To compare the effects of alpha-linolenic acid (ALA, C18:3n-3) to those of eicosapentaenoic acid (EPA, C20:5n-3) plus docosahexaenoic acid (DHA, C22:6n-3) on cardiovascular risk markers in healthy elderly subjects.
A randomized double-blind nutritional intervention study.
Department of Human Biology, Maastricht University, the Netherlands.
Thirty-seven mildly hypercholesterolemic subjects, 14 men and 23 women aged between 60 and 78 years.
During a run-in period of 3 weeks, subjects consumed an oleic acid-rich diet. The following 6 weeks, 10 subjects remained on the control diet, 13 subjects consumed an ALA-rich diet (6.8 g/day) and 14 subjects an EPA/DHA-rich diet (1.05 g EPA/day+0.55 g DHA/day).
Both n-3 fatty acid diets did not change concentrations of total-cholesterol, LDL-cholesterol, HDL-cholesterol, triacylglycerol and apoA-1 when compared with the oleic acid-rich diet. However, after the EPA/DHA-rich diet, LDL-cholesterol increased by 0.39 mmol/l (P=0.0323, 95% CI (0.030, 0.780 mmol/l)) when compared with the ALA-rich diet. Intake of EPA/DHA also increased apoB concentrations by 14 mg/dl (P=0.0031, 95% CI (4, 23 mg/dl)) and 12 mg/dl (P=0.005, 95% CI (3, 21 mg/dl)) versus the oleic acid and ALA-rich diet, respectively. Except for an EPA/DHA-induced increase in tissue factor pathway inhibitor (TFPI) of 14.6% (P=0.0184 versus ALA diet, 95% CI (1.5, 18.3%)), changes in markers of hemostasis and endothelial integrity did not reach statistical significance following consumption of the two n-3 fatty acid diets.
In healthy elderly subjects, ALA might affect concentrations of LDL-cholesterol and apoB more favorably than EPA/DHA, whereas EPA/DHA seems to affect TFPI more beneficially.
Several intervention studies, such as the GISSI-Prevenzione trial and the Cardiovascular Health Study, have shown that an increased intake of eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3) lowers the risk of coronary heart disease (CHD) (GISSI-Prevenzione-Investigators, 1999; Lemaitre et al., 2003). Humans can acquire these long-chain fatty acids (LCFAs) of the n-3 family directly through consumption of oily fish and seafood, as well as through conversion of alpha-linolenic acid (ALA, C18:3n-3), a plant-derived n-3 fatty acid which may also protect against CHD (de Lorgeril et al., 1994). However, results from tracer studies indicate that ALA conversion is too limited to function as a surrogate for fish intake (Emken et al., 1994; Pawlosky et al., 2001; Burdge, 2004; Goyens et al., 2005). This suggests that these n-3 fatty acids derived from different sources might have their own specific effects on cardiovascular risk markers. However, the number of human studies that have directly compared the influence of ALA and its LCFA derivates on a wide range of cardiovascular risk markers is sparse. It is known, however, that the potential to lower triacylglycerol concentrations in blood by the marine fatty acids is not shared by ALA (Harris, 1997). In contrast, results from a recent study by Finnegan et al. (2003a, 2003b) suggest that ALA and EPA/DHA have comparable effects on blood coagulation and fibrinolytic factors. Studies with regard to the effects of plant and marine derived n-3 fatty acids on endothelial markers are still sparse.
Most studies so far have been performed in young and middle-aged subjects. Surprisingly, less effort has been made to elucidate how ALA and fish oil affect cardiovascular risk markers in elderly subjects, considering that the risk for CHD builds up with increasing age and the occurrence of CHD is most overt from the age of 60 years (Assmann et al., 1999). As decreasing cardiovascular risk is of benefit for this population, the elderly may also profit from increased n-3 fatty acid consumption to lower the cardiovascular risk (Mozaffarian et al., 2003a, 2003b). However, for aged subjects it is not clear to what extent cardiovascular risk markers are susceptible to dietary modulation with n-3 fatty acids. Therefore, the aim of the present study was to assess the effects of ALA with those of EPA/DHA on lipoprotein profile, on coagulation and fibrinolytic factors, and on endothelial function in subjects aged between 60 and 78 years.
