© 2000 American Heart Association, Inc.
Thrombosis |
Effect of 
-3 Fatty Acids and Simvastatin on Hemostatic Risk Factors and Postprandial Hyperlipemia in Patients With Combined Hyperlipemia
From the Department of Medicine (A.N., J.-B.H., H.N.), Institute of Clinical Medicine, and the Institute of Community Medicine (K.H.B.), University of Tromsø, Tromsø, Norway, and the Department of Medicine (P.M.S.), Ullevål Hospital, University of Oslo, Oslo, Norway.
Correspondence to Prof A. Nordøy, Department of Medicine, University Hospital, 9038 Tromsø, Norway. E-mail medan{at}rito.no
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Abstract |
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Abstract—Patients with combined hyperlipemia have lipid abnormalities associated with an increased tendency to develop atherosclerosis and thrombosis. This tendency may be accelerated during postprandial hyperlipemia. In the present double-blind parallel study, 41 patients with combined hyperlipemia and serum triacylglycerols between 2.0 and 15.0 mmol/L and serum total cholesterol >5.3 mmol/L at the end of a 3-month dietary run-in period were treated with simvastatin at 20 mg/d for at least 10 weeks; patients were then randomized into 2 groups receiving simvastatin+
-3
fatty acids at 3.36 g/d or placebo (corn oil) for an additional 5
weeks. Hemostatic variables that have been associated with
increased thrombotic tendency were evaluated with subjects in the
fasting state and during postprandial hyperlipemia before and after
combined treatment. Supplementation of -3 fatty acid reduced tissue
factor pathway inhibitor antigen (P<0.05)
in the fasting state, reduced the degree of postprandial hyperlipemia
(P<0.005), and reduced activated factor VII
concentration appearing during postprandial hyperlipemia. In
conclusion, -3 fatty acids given in addition to
simvastatin to patients with combined hyperlipemia reduced
the free tissue factor pathway inhibitor fraction in the
fasting state and inhibited the activation of factor VII occurring
during postprandial lipemia, thus representing a potential
beneficial effect on the hemostatic risk profile in this patient
group.
Key Words: combined hyperlipemia • postprandial hyperlipemia • hemostatic risk factors
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Introduction |
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Rupture of an atherosclerotic plaque with subsequent formation of an occlusive thrombus is the major cause of myocardial infarction.1 The extrinsic coagulation system has been suggested to play a crucial role in the initiation of blood coagulation in atherosclerotic disease.2 Tissue factor (TF) is an integral membrane protein that functions as a cofactor to enhance the proteolytic activity of activated factor VII (FVIIa) toward factor IX and factor X, which leads to the formation of a fibrin clot.3 TF is synthesized in perturbed endothelial cells,4 which may render them thrombogenic, and is also present in the cores of atherosclerotic plaques.5 Thus, transient exposure of TF at the surface of atherosclerotic plaque or perturbed endothelial cells may cause low-grade triggering of blood coagulation. TF pathway inhibitor (TFPI) is a potent inhibitor of TF-induced coagulation, which exerts its function by neutralizing the catalytic activity of factor Xa and by feedback inhibition of the TF-FVIIa complex.6 7
Factor VII (FVII) is the first enzyme involved in the extrinsic pathway of blood coagulation. The major proportion of FVII circulates in plasma in the zymogen form, whereas low but significant levels appear in an activated form (FVIIa), which serves as the primer for triggering the clotting cascade.8 9 10 In epidemiological studies, the coagulation activity of factor VII (FVIIc) is positively correlated to serum triglycerides11 (less consistently to serum cholesterol) and is found to predict coronary heart disease (CHD).12 13 Reliable assays for determination of FVIIa have been developed recently,14 15 and measurement of FVIIa has been found to be highly relevant for understanding the role of FVII in CHD. FVIIa has been found to be elevated in acute coronary syndromes14 15 but unchanged in a follow-up study of patients suffering from myocardial infarction at a young age.16
Familial combined hyperlipemia is the most common form of hyperlipemia in young survivors of myocardial infarction.17 These lipid abnormalities are caused by a heterogeneous combination of predisposing and environmental factors. Affected individuals have elevated concentrations of LDL, VLDL, or both. Such lipid profiles are frequently associated with an unfavorable decrease in HDL concentration, an elevated apolipoprotein B concentration, and increased prevalence of atherogenic small dense LDL particles.18
Subjects with combined hyperlipemia commonly show changes in hemostatic variables associated with increased risk for developing thrombotic events. These changes have been associated with increased procoagulant activity and with inhibition of the fibrinolytic potential. The patients also commonly show insulin resistance that is probably related to an excessive postprandial release of free fatty acids (FFAs) caused by impaired suppression of hormone-sensitive lipase; however, other mechanisms are also involved.19 Characteristically, the postprandial hyperlipemia in patients with combined hyperlipemia is usually excessive with regard to extent and duration.
