© 1996 American Heart Association, Inc.
Articles |
Effects of Partially Hydrogenated Fish Oil, Partially Hydrogenated Soybean Oil, and Butter on Hemostatic Variables in Men
From the Institute for Nutrition Research (K.A., J.I.P.) and the Section for Dietary Research (B.S.), University of Oslo; the Research Forum, Ullevaal University Hospital (I.S.), Oslo; and Akershus College (J.I.P.), Bekkestua, Norway.
Correspondence to Professor Dr Med Jan I. Pedersen, Institute for Nutrition Research, University of Oslo, PO Box 1046 Blindern, 0316 Oslo, Norway. E-mail j.i.pedersen@basalmed.uio.no.
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Abstract |
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Abstract We have compared the effects of partially hydrogenated fish oil (PHFO diet), partially hydrogenated soybean oil (PHSO diet), and butterfat (butter diet) on fibrinolytic and coagulation variables in 31 young men. The three test margarines, which contributed 78% of total fat in the diets, contained 70% butterfat, PHSO, or PHFO, each with 30% of soybean oil. Fat provided
35% of energy, and the content of trans-fatty acids was
0.9%, 8.5%, and 8.0% of energy in the butter diet, PHSO diet, and
PHFO diet, respectively. All diets contained 420 mg
cholesterol per 10 megajoules per day. All subjects
consumed all three test diets for 3 weeks, in a random order (crossover
design). The PHSO diet resulted in higher levels of
plasminogen activator inhibitor
type 1 antigen and plasminogen activator
inhibitor type 1 activity than the two other test diets.
Fibrinogen increased on the butter diet compared with the PHFO diet. No
significant differences in the levels of factor VII,
fibrinopeptide A, D-dimer, tissue
plasminogen activator or
ß-thromboglobulin were observed between the three
test diets. The PHFO and the PHSO diets have previously been shown to
result in higher levels of Lp(a) compared with the butter diet. The
present findings indicate that PHSO has unfavorable
antifibrinolytic effects relative to PHFO and butter and that butter
may be procoagulant relative to PHFO. More controlled dietary studies
are needed to assess definitely the impact of different hydrogenated
fats on risk of coronary heart disease.
Key Words: fibrinolysis • coagulation • hydrogenation • trans-fatty acids • diet
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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It is now generally accepted that thrombogenesis, as well as atheroma formation, is involved in the evolution of atherosclerotic cardiovascular disease.1 2 In contrast to lipid variables, however, hemostatic variables have not been extensively investigated in epidemiological or controlled dietary studies,3 4 5 6 7 although indications are strong that increased levels of fibrinogen,3 4 5 6 7 FVII,3 7 PAI-1,4 8 9 10 and Lp(a)11 12 are important risk indicators for coronary heart disease.
Recent studies indicate that hemostatic variables are influenced by dietary factors. Thus, switching from a very high- to a very low-fat diet was reported to lower fasting FVIIc.13 Changing from a western type high-fat to a low-fat/high-fiber diet also reduced fasting FVIIc levels and increased fibrinolytic activity both in short- and long-term experiments.14 15 Total fat content by itself does not appear to have an independent effect on fasting FVIIc.16 A high-fat diet may, however, induce postprandial activation of FVII.17 Plasminogen, TPA, and PAI-1 are also reported to be reduced by a low-fat/high-complex-carbohydrate diet.18 Any influence of individual fatty acids on these factors is not known. An exchange of polyunsaturated fat for saturated fat does not appear to influence FVII.19 20 Stearic acid has been reported to be associated with both increase21 and decrease22 in FVIIc.
Partially hydrogenated vegetable and marine oils have for several
decades been used in the production of margarines and
shortenings.23 24 25 26 The
intake of partially hydrogenated
oils is not negligible in most
countries.23 24 25 26 In
Norway,
for example, the daily per capita intake of PHFO and PHSO contributes
to 10% and 5% of total fat intake, respectively.27
During the hydrogenation process, trans-fatty acids are
formed from the corresponding cis isomeric fatty
acids.23 24 25 26 Recent
studies have shown that
trans-fatty acids from partially hydrogenated vegetable oils
increase serum total and LDL cholesterol and decrease HDL
cholesterol compared with oleic, linoleic, or stearic
acid.28 29 30 31 32 33 34 35 36
Also, clinical and epidemiological studies have
indicated that intake of these acids may be related to
cardiovascular disease
risk.35 36 37 38 An
additional adverse effect of trans-fatty acids might be a
competition with essential fatty acids in enzymatic reactions involved
in synthesis of prostaglandin and other eicosanoids, which
may affect platelet activity and other critical hemostatic
functions.39 40 41 However, to our
knowledge, the effects of
partially hydrogenated oils on hemostatic variables have not
previously been studied under controlled conditions in humans.