Materials and methods
Subjects were recruited in Maastricht and surroundings through advertisements in local newspapers and posters in university and public buildings. People, who were interested, were informed in detail about the nature and purpose of the study, which was approved by the Medical Ethics Committee of Maastricht University. After giving their written informed consent, 48 volunteers participated in the screening procedure, which consisted of measurements of height, weight and blood pressure, and collection of a morning specimen of urine to verify the absence of glucose and protein. Further, subjects had to fill out a medical questionnaire, while two fasting blood samples, separated by a period of at least 3 days, were drawn to determine serum lipids and lipoprotein concentrations. A total of 41 subjects, who met the following inclusion criteria, were enrolled in the study: serum total cholesterol concentration<8.0 mmol/l, triacylglycerol concentration<3.0 mmol/l, absence of glucose and proteinuria, and no use of medication or prescribed diets known to affect the parameters of interest. All subjects were apparently healthy, as indicated by a medical questionnaire. Two subjects were excluded during the study, as they had to take non-steroidal anti-inflammatory drugs, whereas one subject stopped due to family circumstances. The remaining 38 mildly hypercholesterolemic subjects, 14 men and 23 women, completed the study. The subjects’ characteristics of each study group as measured at the start of the study are presented in Table 1. Thirty-seven subjects were studied as one female subject was excluded prior to analysis of the results, due to incomplete data.
Experimental design and diets
During the run-in period of 3 weeks, all 37 subjects consumed an oleic acid-rich diet. For the subsequent 6 weeks, 10 subjects continued on the run-in oleic acid diet, 13 subjects received a diet rich in ALA and the remaining 14 subjects received a diet enriched with EPA and DHA. Subjects were randomly allocated to the three intervention groups, stratified for gender, as was described previously (Wensing et al., 1999).
Subjects were provided with a specific amount of products made from experimental shortenings (Table 2). The experimental products were free of charge and consisted of chocolate paste, pies, cake and spreads. They were supplied, on a weekly basis, to each participant individually. In order to prevent oxidation of the highly unsaturated fatty acids, no heating was used for the preparation of the experimental products and subjects were not allowed to use the spreads for baking or frying. Each subject consumed on average 30 g of experimental shortenings, which provided 6.8 g ALA for the ALA group and 1.05 g EPA plus 0.55 g DHA for the EPA/DHA group. At the end of both the run-in and the intervention periods, subjects had to weigh and record their food intakes for two working days and one weekend day to estimate energy and nutrient intakes (Nevo, 1989). In addition, subjects were asked to list in a diary any signs of illness, medication used, alcoholic beverages and deviations from the study protocol. Diaries were checked weekly and in the presence of the subjects. Subjects of the oleic acid and ALA group were not allowed to consume fish or seafood. Further, all subjects were asked not to change their usual physical activity pattern, smoking habits and use of oral contraceptives during the course of the study. Body weight, without shoes or heavy clothing, was recorded once a week and, if necessary, energy intake was adjusted.
Blood sampling and analyses
During the last week of both the run-in and experimental periods, blood was sampled three times after an overnight fast of at least 12 h, abstinence of smoking on the morning before blood sampling and a 24-h abstinence of alcohol. After 15 min of rest, an infusion needle (1.0 mm/G19, Microflex, Ecouen, France) was inserted into an antecubetal vein with the subject in a recumbent position. Blood was first drawn into a 10-ml clotting tube for measurements of serum lipids and lipoproteins. Then blood was sampled into two 5 ml tubes containing citrate, theophylline, adenosine and dipyridamole (CTAD) and centrifuged at 2000 g (10 min, 4°C). One tube was kept for analysis of plasminogen activator inhibitor (PAI) activity, whereas the other tube was further centrifuged at 11 500 g (30 min, 4°C) and used for analysis of coagulation factors. Standard pool plasmas were obtained from 15 normolipidemic men and women according to the methods described above. Factor VIIam and tissue factor pathway inhibitor (TFPI) activities were expressed as percentage of standard plasma. After clotting for at least 1 h at room temperature, serum was obtained by centrifugation of the clotting tubes at 2000 g for 30 min at 4°C. Serum samples were stored at −80°C until later analysis. At the end of the study, the three samples from the run-in period as well as the three samples from the experimental period were pooled (1:1:1, v/v) prior to the analyses and all samples from one subject were analyzed within one run.