We have recently investigated the effects of simvastatin
and -3 fatty acids (-3 FAs) on lipids, lipoproteins, and
antioxidant capacity in a heterogeneous group of patients
with combined or mixed hyperlipemia.20 The combination of
these 2 treatments efficiently reduced serum LDL and VLDL
cholesterol and triglycerides with an increase
in HDL cholesterol. We also have confirmed that these
patients have changes in the hemostatic variables increasing their
tendency to thrombotic events.21 During postprandial
hyperlipemia, these subjects showed a highly significant increase in
FVIIa.
In the present study, we have evaluated the effect of
simvastatin and -3 FA on the hemostatic risk profile
associated with combined hyperlipemia. We have also examined the effect
of the combined treatment on the degree of postprandial hyperlipemia
and the activation of FVII associated with intake of a standardized
fat-rich meal.
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Methods |
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Patients
Forty-one patients (12 women and 29 men) aged 25 to 60 years referred to The Lipid Clinic at the Department of Medicine, University Hospital of Tromsø, for combined hyperlipemia were recruited for the study. All subjects had been consuming habitual diets, and none were taking lipid-lowering medication, antioxidants, or fish oil concentrates at the time when they were recruited for the study. Seventeen were regular smokers. Before entry into the drug-intervention phase of the study, a mean fasting serum triacylglycerol (TAG) concentration (after a 16-week dietary run-in period) between 2.0 and 15.0 mmol/L and serum total cholesterol >5.3 mmol/L were required.20 The subjects’ characteristics, including body weight, body mass index, and serum lipid levels, are given in Table 1
. Two of the participants
had experienced acute myocardial infarction 2 and 3 years before,
respectively, but were now without symptoms. These 2 patients also had
well-regulated diabetes mellitus that was treated with diet only. The
others had no cardiovascular, liver, or renal diseases,
bleeding disorders, alcoholism, or other diseases that might influence
lipid metabolism or hemostasis. In addition, none used
drugs affecting lipid metabolism or hemostasis. The study
was approved by the Regional Board of Research Ethics, and each subject
gave written informed consent. The study was conducted at the Clinical
Research Center at the University Hospital.
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Study Design
This double-blind placebo-controlled trial with patients
randomized for age and sex was initiated with a 16-week dietary run-in
period during which the participants were following guidelines aiming
at a dietary composition in which the energy supplied from
carbohydrates, fats, and proteins was 
54%, 30%, and 15%,
respectively. At a maximum of 6-day intervals at the end of the dietary
run-in period, 2 blood samples were collected from all patients after
12 hours of fasting. The means of the results obtained by lipid
analysis after the diet were used as baseline values. Physical
examination, a dietary interview, and a fat tolerance test were
performed. The patients were then treated with simvastatin
(Zocor, MSD Norge A/S) at 20 mg/d (evening) for 5 to 10 weeks. The
patients were finally again randomized (by age and sex) into 2 groups,
each including an equal number of participants that had used
simvastatin for 5 or 10 weeks, respectively. All patients
were then, for the last 5 weeks, given simvastatin at 20
mg/d. In addition, one of the 2 groups (n=21) was given a supplement of
highly purified -3 FAs given as 4 g/d of ethyl esters of
eicosahexaenoic acid (45%) and docosahexaenoic acid 39%, (Omacor
Pharmacia and Upjohn AS), and the other group (n=20) was given placebo
(4 g corn oil/d) in indistinguishable soft gelatin capsules, each
containing 1 g of oil. Further details of the Omacor and the
placebo capsules have been reported previously.20
Blood Collection
With patients in the fasting state, blood samples were collected
twice before any intervention with drugs and twice at the end of the
last intervention period, 15 weeks later. In addition, blood samples
were collected 5 times during the fat-load tests, which were also
carried out before any drug intervention and at the end of the study.
Lipids, lipoproteins, glucose, and insulin were measured in all blood
samples. Blood for preparation of plasma for measurement of FFAs was
collected into Vacutainers containing disodium EDTA as anticoagulant
(0.12 mL EDTA K3, 0.34 mol/L per tube) and kept
on melting ice until centrifugation at 2000g
for 15 minutes at 4°C. Plasma was transferred into sterile cryovials
in aliquots of 1 mL, flushed with nitrogen, and stored at -70°C
until analysis. Separate blood samples were collected by
antecubital vein puncture in the other arm for coagulation and
fibrinolytic assays with patients in the fasting state and at 4 hours
and 8 hours after the fat-load test. Blood samples were collected into
Vacutainer tubes containing either 1.7 mg/mL disodium EDTA or 1/10 vol
of 0.129 mmol/L sodium citrate for lipid analysis or for
coagulation and fibrinolysis assays, respectively.
