© 1997 American Heart Association, Inc.
Articles |
Fibrinolytic Function After Dietary Supplementation With 
3 Polyunsaturated Fatty Acids
From the Institutes of Clinical Medicine (I.T.), Community Medicine (K.H.B.), and Medical Biology (O.C.I.), University of Tromsø; and the Department of Internal Medicine, Tromsø University Hospital (A.N., T.J.), Norway.
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Abstract |
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Abstract Hypertension is associated with derangements in glucose and lipid metabolism. Increased levels of plasminogen activator inhibitor type 1 (PAI-1) are thought to potentiate the development of coronary events in this condition. Fish oil (
3 polyunsaturated fatty acids [PUFAs]) have lipid-lowering effects, but the cardioprotective potential has been questioned because fish oil has been found to increase PAI-1 activity. This study was performed to determine the effects of 3 PUFAs on the fibrinolytic function in hypertension. Seventy-eight persons with untreated hypertension were included in a 16-week, double-blind, randomized, controlled intervention study with 4 g/d of eicosapentaenoic and docosahexaenoic acids or corn oil placebo. Plasma PAI-1 activity, tissue plasminogen activator (tPA) activity, levels of fibrinogen and factor VIIc, and platelet count were measured before and after intervention (mean±SE). PAI-1 activity changed similarly in the fish oil and corn oil groups (1.8±1.0 U/mL versus 3.5±1.2 U/mL, P=.25), as did tPA (-0.02±0.02 IU/mL versus -0.13±0.03 IU/mL, P=.28), levels of factor VIIc (6±5% versus 5±4%, P>.3), and platelet count (2±7x109/L versus 3±5x109/L, P>.3). None of these variables changed from pretreatment levels during fish oil intake. Fibrinogen levels increased significantly both during fish oil (0.6±0.1 g/L, P=.0001) and corn oil (0.4±0.1 g/L, P=.002) intake. There was no between-group difference (P>.3). In conclusion, a daily intake of 4 g 3 PUFAs does not affect PAI-1 and tPA activity in persons with hypertension. A modest increase in fibrinogen levels was observed after both fish oil and corn oil intake.
Key Words: hypertension • 3 PUFA • plasminogen activator inhibitor type 1 • fibrinolysis
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Introduction |
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Plasma PAI-1 is an inhibitor of fibrinolysis1 that has been associated with several metabolic risk factors for cardiovascular disease.2 3 4 5 6 7 "> Increased PAI-1 activity may therefore be a link between metabolic disturbances and the development of thrombosis and myocardial infarction.8 9 10 Hypertension has been associated with elevated PAI-1 activity11 12 and abnormalities in insulin and lipid metabolism.13 14
Dietary supplementation with fish oil may lower blood pressure in hypertension15 16 17 and may therefore be used in the prevention of cardiovascular disease in hypertensive patients. Fish oil contains the long-chain eicosapentaenoic and docosahexaenoic acids of the 3 family. The incorporation of these fatty acids into cell membranes may favorably affect platelet aggregation18 19 ; triglyceride, VLDL triglyceride20 21 22 , and apoprotein B turnover;23 vascular prostaglandin formation15 18 24 ; and blood pressure.15 16 17 However, conflicting results have been reported on the influence of fish oil on fibrinolytic activity. Some studies25 26 27 28 29 30 report impaired fibrinolytic capacity during dietary fish oil supplementation, while other studies find improvement31 32 or no effects at all.33 34 35 36 37 38 39
In the present study we have examined the influence of dietary fish oil supplementation on fibrinolytic function in persons with untreated essential hypertension in a randomized, double-blind, controlled trial.
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Methods |
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Participants and Study Design
Details about the selection of participants and study design have been presented elsewhere.17 One hundred three hypertensive persons were recruited from a population health survey conducted in Tromsø, Norway.40 Fifty-eight subjects did not use prescribed drugs, had body mass index (weight in kilograms divided by the square of the height in meters) <32 kg/m2, systolic blood pressure <190 mm Hg and diastolic pressure between 90 and 110 mm Hg on three separate occasions, and appeared otherwise healthy on clinical examination. These persons participated in the present study, together with 26 hypertensive persons recruited from the primary health care services according to identical criteria. All participants completed a questionnaire about physical activity, alcohol use, and smoking habits. Physical activity was assessed by the number of hours of physical activity per week, and alcohol intake was assessed by the amount of alcohol consumed per day in grams. Four of the volunteers had been treated with antihypertensive drugs (atenolol, amlodipine, or felodipine). This treatment was discontinued at least 8 weeks before the trial. Any intake of cod liver oil supplement was discontinued 12 months before the study started. The participants were encouraged not to change their diet or lifestyle throughout the study. The study was approved by the Regional Board of Research Ethics, and each participant gave written informed consent before participation.