Serum concentrations of total cholesterol (CHOD-PAP method; Monotest cholesterol, Boehringer Mannheim, Mannheim, Germany), HDL cholesterol (precipitation method; Monotest cholesterol, Boehringer Mannheim, Mannheim, Germany) and triacylglycerols (GPO-Trinder; Sigma Diagnostics, St Louis, MO, USA) were analyzed enzymatically. Concentrations of LDL cholesterol were calculated with the Friedewald equations (Friedewald et al., 1972). Apolipoprotein (apo) A-1 and apoB were measured in serum, with an immunoturbidimetric reaction (UNI-KIT apoA-I and UNI-KIT apoB, Roche, Basel, Switzerland). Plasma fibrinogen concentrations were measured according to the method of Clauss (1957). Factor VII amidolytic (factor VIIam) activity was determined using a two-stage chromogenic assay as described elsewhere (Coaset F.VII, Chromogenix Instrumentation Laboratory, Milano, Italy), while prothrombin activation fragment 1+2 was determined with an enzyme-linked immunoassay (ELISA; Enzygnost F 1+2 micro, Behring Diagnostics Inc., Westwood, MA, USA) (Temme et al., 1999). TFPI activity was determined according to the method of Sandset et al. (1987), and PAI activity was measured with a two-stage indirect chromogenic assay (Spectrolyse®/pL PAI, Biopool, Umea, Sweden). Commercially available ELISAs were used to measure concentrations of von Willebrand factor (Asserachrom vWF, Boehringer Mannheim, Germany), thrombomodulin (Asserachrom Thrombomodulin, Diagnostica Stago, Asnière, France), E-selectin (sE-selectin ELISA, Bender MedSystems, Boehringer Ingelheim Bioproducts, Germany), P-selectin (sP-selectin ELISA, Bender MedSystems, Boehringer Ingelheim Bioproducts, Germany) and vascular cell adhesion molecule-1 (sVCAM-1 ELISA, Bender MedSystems, Boehringer Ingelheim Bioproducts, Germany). Analysis of the fatty acid composition of erythrocyte neutral phospholipids has already been described in detail (Wensing et al., 1999).
The statistical power to detect a true difference of at least 20% in the parameters of interest was more than 80% for the thrombotic parameters and more than 90% for the lipoproteins. For each subject, the responses to the treatments were analyzed with one-factor analysis of covariance, using the GLM procedure in SAS (SAS version 8.0, Copyright 1999 SAS Institute Inc., Cary, NC, USA). The parameters of interest followed a normal distribution. The values at the end of the experimental period represented the dependent variables, whereas the values at the end of the run-in period were included as covariates and the type of the diet was defined as a fixed factor. When a significant effect of the diet was found (P<0.05), a Tukey post-hoc test was used to compare the diets pairwise. All values were expressed as means with their standard deviation.
Body weight, dietary intake and erythrocyte phospholipid composition
Changes in body weight during the experimental period were not significantly different (P=0.201) between the three groups and were −0.1±0.8 kg (mean±s.d.) for the oleic acid group, 0.1±1.2 kg for the ALA group and 0.5±0.6 kg for the EPA/DHA group. Energy intake during the study was not significantly different between the three study groups (Table 3). Compared to the oleic acid group, MUFA intake decreased however significantly by 3.6.En% in the ALA group (P=0.027, 95% CI (−5.3, −0.3 En%)). The total PUFA intake was increased in the ALA group by 5.1 En% when compared to the oleic acid group (P<0.001, 95% CI (1.7, 6.4 En%)) and by 3.1 En% when compared to the EPA/DHA group (P=0.02, 95% CI (0.4, 4.4 En%)).
The effects of the three study diets on the fatty acid composition of the erythrocytes neutral phospholipids have already been described (Wensing et al., 1999). Briefly, none of the three diets changed the proportions of SAFA, MUFA and PUFA significantly in the erythrocyte phospholipids. As expected, the proportion of ALA remained unchanged after consumption of the oleic acid and EPA/DHA diet, whereas it significantly increased with 0.4% after consumption of the ALA diet (P<0.001 versus control diet and versus EPA/DHA diet). Compared to the oleic acid and ALA groups, the proportion of C18:2n-6 decreased significantly with 2.2% in the EPA/DHA group (P<0.01 versus control group and P<0.001 versus ALA group). This decrease was accompanied by a significant increase of 1.3% in the proportion of EPA (P=0.001 versus control and versus ALA group) and of 0.8% in the proportion of DHA (P=0.001 versus control and versus ALA group).
