of fatty acids and coagulation factors were examined with Pearson correlation coefficients and linear regression. Multivariate associations were examined by ANCOVA and tests of linear trend using the general linear-models procedure of SAS.19 Age, study area, total cholesterol, current smoking, HDL cholesterol, triglycerides, and body mass index were used as covariates. Because of skewed distribution, Lp(a) was logarithmically transformed (natural logarithm) for the analyses. In tables, however, it is presented as back-transformed to the geometric mean.
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Results |
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The characteristics of the study population are given in Table 1
. The mean age was 55 years and the mean total cholesterol, 6.0 mmol/L for both male and female participants. A quarter of the men and 14% of the women were current smokers.
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Palmitic acid (16:0) and linoleic acid (18:2 n-3) were the most abundant fatty acids. Palmitic acid composed 30.0±1.8% (mean±SD) of all fatty acids in men and 29.7±1.6% in women. Linoleic acid composed 21.0±3.2% in men and 21.2±3.2% in women. The proportion of stearic acid (18:0) was 14.9±1.1% in men and 14.8±1.2% in women, and the proportion of oleic acid (18:1 n-9), 11.6±2.1% in men and 12.0±2.4% in women. Dihomogammalinoleic acid (20:3 n-6) contributed 2.7±0.7% both in men and in women.
Palmitic acid explained 5.2% of the variance in plasminogen among men (P<.0001) and 5.8% among women (P<.0001). Linoleic acid explained 4.1% of the variance in plasminogen in both sexes (P<.0001). It also explained 1.1% of the variance in fibrinogen among men (P=.04) and 3.2% among women (P=.0006). Dihomogammalinoleic acid (20:3 n-6) explained 3.7% of the variance in FVII:Ag in men (P=.0003) and 4.6% in women (P<.0001). In addition, in women, dihomogammalinoleic acid explained 5.6% (P<.0001), 4.8% (P<.0001), and 2.4% (P=.003) of the variances in FVII:C, fibrinogen, and plasminogen, respectively. None of the fatty acids were correlated with FVII:C among men, and no correlations were observed between fatty acids and Lp(a) in either sex.
For multivariate analyses, we divided the fatty acids into quartiles and computed the adjusted means of hemostatic factors for each quartile. These were then tested for linear trend as well as for heterogeneity between the groups. The findings observed in univariate analyses remained significant after multivariate adjustment for age, study area, total cholesterol, current smoking, HDL cholesterol, triglycerides, and body mass index (Table 2). Interestingly, there was now in both sexes a clear declining trend in fibrinogen with increasing category of linoleic acid. The differences in adjusted fibrinogen between the lowest and the highest quartiles of linoleic acid were 0.27 g/L in men and 0.22 g/L in women. Somewhat surprisingly, n-3 fatty acids in serum phospholipids showed very little association with the hemostatic factors measured. Only among women was a moderately strong declining trend observed in FVII:C with increasing category of docosahexaenoic acid (22:6 n-3).
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by Quartile of Fatty Acids in Serum PhospholipidsWhen both sexes were included in the same model, there was a significant sex-by–dihomogammalinoleic acid interaction on fibrinogen (P=.0006, ANCOVA adjusting for age and study area), FVII:C (P=.002), and FVII:Ag (P=.01), suggesting stronger associations in women than in men. The inverse association of docosahexaenoic acid with FVII:C was also significantly stronger in women than in men (P=.03). The inclusion of only women using hormone replacement therapy or, alternatively, only women not using hormone replacement therapy did not substantially alter these interactions.
We further compared the adjusted means of hemostatic factors among persons who had palmitic acid above the sex-specific median and linoleic acid below the sex-specific median of the study population with the corresponding adjusted means of persons who had palmitic acid below and linoleic acid above the sex-specific median of the study population (Table 3). Consistent with other analyses, men and women with high palmitic and low linoleic acid had a significantly higher level of fibrinogen and plasminogen than men and women with low palmitic acid and high linoleic acid. No difference was observed in FVII:C, FVII:Ag, or Lp(a). In addition to the covariates explained above, we adjusted further for such lifestyle-related factors as self-reported alcohol consumption, leisure time physical activity, and, among women, hormone replacement therapy, but the findings remained unaltered.
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Discussion |
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Linoleic acid, the most abundant polyunsaturated fatty acid in serum phospholipids, was inversely associated with plasma fibrinogen and plasminogen levels, and palmitic acid, the most abundant saturated fatty acid in serum phospholipids, was positively associated with plasminogen. These associations were independent of several potential confounding factors, including plasma lipids. Miettinen and coworkers,1 in a prospective case-control study, found that the fatty acid composition of serum phospholipids was predictive of myocardial infarction or CHD death in middle-aged men. In particular, the proportion of linoleic acid showed an inverse dose-response relation with future coronary events. The case and control subjects were matched by serum cholesterol level, so the results were independent of cholesterol. Our present results fit nicely together with this earlier study and suggest that the mechanism for the increased CHD risk of persons with low levels of linoleic acid in serum phospholipids may be an increased tendency to thrombus formation, increased viscosity, or alternatively, increased amounts of atherosclerotic lesions in their arteries, showing inflammatory activity and raising the level of acute-phase reactants.