We have previously studied the effects of dietary PHFO, PHSO, and butterfat on serum lipoproteins in 31 healthy young men.27 Our results showed that PHFO adversely affected serum lipoproteins at least to the same extent as butterfat. PHSO was less potent in this regard compared with both PHFO and butterfat.27 In the present study, we have investigated the effects on hemostatic variables of PHFO compared with those of PHSO and butterfat in a strictly controlled dietary study.
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Methods |
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Subjects and Their Baseline Characteristics
The 31 experimental subjects were male students studying domestic and kitchen management.27 The median age of the participants was 27 years and the median body mass index 25.7 (kg/m2). Thirteen men (39%) were smokers, and they smoked on average 14 cigarettes per day. They were all in good health, with no history of coronary heart disease. Thirty-nine percent of the men had relatives with a known history of cardiovascular disease, none of which had been identified as familial hypercholesterolemia.
Before the study began, the men answered a quantitative food frequency questionnaire.27 The median level of total fat in the habitual diet was found to be 35% of energy (lower quartile: 27% and upper quartile: 38%), and the median intake of linoleic and linolenic acid was 13 g (lower quartile: 9 g and upper quartile: 21 g) and 2 g (lower quartile: 1 g and upper quartile: 2 g), respectively. The median intake of dietary cholesterol was 486 mg/d (lower quartile: 380 and upper quartile: 624 mg/d). The ratio between the intake of polyunsaturated and saturated fatty acids was estimated at 0.4 (lower quartile: 0.3 and upper quartile: 0.6).
The protocol and aims of the study were fully explained to the subjects, who gave their written consent before entry into the study. Approval of the study was obtained from the Regional Committee for Ethics in Biomedical Research.
Experimental Design
The study was conducted as an
intraindividual comparison of the
effects on fibrinolytic and coagulation variables of three test
diets differing in such a way that the same amount of butterfat in one
diet (butter diet) was exchanged with a certain amount of either PHSO
(PHSO diet) or PHFO (PHFO diet).27 The participants
received three different test diets in a random order in such a way
that each diet was consumed by one third of the persons in each period.
In this way, variation due to residual effects of the previous diet or
to drift of variables over time could be minimized. At the end of
one test period, subjects were crossed over to the next diet, with a
washout period of 1 week. The participants were allowed to return to
their normal eating and living habits during this week. Participants
were blinded as to which fat they were receiving in the test periods
(one-blind study). All participants were encouraged to maintain
their normal lifestyle preferences throughout the study period and to
report in a diary any deviation from their usual behavior. They were
asked to abstain from alcohol consumption during the study period.
Body weight was monitored twice a week (nonfasting) and at the start and end of each study period (fasting). The body weights were measured in light clothes on a digital balance (SECA) and read to the nearest 0.1 kg. Body heights were measured without shoes and read to the nearest 0.1 cm. Adjustments in energy intake were made in the individual meal plan according to changes in the body weight. Dietary compliance was monitored regularly by interviews and diaries. It turned out that individual compliance to the diets could be improved if the washout periods included 2 weekends instead of 1. Most men, therefore, received the diets for 19 days, not 21 days.
It has been demonstrated that the levels of FVII,19 42 TPA,18 43 PAI,18 43 and Lp(a)27 are changed within 3 weeks on a controlled diet, although it has not been evaluated whether these levels are stable levels.
Experimental Test Diets
Only ordinary raw materials for the
food industry were used in
our study, and the partially hydrogenated oils were taken directly from
the production line.27 The three test fats
consisted of PHSO, PHFO, and butterfat. Thirty percent of refined
soybean oil was added to each of the three test fats to obtain a
sufficient and equal content of linoleic and 
-linolenic
acid in the diets. The specially produced test margarines were
estimated to contribute to 78% of total fat and 27% of total energy.