Lipids and lipoproteins
Changes in total cholesterol were not significantly different between the three groups (Table 4). Compared with the oleic acid diet, the ALA diet and the EPA/DHA diet also had similar effects on LDL. When compared with the ALA group, however, the EPA/DHA diet increased LDL cholesterol with 0.39 mmol/l (P=0.0323, 95% confidence interval for the difference in change: (0.030, 0.780 mmol/l)). These effects were also evident for apoB. No difference was observed between the oleic acid group and the ALA group, while apoB concentrations increased in the EPA/DHA group with 14 mg/dl (P=0.0031, 95% CI (4, 23 mg/dl)) when compared with the oleic acid group and with 12 mg/dl when compared with the ALA group (P=0.005, 95% CI (3, 21 mg/dl)). Triacylglycerol concentrations decreased insignificantly on the EPA/DHA group when compared to both the oleic acid and ALA group. Changes in HDL cholesterol, the total to HDL cholesterol ratio and apoA-I were also comparable between the three diets.
Markers for endothelial function, adhesion molecules, blood coagulation and fibrinolytic parameters
The change in TFPI was significantly different between the ALA and EPA/DHA group (P=0.0184, 95% CI (1.5, 18.3%)) (Table 5). Other changes in markers for blood coagulation and fibrinolysis were not different between the three groups. No significant dietary effects were found on markers for endothelial function (Table 6).
In the present study, the effects of the plant-derived ALA and the fish-derived EPA and DHA were examined on cardiovascular risk markers in mildly hypercholesterolemic elderly subjects. We found that EPA/DHA significantly increased LDL-cholesterol and apoB concentrations as well as TFPI activity when compared with ALA.
The number of studies which have addressed side-by-side the effects of ALA and EPA/DHA on cardiovascular risk markers is scarce. In a recent study, Finnegan et al. (2003b) gave hyperlipidemic subjects aged 25–72 years for 4 weeks an n-6 fatty acid-rich control diet. For the next 6 months, subjects were randomized over the control diet, a diet providing 0.8 or 1.7 g EPA/DHA per day, or a diet supplying 4.5 or 9.5 g ALA daily. None of the diets enriched with n-3 polyunsaturated fatty acids changed fasting serum lipid concentrations, when compared with the n-6 fatty acid control diet. These results agreed well with our results, as we also observed no significant changes in serum lipid and lipoprotein concentrations of the two n-3 fatty acid diets, when compared with the control diet rich in oleic acid. Finnigan et al. (2003b) further reported that serum triacylglycerol concentrations decreased and those of LDL tended to increase in the group consuming 1.7 g EPA/DHA when compared to the 9.5 g ALA group. In our study, EPA/DHA also increased LDL cholesterol concentration when compared with ALA. An LDL-cholesterol increasing effect of fish oil is a common phenomenon, especially in hypertriglyceridemic subjects (Harris, 1997). Furthermore, we did not observe a significant hypotriglyceridemic effect after a comparable EPA/DHA intake of 1.6 g/day either. However, as reviewed by Harris, triacylglycerol decreased (from 1 to 34% compared to control) in studies which provided less than 2 g EPA/DHA per day, but this decrease was often not statistically significant (Harris, 2001). Furthermore, subjects in the present study had rather low baseline triacylglycerol concentration, which might have hampered a possible triacylglycerol-lowering effect of marine fatty acids.
It has been suggested by Sanders (1996) that elderly might benefit more from an improvement of factors influencing blood clotting and fibrinolysis than of other factors involved in the atherogenic process. The few studies in young and middle-aged subjects that have examined the influence of ALA on factors of coagulation or fibrinolysis did, in general, not report any significant effects (Allman-Farinelli et al., 1999), whereas studies with fish fatty acids yielded equivocal results. The activity of the fibrinolytic factor PAI-1, for example, did either not change or even increased after EPA/DHA supplementation (Hornstra, 2001; Miller, 2005). In view of these contrasting findings, Hansen et al. (2000) therefore pooled data obtained from 17 studies which provided n-3 fatty acids in doses varying from 1.6 to 9.0 g/day. It was concluded that there is no strong evidence for unfavorable, clinically relevant effects of n-3 fatty acids on PAI-1 activity in plasma (Hansen et al., 2000). However, as recently reviewed (Wijendran and Hayes, 2004), modulating effects of EPA/DHA on coagulation factors such as fibrinogen, factor VII and Willebrand factor were in general observed after intakes of at least 4 g/day, while most studies could not detect an effect when EPA/DHA intake was between 0.9 and 4 g/day. In addition, studies that have specifically compared side-by-side effects of plant and marine derived n-3 fatty acids suggest that these fatty acids have similar effects on hemostasis and fibrinolysis in young and middle-aged subjects, both at realistic and rather high intakes (Freese and Mutanen, 1997; Finnegan et al., 2003a). Though most markers of blood coagulation and fibrinolysis did not change significantly after consumption of any of our study diets, we did observe an increase in TFPI activity after consumption of the EPA/DHA diet when compared to the ALA diet. However, we did not find an effect of the EPA/DHA diet on TFPI activity when compared to the oleic-acid rich control diet. Grundt et al. (1999) found also no effect on TFPI when subjects with combined hyperlipidemia consumed for 12 weeks either a daily supplement of 4 g EPA/DHA or a corn oil supplement, rich in linoleic acid. In contrast, Berretini et al. (1996) found a significant increase in TFPI levels in plasma of subjects with chronic atherosclerotic disease following a daily supplementation with 3 g EPA/DHA over a period of 16 weeks (Berrettini et al., 1996).