There is ample evidence that plasma fibrinogen level is predictive for future myocardial infarction20 21 22 and stroke23 events. Much scantier data exist regarding plasminogen, but a recent study from Germany reported that plasminogen was positively correlated with the degree of coronary atherosclerosis on angiography.24 This suggests that elevated plasminogen may be a marker for increased risk of coronary events, although it is not known whether plasminogen is causally involved in the pathogenesis of CHD through its role in fibrinolysis. Plasminogen is an acute-phase reactant, and it is possible that elevated plasminogen values reflect only the low-grade inflammation process in atherosclerotic arteries, as the investigators of the ECAT Angina Pectoris Study Group have suggested.25
Lp(a) is structurally closely related to plasminogen and is known as a stable, hereditary risk factor, which is only little affected by dietary or other environmental factors, such as female hormones, possibly alcohol,26 and trans-monounsaturated fatty acids.27 It was therefore not a surprise that we found no associations between Lp(a) and the fatty acid composition of serum phospholipids in the present cross-sectional, population-based study.
Reports on the effects of individual fatty acids on FVII have produced variable results. Mitropoulos and coworkers5 reported that dietary fat induces an increase in FVII:C through an increase in plasma free stearic acid concentration. Also, Folsom and coworkers8 reported a positive association of FVII:C with stearic acid as well as with the proportion of total saturated fatty acids in plasma phospholipids and a negative association between FVII:C and the proportion of linoleic acid in plasma phospholipids. On the other hand, Tholstrup and coworkers6 reported that fat high in stearic acid had a favorable effect on FVII:C compared with fats high in palmitic acid or high in myristic and lauric acids. These differences are largely explained by different study designs and by the rapid metabolism of stearic acid to oleic acid, which is metabolically fairly neutral.
We were unable to directly confirm any of the findings described above, possibly because the proportion of stearic acid in serum phospholipid fraction does not reflect very well the amount of stearic acid in the diet. We found, however, a strong positive association between FVII:Ag and dihomogammalinoleic acid in both sexes and between FVII:C and dihomogammalinoleic acid in women. Interestingly, the proportion of dihomogammalinoleic acid in serum phospholipids has been significantly higher in CHD patients than in healthy control subjects.3 Furthermore, there is experimental evidence that a high proportion of linoleic acid in the diet leads to a low proportion of dihomogammalinoleic acid in serum phospholipids, and a diet rich in milk fat but low in linoleic acid leads to a high proportion of dihomogammalinoleic acid in serum phospholipids.28 Therefore, our findings are consistent with those of Folsom and coworkers and support the concept that a relatively high proportion of linoleic acid in dietary fat leads to lower levels of FVII.
A limitation of our study is its cross-sectional nature, which does not allow causal conclusions. For example, in most studies, changes in dietary fat have not produced a change in plasma fibrinogen,29 30 31 although there are exceptions.7 32 Thus, it is possible and even likely that diets high in linoleic acid may not decrease fibrinogen directly but are linked to other personal characteristics or to the amount of inflammatory atherosclerotic lesions, which in turn change fibrinogen level. The latter explanation seems more plausible, because the association remained remarkably stable after adjustment for multiple potential confounders. Furthermore, the strength of the observed associations and their potential physiological significance deserve consideration. In the present study, the difference in fibrinogen between persons who had high palmitic and low linoleic acid and persons who had low palmitic and high linoleic acid was 
9% in both sexes. In the Northwick Park Heart Study,20 the difference in fibrinogen between persons who developed ischemic heart disease and those who remained healthy was 0.25 g/L, ie, 8.6%. This suggests that the differences observed in the present study are not trivial.
The fatty acid composition of serum phospholipids is more stable than the fatty acid composition of serum triglycerides and reflects, with some limitations, the type of dietary fat in the habitual diet.33 34 35 36 This is particularly true for linoleic acid, which originates from diet and reflects the consumption of vegetable oils in relation to other types of fat. Therefore, the group with a lower than average proportion of palmitic acid and a higher than average proportion of linoleic acid is likely to represent persons whose fat intake consists predominantly of vegetable fat. Our results suggest that this type of diet is associated with a more favorable coagulation profile than a diet low in linoleic acid. This finding was independent of serum lipids, but it is not clear whether the association is due to the effects of fatty acids on coagulation or rather reflects the low-grade inflammatory process in the arteries.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The FINRISK Hemostasis Study was supported by a grant from the Finnish Heart Association (19 February Fund).
Received January 26, 1996; accepted August 22, 1996.
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References |
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