The subjects were randomly assigned to receive either fish oil or corn oil by using a computer-based random number generator.17 The participants and all involved personnel were blinded to treatment assignments. The fish oil group received 85% eicosapentaenoic acid (C20:5 3) and docosahexaenoic acid (C22:6 3) (4 g/d) as ethyl esters (Omacor, Pronova Biocare, Oslo, Norway). To compensate for the extra daily energy intake during fish oil supplementation, the control group was given 4 g/d corn oil containing 56% linoleic (C18:2 6) and 26% oleic (C18:1 9) acids. The oils were given in indistinguishable soft gelatin capsules, each containing 1 g of oil. The intervention period lasted for 16 weeks. Compliance was checked by counting leftover capsules and by measuring the concentrations of fatty acids in plasma phospholipids before and after intervention.
Clinical and Laboratory Measurements
Clinical and laboratory measurements were performed during the last week before treatment and during the last week of intervention. A weight-maintenance diet was held 3 days before experiments, and the participants were asked to abstain from alcohol in this period. All studies were started at 8 AM after an overnight fast, and samples for measurements of fibrinolytic activity were drawn between 8 and 8:30 AM. Blood was drawn from a cannulated dorsal hand vein without stasis, and the blood was arterialized by keeping the hand in a heating device at 65°C.41
PAI-1 activity was measured with a commercial two-stage indirect enzymatic kit (Spectrolyse, Biopool AB).42 The interassay CV was 13.9%. Samples for measurement of tPA activity were collected in Biopool Stabilyte blood-collection tubes and determined according to Wiman et al43 as previously described.44 The interassay CV was 9.9%. Plasma fibrinogen was measured with an ACL 3000 coagulation system manufactured by Instrumentation Laboratory SpA. The reagents were IL Test PT-Fibrinogen, catalog No. 97567-10. Coagulation factor VII (percent activity) was measured with the same instrument. Factor VII–deficient plasma (Instrumentation Laboratory, catalog No. 84662-50), calibration plasma, and additional reagents were delivered from the same manufacturer. Blood platelets were counted with a Coulter STKS instrument from Coulter Electronics Limited.
A standard hyperglycemic clamp was performed as previously described17 45 46 to measure the degree of insulin resistance. Insulin resistance was assessed by the insulin sensitivity index, calculated by dividing the mean glucose infusion rate during the last hour of the clamp period (micromoles per kilogram per minute) by the average plasma insulin concentration in the same period of time (picomoles per liter). Plasma glucose levels were analyzed by a Yellow Springs Instruments glucose analyzer (2300 STAT PLUS). Plasma insulin47 was measured by a radioimmunoassay method without cross-reactivity with C-peptide and with a cross-reactivity between insulin and proinsulin of <15%. Proinsulin was measured with an immunofluorometric method as previously described48 , using monoclonal antibodies, one directed against insulin and another against C-peptide (PEP-001 and HUI-001 from Novo Nordisk). Cross-reactivities with insulin, C-peptide, and 65,66-split proinsulin were <1% and with 32,33-split proinsulin 66%. The lower limit of detection was 1 pmol/L and CV was <10% at all concentration levels.
Triglyceride levels were measured on a Hitachi 737 Automatic Analyzer with a kit from Boehringer Mannheim. Serum NEFAs were analyzed by an acyl-CoA oxidase–based colorimetric kit (Wako Nefa C Kit). Serum phospholipid fatty acids were analyzed as previously described17 and reported in micromoles per liter. Phospholipid content of 3 PUFAs was calculated as the sum of C18:3 3, C20:5 3, C22:5 3, and C22:6 3 fatty acid. Phospholipid content of 6 PUFAs was calculated as the sum of C18:2 6, C20:3 6, C20:4 6, and C22:4 6 fatty acid.