The production and composition of the test margarines are
described in detail elsewhere.27
The test margarines were supplied to the menus as spreads, bakery products, sauces, and other appropriate foods. All three periods comprised a background diet that contained 22% of the total fat (fat from dairy products, meat, cereals, and other sources). Menus for the three experimental diets contained the same basic food items, including egg, meat, fruit, bread, etc. They were as similar in appearance as possible, considering that they contained different test margarines. Monday through Friday of each week, lunch was served in a specially prepared dining room. Dinner and breakfast for the next day were packaged and provided each afternoon. Weekend meals were packaged and provided each Friday afternoon. No foods other than those provided were allowed during the controlled feeding periods. Instant coffee, tea, and mineral water with artificial sweeteners were allowed. Most menu items were weighed out for each individual participant to provide meals with varying energy content. The test diets were served according to four different energy levels: 10 MJ, 13 MJ, 15 MJ, and 17 MJ per day. The contribution of trans-fatty acids from the background diet was minor (<0.5%). The background diet provided 90 mg dietary cholesterol. To balance the different amounts of cholesterol in the test fats, calculated quantities of dried egg powder were added to the PHSO diet (15.0 g/10 MJ) and to the butter diet (9.6 g/10 MJ). Dried egg powder was used as an additive to vanilla sauce, dressings, and other foods as needed. Apart from the nutrient contribution from the dried egg powder to the butter diet and the PHSO diet, the nutrient content of the background diet was planned to be the same for all test diets. The content of oxidized cholesterol products in the dried egg powder was analyzed. We found no significant differences in the levels of important oxidation products between samples collected before the study period and samples collected from the last serving.
The energy
distribution and the fatty acid composition of the duplicate
portions of the three test diets are shown in Table 1
and have previously been extensively discussed.27 The test
diets contained close to 35% of energy from fat, as planned, and the
cholesterol content in the three diets was analyzed
to be 420 mg/10 MJ. Determination of total trans
nonconjugated double bonds by infrared spectrophotometry indicated
somewhat higher total content of trans-fatty acids in the
PHFO diet than determined by gas-liquid
chromatography (GLC). This discrepancy between the two
methods has been discussed in detail elsewhere.27 The
energy intake from trans-fatty acids was calculated from the
GLC analyses to be 0.9% from the butter diet, 8.5% from
the PHSO diet, and 8.0% from the PHFO diet. Except for
cholesterol, the nonglyceride part of the test fats was not
characterized, as commercial PHSO contains <1.0% and commercial PHFO
1.0% (A/S Denofa og Lilleborg Fabriker, personal communication).
All diets contained ample and almost identical amounts of linoleic and
-linolenic acid.
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Blood Sampling and Analyses
Before the trial was started,
each participant received a random
inclusion number that was used for identification and labeling of blood
and serum tubes. Blood samples were collected with minimal stasis from
an antecubital vein (Vacutainer System, Becton Dickinson) after an
overnight fast of between 7 and 10 hours. The participants rested for
at least 15 minutes before venipuncture. Baseline samples
were collected at the start of the first period. All samples were
analyzed within the same run within 1 month after the study was
finished to eliminate variability due to laboratory drift. Sample
treatments were blinded to the analysts, and results were blinded to
the investigators. Samples were submitted to the analytical laboratory
without identification of treatments, and data from the laboratory were
not made available to the investigators until after the analytical data
were finalized. Serum was obtained from Vacutainer tubes devoid of
anticoagulants, by 1500g centrifugation for
10 minutes within 1 hour of venipuncture and stored at
-70°C until analyzed.
Citrated plasma (Vacutainer tubes, containing 0.129 mmol/L trisodium citrate in dilution 1:10) was separated within 15 minutes by centrifugation at 2500g for 30 minutes at 4°C for determinations of PAI-1 activity, PAI-1 antigen, TPA antigen, fibrinogen, and D-dimer. Citrated plasma for determination of coagulation FVII was handled at room temperature to avoid cold activation.
Blood for measurement of FPA was collected in 5-mL tubes containing 1000 U/mL heparin (Nycomed) and 1000 U/mL aprotinin (Tracylol, Bayer) in 0.15 mol/L NaCl (1 vol anticoagulant solution to 9 vol of blood) and separated by centrifugation at 2500g for 30 minutes at 4°C.
Sample collection and preparation for determination of ßTG were done according to the manufacturer of Diatube H, which contains citrate supplemented with inhibitors of platelet aggregation: theophylline, adenosine, and dipyridamole (Diagnostica Stago).