Samples for measurement of tissue plasminogen
activator (tPA) activity were collected into Biopool
Stabilite blood collection tubes (Biopool AB). Plasma was prepared by
centrifugation at 2000g for 15 minutes at
22°C, and aliquots were transferred into sterile cryovials of 1 mL,
flushed with N2, and stored at -70°C.
Oral Fat-Load Test
The oral fat-load test was carried out at the end of the dietary
run-in period and after the final intervention period in each subject.
Between 7 and 8 AM after an overnight fast, a needle was
inserted into the patient’s antecubital vein, and fasting blood
samples were drawn. A fatty meal consisting of 200 mL cream (36% fat),
1 egg yolk, and 2 waffles containing a total of 78 g fat, 490 mg
cholesterol, and 760 kcal energy was given. The meal was
ingested over a 15-minute period and was well tolerated by all
participants. Apart from the test meal, only no-caloric mineral water
and an apple were allowed between the test meal and the 8-hour blood
sample drawing. The extent of postprandial
hypertriglyceridemia was assessed by the
response areas under the curve (AUCs: integrated, absolute, and
incremental [iAUC]) of plasma TAG measured every second hour over the
8-hour study period and by the triglyceridemic
response defined as average of the 2 highest postprandial TAG
concentrations minus the baseline concentration according to Patch et
al.22 Total serum cholesterol was measured in
parallel with TAG, whereas serum FFAs were measured at baseline and at
4 and 6 hours after intake of the meal. Serum insulin, glucose, and the
hemostatic variables included (see below) were measured in the
fasting state and at 4 and 8 hours after intake of the meal.
Clinical and Laboratory Measurements
All methods used for lipid, glucose, and insulin
analyses have recently been described,20 except
for the following modifications: serum FFAs and total phospholipid FAs
were, after separation, transmethylated with 1% and 2% sulfuric acid,
respectively, in methanol, extracted into hexane, and evaporated into
dryness. The following hemostatic variables were investigated by
routine methods and included the following coagulation variables,
all related to the extrinsic coagulation system: total
FVIIc, activated 2-chain form of FVII
(FVIIa), total amount of FVII antigen
(FVIIag), lipoprotein-bound TFPI activity
(TFPIa), and lipoprotein-free TFPI antigen
(TFPIag). In addition, von Willebrand
factor activity, clottable fibrinogen and the fibrinolytic modulators,
plasminogen activator inhibitor
activity (PAI-1a), and tPA antigen
(tPAag) were included. Routine hematology,
including red and white blood cell counts, and platelet
parameters were followed throughout.
Statistical Analysis
Independent relations between fasting lipid levels, hemostatic
variables, and glucose/insulin levels and postprandial hyperlipemia
were investigated by multiple linear regression. Spearman correlation
coefficients were used to examine correlations between changes in
hemostatic variables and lipid values. Differences in coagulation
factors and fibrinolytic activity before and after a standardized fat
meal were tested by 1-sample t test. Two-sided probability
values of P<0.05 were considered to indicate statistical
significance. ANOVA was used to assess differences between groups in
the fasting levels and in AUCs and iAUCs. The SAS software package was
used.23
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Results |
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Patients
All patients remained in the study throughout the entire study period. The compliance based on capsules consumed and increase of
-3
FA in serum phospholipids was excellent.20 The group
characteristics given in Table 1
showed no significant
differences between the 2 groups. Simvastatin and -3 FA
compared with simvastatin and placebo reduced serum
concentrations of total cholesterol (P=0.05),
TAGs (P<0.01), and apolipoprotein E (P<0.05) as
recently described.20
Effects on Hemostatic Variables
As shown in Table 2, only
TFPIag concentrations were significantly more
reduced (P<0.05) by the combination of
simvastatin and -3 FA than they were in the control
group. When the hemostatic parameters were compared within
the 2 groups, a similar trend was seen in both groups, with increased
concentrations of fibrinogen, FVIIa, and
PAI-1a and a reduction in the concentrations of
FVIIag, TFPIa, and
TFPIag. However, only in the group given
supplementation of -3 FA did these deviations become significant.