Plasma glucose concentrations were analyzed immediately during the studies, and all other blood samples were stored at -70°C until completion of study. The waist-to-hip ratio was calculated as the body circumference at the level midway between the inferior border of the rib cage and superior border of the iliac crest divided by the maximal circumference of the buttocks.49 Data for plasma glucose, insulin, insulin sensitivity, triglycerides, body mass index, waist-to-hip ratio, and body weight have been presented previously.17
Statistical Analysis
The data were analyzed using the SAS software package.50 All data were checked with regard to frequency distribution and transformed to normal distribution by logarithmic transformation when appropriate. One-sample t tests were used to compare values obtained before and after intervention. Changes during intervention were calculated as the value obtained at the end minus the value obtained at the beginning of intervention. Two-sample t tests were used for between-group comparisons. Differences in categorical data were tested with the 
2 test. Correlations were tested by linear regression analysis and by computing Pearson correlation coefficients. ANCOVA was used for adjustments. Multiple regression analyses were used to examine independent predictors of changes during intervention in PAI-1 activity, tPA activity, and fibrinogen levels. Regression to the mean was controlled for by including the average level of predictor variables (sum of before and after values divided by two) as covariates in the regression models. Pooled data from both groups were used in these analyses, since the results were similar in the fish oil and corn oil group when tested for interaction. All results are given as mean±SE unless otherwise noted. We considered P<.05 to be statistically significant.
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Results |
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Four persons in the fish oil group and two persons in the corn oil group withdrew from the study. In the fish oil group, one withdrawal was due to the development of angina pectoris, one due to initiation of antihypertensive treatment, and two due to personal reasons. In the corn oil group, both withdrawals were due to personal reasons. No serious side effects were observed. Compliance according to capsule count was 96.5%.
Baseline characteristics of the fish oil group and the corn oil group are given in Table 1
. Body mass index, waist-to-hip ratio, plasma glucose, insulin, and proinsulin levels were higher in the corn oil group. After adjustment by ANCOVA for the differences in body mass index and waist-to-hip ratio, baseline levels of glucose, insulin, and proinsulin were no longer statistically different in the two groups. The degree of physical activity and alcohol intake did not differ in the groups (data not shown). Because the randomization procedure gave an imbalance in body mass index and waist-to-hip ratio, all data were reanalyzed with adjustment for differences in these variables. This did not alter the results notably, and we therefore present unadjusted data.
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Plasma Phospholipid Content of 3 and 6 PUFAs, Triglyceride and NEFA Levels, and Body Weight
As expected, plasma phospholipid content of 3 PUFAs increased during fish oil treatment, whereas it did not change in the corn oil group (Table 2). Plasma phospholipid content of 6 PUFAs increased in the corn oil group and did not change in the fish oil group; the difference was not significant (P=.30). Levels of triglycerides decreased in the fish oil group (-0.11±0.07 mmol/L, P=.11) and increased in the corn oil group (0.17±0.08 mmol/L, P=.04). The difference between the groups was significant (P=.01). NEFA levels did not change significantly in either group. Mean body weight increased 1.1 kg during fish oil intake (P=.003); the difference between groups was not significant. A small increase in proinsulin seemed to occur during fish oil intake, but this change was no longer significant after adjustment for body mass index and weight gain. We previously reported that plasma glucose and insulin levels, as well as insulin sensitivity, did not change significantly during fish oil or corn oil treatment.17
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PAI-1 Activity
PAI-1 activity did not change significantly during fish oil treatment (Table 2
). After corn oil treatment, PAI-1 activity rose by 3.5±1.2 U/mL (P=.009). The difference between the groups was not significant. Table 3 shows that increments in levels of NEFAs, insulin, and body weight were independently associated with an increase in PAI-1 activity, whereas triglycerides showed no independent relation to PAI-1 activity. The inclusion of changes in phospholipid content of 3 PUFAs, 6 PUFAs, total unsaturated fatty acids, or saturated fatty acids did not add significantly to the model (data not shown).
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tPA Activity
tPA activity did not change during fish oil intake (Table 2). A significant fall in tPA activity was observed after corn oil treatment (-0.13±0.03 IU/mL, P=.0005), but the difference between the fish oil group and corn oil group was not significant. Multivariate analysis (Table 3) showed that changes in body weight, triglycerides, NEFAs, and insulin were not independently associated with a change in tPA activity. Changes in phospholipid fatty acids did not add significantly to the model (data not shown).
Plasma Fibrinogen, Factor VIIc, and Platelet Number
Levels of fibrinogen increased by 0.6±0.1 g/L (P=.0001) during fish oil treatment and by 0.4±0.1 g/L (P=.002) during corn oil treatment (Table 2). The changes were similar in both groups (P>.30). No independent associations were found with multivariate analyses between changes in fibrinogen levels and changes in body weight, lipid levels, insulin (Table 3), or phospholipid contents of the different families of fatty acids (data not shown).
None of the groups showed changes in levels of coagulation factor VII or platelet count during treatment.
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Discussion |
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Daily dietary supplementation with 4 g of
3 PUFAs did not specifically influence the fibrinolytic capacity compared with a similar caloric intake of 6 PUFAs. However, an increase in fibrinogen levels was seen in both groups.