Results of Miles et al. (2001) suggested that effects of fish oil on endothelial activation were age-dependent. In that study, fish oil did not affect sVCAM-1 and increased sE-selectin in young men (<40 years), but significantly decreased sVCAM-1 and tended to lower sE-selectin in the older subjects (>55 years). Thies et al. (2001) compared the influence of moderate intakes of ALA, DHA and fish oil on plasma-soluble adhesion molecules It was found that, in contrast to DHA alone, both ALA and fish oil supplementation decreased sVCAM-1 and sE-selectin compared to the placebo supplement (an 80:20 mix of palm and sunflowerseed oils). This finding implies that the observed favorable effects are specific for EPA and/or ALA. Zhao et al. (2004) also found a decrease in sVCAM-1 and sE-selectin in hypercholesterolemic subjects aged between 36 and 65 years, after consumption of a diet rich in ALA (6.5 En% ALA/d or 13–28 g/day). In the study by Rallidis et al. (2004) a decrease in sVCAM-1, but not in sE-selectin, was observed in dyslipidemic subjects, after intake of 8.1 g ALA/day (15 ml/day of linseed oil) over a period of 12 weeks. In contrast to these studies, our study shows that all three diets had comparable effects on plasma-soluble adhesion molecules and soluble selectins. Hence, based on our results, we cannot attribute a beneficial effect to ALA or the marine fatty acids with regard to markers of endothelial integrity in healthy elderly. We do not think that the amount of ingested EPA/DHA in the present study was too low to induce an effect on endothelial markers, as other studies showed beneficial effects after low to moderate intakes of n-3 fish fatty acids (Miles et al., 2001; Thies et al., 2001; Baro et al., 2003; Berstad et al., 2003; Hjerkinn et al., 2005). Our study duration was however shorter than those of other studies, which may have masked any beneficial effects of EPA/DHA on these endothelial markers. In combination with the study duration, the intake of ALA might also have been too low to observe effects on sVCAM-1 and sE-selectin within a period of 6 weeks. Even though ALA intake in the study by Thies et al. (2001) was lower (2 g/day) than in the present study, the study duration was two times longer. In contrast, the study by Zhao et al. (2004) also lasted 6 weeks, but ALA intake was at least twice as high. Thus, no clear explanation exists to explain the divergent effects of ALA on endothelial markers.
In summary, our findings indicate that n-3 fatty acids from both plant and marine sources do not affect the lipid profile equally favorable in elderly subjects as oleic acid. Except for the already beneficial effects on aggregation (Wensing et al., 1999), fish fatty acids also seem to influence TFPI activity favorably. These positive effects of EPA/DHA are however counterbalanced by an increase in LDL-cholesterol and apoB concentrations. Adhesion molecules were not affected by any of the n-3 fatty acids when compared to oleic acid.
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Guarantors: PLL Goyens and RP Mensink.
Contributors: PLLG and RPM participated intellectually in the development of the paper.
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Goyens, P., Mensink, R. Effects of alpha-linolenic acid versus those of EPA/DHA on cardiovascular risk markers in healthy elderly subjects. Eur J Clin Nutr 60, 978–984 (2006). https://doi.org/10.1038/sj.ejcn.1602408
- alpha-linolenic acid
- linoleic acid
- cardiovascular risk markers
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