Blood platelet count and mean platelet volume were not
significantly influenced by treatment (results not shown).
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Postprandial Hyperlipemia and Glucose Metabolism
A highly significant reduction in postprandial hyperlipemia
measured both as incremental TAG concentrations (iAUC) and as
triglyceridemic response was observed (Table 3, Figure 1) after combined treatment with
simvastatin and -3 FA compared with
simvastatin alone. As shown in Figure 2, the concentration of total FFAs showed
a decline at 4 hours and only a moderate but significant
(P<0.05) increase at 6 hours after the fat load in these
patients with combined hyperlipemia. After intervention, both groups
showed significant reductions in fasting concentrations of FFA, an
increase of 200% after 4 hours, and a final decline at 6 hours. No
effect attributable to the supplement of -3 FA was seen. No
significant differences in the concentrations of total
cholesterol during postprandial hyperlipemia were observed
between the 2 groups before or after intervention (results not
shown).
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|
) and after (•) treatment with simvastatin
plus 
) and after (
) treatment with
simvastatin plus corn oil. Values are mean±SD.
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A moderate nonsignificant increase in glucose and insulin
concentrations occurred during postprandial hyperlipemia in both groups
before and after treatment (Table 3). A significant increase
(P<0.05) in the insulin/glucose ratio was observed in the
group given simvastatin plus omega-3 FA (Table 3).
Postprandial Hyperlipemia and Hemostatic Variables
As shown in Figure 3, a trend toward
increased concentrations of FVIIc and
FVIIa was observed during postprandial
hyperlipemia. This increase of FVIIa during
postprandial hyperlipemia was significantly reduced
(P<0.05) after treatment with simvastatin and
-3 FA. None of the other coagulation variables measured during
postprandial hyperlipemia showed significant changes after treatment
with simvastatin and -3 FA (results not shown). Both
tPAag and PAI-1a showed a
decline 8 hours after intake of the standardized meal without
significant differences between the 2 groups after intervention (Figure 4).
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Discussion |
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Epidemiological, clinical, and experimental studies have shown that dyslipidemia associated with insulin resistance and hypertension also may include a procoagulant state with activation of the coagulation system and inhibition of the fibrinolytic activities.11 24 25 In the early prospective epidemiological studies, it was shown that FVIIc, fibrinogen, PAI-1a, and tPAag may represent independent risk factors for development of CHD.11 24 25 In a recent study of patients with combined hyperlipemia, we have confirmed that FVIIag and FVIIc are correlated with the triglyceride-rich lipoproteins, particularly with the concentration of intermediate density lipoproteins (IDL) TAGs.21 TFPIa showed a significant correlation with the concentration of LDL, a lipoprotein fraction also associated with increased risk for CHD.
In human plasma, 80% of TFPI is bound to lipoproteins, especially LDL,
whereas 10% to 20% circulates in a free form.26 A
positive correlation between the total plasma TFPI activity and LDL
cholesterol/apolipoprotein B has been reported in normal
individuals27 and in hypercholesterolemic
patients.28 29 In the present study, we found that
treatment with simvastatin alone induced a significant
reduction of triglyceride-rich lipoproteins and LDL that
was paralleled by a reduction of TFPIa. As
previously shown, this reduction was directly correlated to the
reduction of LDL, which was due to a specific decrease in LDL-TFPI
complexes in plasma.28 29 30 No further decrease in the
total inhibitory capacity of TFPI, reflected by the
TFPIa method, was seen after adding -3 FA as a
supplement to simvastatin. The free form of plasma TFPI,
reflected by the TFPIag method, was unchanged by
statins alone but showed a modest decrease by adding -3 FA to statin
treatment. The mechanism beyond this observation is unknown. However,
it has been reported recently that the free form of TFPI showed a weak,
but positive, correlation to the concentrations of both
triglycerides and cholesterol in human
plasma.31 Thus, if this relation is causal, it would be
expected that a decrease in these serum lipids would be accompanied by
a decrease in TFPIag. In the present study,
we actually observed that combined treatment with
simvastatin and -3 FA suppressed serum
cholesterol and triglycerides more efficiently
than simvastatin alone. The clinical significance of the
reduced TFPI activity seen by simvastatin and -3 FA
treatment is unknown.
A significant reduction in total FVIIag was
followed by a 30% increase in the amount of
FVIIa in those patients taking
simvastatin and -3 FA. The mechanism(s) for this
apparent unfavorable shift in the FVII status is unknown. It may be
speculated that the decreased plasma TFPI would attenuate its ability
to inhibit low-grade triggering of the coagulation cascade. However,
precautions should be taken. First, these results were not
significantly different from those observed in the corn oil group, and
even though a similar trend was observed in the corn oil group, the
changes did not reach statistical significance. Second, the surprising
findings should be confirmed in other studies.