Inconsistent results have previously been reported on the effect of 3 PUFAs on the fibrinolytic capacity.25 26 27 28 29 30 31 32 33 34 35 36 37 38 Mehta et al31 reported that fish oil intake caused a fall in PAI-1 activity that paralleled the triglyceride-lowering effect. In contrast, Schmidt et al30 observed a dose-dependent increase in PAI-1 activity and a dose-dependent decrease in triglyceride levels during fish oil treatment. Several studies25 26 27 28 29 have reported that fish oil may adversely affect the fibrinolytic potential, although the mechanism for this is unclear. We did not find any increment in PAI-1 activity during fish oil intake. However, PAI-1 activity increased from baseline in the corn oil group, together with increments in triglyceride levels. Increments in NEFA levels, insulin levels, and body weight were found to be significantly associated with an increment in PAI-1 activity, independent of a change in triglyceride levels and type of intervention. Insulin stimulates lipoprotein lipase and inhibits hormone-sensitive lipase51 and leads to increased NEFA flux to the liver and adipocytes, which may result in both weight gain and increased hepatic triglyceride synthesis.52 It is possible that the observed increase in PAI-1 activity may be associated with an increment in NEFA availability and increased NEFA processing. However, the changes in levels of NEFA, insulin, and body weight accounted for only 20% of the variation of PAI-1 activity. Thus, factors not accounted for in this study, such as changes in dietary habits or lifestyle, may have influenced the PAI-1 activity in the corn oil group, although physical activity, smoking, and alcohol habits did not seem to play an important role in the present study. The inconsistencies in the results of the present study and in earlier studies on fish oil and PAI-1 activity may be partly due to limitations in study design to account for potential confounding factors.27 30 31 32 Plasma phospholipid fatty acid composition reflects the composition of fatty acids in the cell membrane.53 54 Since we did not find any relations between plasma phospholipid fatty acids and PAI-1 activity, it is not likely that incorporation into the cell membrane of the different families of PUFA induces any changes in fibrinolytic capacity.
We found no effects of fish oil intake on tPA activity. However, a decrease in tPA activity was found in the corn oil group. Subgroup analyses indicated that the decrease was most pronounced in persons with the highest body mass index and the highest increase in triglycerides and plasma phospholipid content of saturated fatty acids. No independent predictors of changes in tPA activity was found. The tPA data indicate that changes in lipid metabolism may be associated with changes in the fibrinolytic potential. However, the factors found to be associated with a fall in tPA activity accounted for only 10% of the variation of tPA activity, and we did not find that the increment in phospholipid content of unsaturated fatty acids and fatty acids of the 6 or 3 families influenced the tPA activity in the groups. The fall in tPA activity observed in the corn oil group may therefore also have been due to factors other than intake of corn oil. In a previous study, daily intake of 6 g corn oil induced no changes in tPA activity in normotensive, healthy persons.38
In the present study, levels of fibrinogen increased to about the same extent during intake of fish oil and corn oil (27% and 18%, respectively). In both groups, participants with high body mass index seemed to have the most pronounced increment in fibrinogen during intervention. Changes in body weight, type of intervention, or changes in levels of insulin, triglycerides, NEFA, and phospholipid content of the different families of fatty acids did not influence the change in fibrinogen. The increment in fibrinogen levels after fish oil treatment has been described in some studies,37 55 56 whereas other studies reported either no change16 26 or a decrease.57 58 59 Plasma fibrinogen level is an independent risk factor for coronary heart disease.8 60 Fibrinogen is also an acute-phase reactant. Theoretically, acute-phase–type reactions could be induced by dietary supplements of PUFAs, since consumption of highly unsaturated fatty acids increases the lipid peroxidation.61 Thus, increased oxidative stress could possibly initiate an acute-phase reaction, with fluctuations in both fibrinogen levels and PAI-1 activity, dependent on the concomitant dietary intake of antioxidants.
In conclusion, intervention with fish oil does not adversely affect the fibrinolytic function in hypertensive subjects. As no change was observed in glucose homeostasis17 and a reduction in triglycerides was demonstrated, dietary supplementation with fish oil may safely be recommended in essential hypertension.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by grants from the Norwegian Diabetes Association, Nordic Research Funding, The Research Council of Norway, and Pronova Biocare, Oslo, Norway, who provided the test medication. We thank the staff of the General Clinical Research Centre and appreciate the technical assistance of Jorunn Eikrem, Åse Lund Bendiksen, and Hege Iversen.
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Footnotes |
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Reprint requests to Ingrid Toft, MD, Department of Medicine, University Hospital of Tromsø, N-9038 Tromsø, Norway.
Received March 26, 1996; accepted August 5, 1996.
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