PAI-1 activity was measured amidolytically, according to Chmielewska et al.44 ELISA with a double antibody technique was used for determinations of PAI-1 antigen (measuring free PAI-1 as well as in complex with TPA) and TPA antigen (measuring free TPA as well as in complex with PAI-1). We did not measure TPA activity in this study for practical reasons, ie, a special medium is needed for blood collection. Commercially available kits (Biopool AB) were used, Spectrolyse/pL, TintElize PAI-1, and TintElize t-PA, respectively. The interassay CVs were 4.5% for PAI-1 activity, 9.8% for PAI-1 antigen, and 8.4% for TPA antigen.
D-Dimer was determined by ELISA (Asserachrom D-di, Diagnostica Stago) and expressed as fibrinogen equivalents, interassay CV, 6.5%.
Fibrinogen was measured according to Clauss,45 using an ACL-3000 Coagulation System analyzer (Instrumentation Laboratory); interassay CV, 4.8%.
FVII activity was determined in a two-stage chromogenic assay (Coa-Set FVII containing human placenta thromboplastin, Chromogenics AB); interassay CV, 2.1%.
FPA was assayed by radioimmunoassay, essentially according to Nossel et al,46 with modifications described by Skjønsberg et al47 ; interassay CV, 6.7%.
ßTG was measured by ELISA (Asserachrom ßTG, Diagnostica Stago); interassay CV, 5.9%.
Serum Lp(a) was quantified by a commercial ELISA kit (TintElize Lp[a], Biopool AB) according to the manufacturer's instructions (CVs at 100 mg/L, 7.7%; at 400 mg/L, 2.7%). All analyses were performed at the Clinical Chemistry Department and Clinical Research Unit, Ullevaal University Hospital, Oslo.
Statistical Methods
Median values together with lower and
upper quartiles are
presented (to enable comparison with results from other
studies, mean values and standard deviations are also
presented). Nonparametrical statistical methods
were chosen because most of the variables studied were highly
skewed and the number of participants was limited. The Quade
test48 was used to examine whether there were differences
between the diets. When a significant diet effect was observed
(P
.05), pairwise comparisons between the three groups were
performed by Wilcoxon signed rank tests, and one-sample
Wilcoxon confidence intervals are presented, all
adjusted using the Bonferroni method.49 Since three
comparisons are involved, the confidence interval given is 98.3%
instead of the usual 95%. Data analysis was performed using
the statistical package Minitab Release 9.
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Results |
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Compliance With the Diets
Compliance with the diets was judged by direct observation of consumption of weekday lunch, weight maintenance, and evaluation of food diaries. Some small deviations from the prescribed diets were noted, as reported elsewhere,27 but it was not considered necessary to exclude any participant from the analysis. The mean body weight decreased by 0.5 kg during the study period, but this difference was not significant.
Levels of Fibrinolytic and Coagulation Factors
The levels of
fibrinolytic and coagulation variables at
baseline and on the three different dietary test fats are given in
Table 2. In Table 3 are given the median
differences between diets and their statistical significance
probabilities.
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Fibrinogen reached a higher level, with borderline significance, on the butter diet compared with the PHFO diet (median difference, 0.1 g/L; P=.02) but did not differ from the slightly lower level on the PHSO diet (median difference, 0.1 g/L; P=.12). No differences in the median levels of fibrinogen were observed between the PHFO diet and PHSO diet.
The PHSO diet resulted in higher levels
(P.01) of
PAI-1 activity (median level, 8.8 U/mL) and PAI-1 antigen (median
level, 14.0 ng/mL) compared with the butter diet (median levels, 6.5
U/mL and 12.0 ng/mL, respectively). The level of PAI-1 activity on the
PHSO diet was higher than that reached on the PHFO diet (median level,
6.4 U/mL, P.01), and the level of PAI-1 antigen was (with
borderline significance) higher than that on the PHFO diet (median
level, 13.0 ng/mL, P=.02).
No significant differences in the levels of FVII, FPA, D-dimer, TPA antigen, or ßTG were observed between the three test diets.
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Discussion |
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In the present study, we have demonstrated that the levels of PAI-1 activity and PAI-1 antigen were significantly elevated on the PHSO diet compared with both the butter diet and the PHFO diet. This finding could indicate an adverse effect on fibrinolysis. Several of the participants in the present study were overweight,27 and impaired fibrinolytic activity has been extensively documented in obese subjects.50 51 Results from the Oslo Diet and Antismoking trial demonstrated that the majority of high-risk men with elevated serum cholesterol levels and elevated triglyceride concentrations had impaired fibrinolytic activity.52 Dietary lowering of serum triglycerides resulted in an improvement of the fibrinolytic capacity.53 The recent study by Folsom et al54 also showed that changes in PAI-1, TPA antigen, and FVII after weight loss were highly correlated with changes in triglycerides. Since no significant changes in body weights or triglycerides were observed in the present study,27 we assume that the effects of the test diets did not depend on these variables.