Previously, it has been shown that subjects with combined hyperlipemia
have a lower concentration of FVIIa than control
subjects with normal plasma lipid levels.32 This
observation has been associated with a low activity of lipoprotein
lipase, an important factor in the metabolic defects
present in many patients with combined hyperlipemia.33
Lipoprotein lipase activity was not evaluated in the present study.
However, it is known that -3 FA may stimulate
lipolysis.34 Thus, lipoprotein lipase may
represent a common link for the reduction of
triglycerides and activation of FVII by supplementation of
-3 FA. The significance of the increase of
FVIIa is not known; however, increased
FVIIa has been associated with increased
thrombotic tendency. Thus, statins and -3 FAs have complex effects
on the extrinsic clotting system. Whether the total thrombotic risk
profile is increased or not is substance for further investigation.
Postprandial Hyperlipemia
Postprandial hypertriglyceridemia may
represent an independent predictor for CHD.35 36
It has been shown that the level of fasting triglycerides
predicts the degree of postprandial lipemia, an association confirmed
in our patients with combined hyperlipemia.37 By treatment
with simvastatin, the degree of postprandial hyperlipemia
was reduced; however, it was reduced significantly more when -3 FAs
were added. This confirms that -3 FA in the diet reduces both the
degree and the extent of postprandial
hypertriglyceridemia.38 39 In
healthy subjects, it has been shown that resistance to insulin-mediated
glucose disposal or compensatory hyperinsulinemia
are predictors of postprandial lipemic response to
meals.40 In the present study, glucose and insulin
concentrations were followed during the postprandial hyperlipemia both
before and after treatment. The insulin/glucose ratio increased
significantly in the group given -3 FAs. The
physiological effect of this is not known. However,
previous studies in healthy subjects, in patients with
non—insulin-dependent diabetes mellitus, and in patients with insulin
resistance have shown that long-term treatment with similar amounts of
-3 FA did not induce any deterioration of glycemic
control.41 42 43 Subgroup analysis in the
present study did not reveal any special group that reacted with an
increased ratio. Furthermore, there was no relation between the effect
on postprandial hyperlipemia and the increased insulin/glucose
ratio.
During postprandial hyperlipemia, there was a trend toward increased
concentrations of FVIIc, unaffected by treatment
with simvastatin or -3 FA. A similar increase in the
concentration of FVIIa was seen, but this
increase was abolished after intervention with simvastatin
and -3 FA, indicating an association with the reduction of
chylomicron and chylomicron remnants. Contrary to the observations by
Silveira et al,32 we observed no positive correlations
between the concentration of FFAs and FVIIa
during postprandial hyperlipemia. This was also the situation when the
concentrations of the individual FAs of the FFA fraction were evaluated
(results not shown). FVIIag showed no changes or
even a reduction during postprandial hyperlipemia, confirming previous
observations.32 44 In summary, both the total coagulant
and activated forms of FVII increased during postprandial
hyperlipemia, both suggesting increased thrombotic tendency. This
tendency could be inhibited by simvastatin and -3
FA.
It has previously been reported that PAI-1a has a strong diurnal variation.42 In the study by Salomaa et al,45 a marked decline in PAI-1a was observed during the 8 hours after the intake of both fat-free meals and meals containing cream or sunflower oil, adding a fat load of 1 g per kilogram of body weight. A similar reduction was seen in the concentration of tPAag. Also, in the present study, a decline of PAI-1a concentration was observed at both 4 and 8 hours after intake of the meals without relation to treatment or TAG levels, indicating that the plasma concentrations of triglycerides have minor effects on the diurnal variation in PAI-1a. As in previous studies, tPAag was also reduced during postprandial hyperlipemia,8 indicating that the total fibrinolytic potential was mainly unaffected by triglyceride concentrations or treatment.
The present study has shown that when patients with combined
hyperlipemia are treated with diet and simvastatin with or
without supplementation of -3 FA, only minor changes occurred in the
concentrations of coagulation factors and fibrinolytic variables
usually associated with increased thrombotic tendency. However, during
postprandial hyperlipemia, which was reduced by both treatments
(significantly more so after -3 FA), the activation of FVII was
significantly reduced, indicating that such treatment may reduce the
thrombotic potential associated with intake of fat-rich meals in these
patients. In addition, such treatment reduces the concentration of
atherogenic lipoproteins.
Received August 12, 1998; accepted February 8, 1999.
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