Several recent clinical and epidemiological studies indicate that PAI-1 is a risk indicator for coronary heart disease.9 10 50 51 To what extent PAI-1 is a causal factor or a marker secondary to the atherosclerotic process remains to be elucidated. Some previously published studies have indicated that altering PAI-1 by dietary means may not necessarily be related to altered risk. Thus, two controlled studies have shown that a moderate fish intake apparently unfavorably increases PAI-1 after periods of 10 days42 and 6 weeks.43 On the other hand Kromhout et al55 reported that consumption of as little as 30 g of fish daily was associated with reduced risk of coronary heart disease, and Burr et al56 reported from the DART study that a moderate intake of fatty fish may reduce mortality in men who have recovered from myocardial infarction.
The explanation for the elevating effect on PAI-1 by the PHSO diet
compared with the two other test diets is not clear. The PHSO diet and
the PHFO diet contained about the same total amount of
trans-fatty acids, 8% of energy, and all three diets
contained ample amounts of linoleic and -linolenic acid.
One major difference between the two diets was the much higher amount
of C18:1 trans-fatty acids (elaidic acid and its isomers) in
the PHSO diet. Although results from long-term studies are
necessary, it is tempting to speculate that the higher level of PAI-1
on the PHSO diet was connected to the higher levels of these isomers.
Interestingly, Kariko and coworkers57 demonstrated that
both docosahexaenoic and dihomogamma linolenic acid selectively
increased PAI-1 mRNA levels in endothelial cells. To
what extent trans isomers of long-chain fatty acids may
have similar effects is unknown.
The butter diet resulted in slightly higher levels of fibrinogen compared with the PHFO diet. Increased levels of fibrinogen have been recognized as an independent risk factor for both cardiovascular morbidity and mortality.3 4 5 6 Fibrinogen was not reduced on a low-fat diet in a long-term study15 or in a short-term study.16 Marckmann et al42 have postulated that 10 study days or less may be too short for detection of effects on fibrinogen. During a 3-week study period, however, fibrinogen increased on a diet high in stearic acid compared with a diet high in myristic and lauric acid.58
No significant differences were found in the levels of other coagulation (FVII, FPA, D-dimer) or platelet (ßTG) parameters or TPA antigen among the diets. Our study is limited by the short study period, and even if significant changes in hemostatic variables have been detected after 2 weeks of dietary modification,14 it is not clear whether new and stable levels of the present hemostatic variables are achieved within 3 weeks.
As we reported elsewhere,27 both the PHSO diet and the PHFO diet resulted in significantly higher levels of Lp(a) compared with the butter diet. The Lp(a)-raising effect of trans-fatty acids has previously been reported by other groups also.29 34 By its structural similarity to plasminogen, it has been suggested that the correlation that has been found between elevated Lp(a) and risk of coronary heart disease is related to a competitive inhibition by Lp(a) of plasminogen and reduced fibrinolytic capacity.11 No direct evidence for such a mechanism has been obtained, however.59
In conclusion, the PHFO diet was associated with the most favorable hemostatic profile, and the PHSO diet with the worst. Both the PHSO diet and the PHFO diet increased the levels of Lp(a), while the butter diet increased the levels of fibrinogen. We have previously demonstrated that PHFO and butter have more potent hypercholesterolemic effect than PHSO.27 Both partially hydrogenated oils and butterfat may thus have certain nutritional disadvantages. Total intake of trans-fatty acids in the present study was four to five times higher than normally found in the diet, and the present findings may not be relevant for more normal dietary intake. More controlled dietary studies are needed in order to rank the observed effects of hydrogenated fats on serum lipids, hemostatic variables, and Lp(a) in relation to risk for coronary heart disease.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was made possible through a generous grant from The Research Society of the Norwegian Edible Fat Producers. We gratefully acknowledge the participants for their sacrifices and interest throughout the study. We are indebted to our technical and kitchen staff for their assistance, and O. Jordal for performing the chromatographic analysis. A/S Denofa og Lilleborg Fabriker are acknowledged for making the test margarines.
Received June 2, 1995; accepted December 13, 1995.
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