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-Linolenic Acid Reduces Inflammatory and Lipid Cardiovascular Risk Factors in Hypercholesterolemic Men and Women1
Departments of
* Nutritional Sciences,
Dairy and Animal Science, and
** Biobehavioral Health, The Pennsylvania State University, University Park, PA and
DuPont Haskell Laboratory for Health and Environmental Sciences, Newark, DE
2To whom correspondence should be addressed. E-mail: pmk3{at}psu.edu.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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-Linolenic acid (ALA) reduces cardiovascular disease (CVD) risk, possibly by favorably changing vascular inflammation and endothelial dysfunction. Inflammatory markers and lipids and lipoproteins were assessed in hypercholesterolemic subjects (n = 23) fed 2 diets low in saturated fat and cholesterol, and high in PUFA varying in ALA (ALA Diet) and linoleic acid (LA Diet) compared with an average American diet (AAD). The ALA Diet provided 17% energy from PUFA (10.5% LA; 6.5% ALA); the LA Diet provided 16.4% energy from PUFA (12.6% LA; 3.6% ALA); and the AAD provided 8.7% energy from PUFA (7.7% LA; 0.8% ALA). The ALA Diet decreased C-reactive protein (CRP, P < 0.01), whereas the LA Diet tended to decrease CRP (P = 0.08). Although the 2 high-PUFA diets similarly decreased intercellular cell adhesion molecule-1 vs. AAD (–19.1% by the ALA Diet, P < 0.01; –11.0% by the LA Diet, P < 0.01), the ALA Diet decreased vascular cell adhesion molecule-1 (VCAM-1, –15.6% vs. –3.1%, P < 0.01) and E-selectin (–14.6% vs. –8.1%, P < 0.01) more than the LA Diet. Changes in CRP and VCAM-1 were inversely associated with changes in serum eicosapentaenoic acid (EPA) (r = –0.496, P = 0.016; r = –0.418, P = 0.047), or EPA plus docosapentaenoic acid (r = –0.409, P = 0.053; r = –0.357, P = 0.091) after subjects consumed the ALA Diet. The 2 high-PUFA diets decreased serum total cholesterol, LDL cholesterol and triglycerides similarly (P < 0.05); the ALA Diet decreased HDL cholesterol and apolipoprotein AI compared with the AAD (P < 0.05). ALA appears to decrease CVD risk by inhibiting vascular inflammation and endothelial activation beyond its lipid-lowering effects.
KEY WORDS: • -linolenic acid • PUFA • C-reactive protein • cell adhesion molecules • lipids and lipoproteins
Activation of the vascular endothelium is an early event in the development of atherosclerosis, and a chronic inflammatory response is involved in atherogenesis (1–3). Recent evidence indicated that markers of inflammation are predictive of cardiovascular disease (CVD)3 risk (3). For example, an elevated C-reactive protein (CRP) is strongly associated with clinical manifestations of atherothrombotic disease (2,4,5). CRP also exerts a direct proinflammatory effect on the human endothelium (6). Increased expression of the proinflammatory cytokines interleukin (IL)-6, IL-1 and tumor necrosis factor- was demonstrated in atherosclerotic lesions, and both monocyte-derived macrophages and activated endothelium produce proinflammatory cytokines (7–9). These cytokines stimulate endothelial expression of cell adhesion molecules, including vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), and E-selectin, which mediate monocyte attachment to the endothelium and transmigration into the subendothelial space.
Studies evaluated the direct antiatherogenic and anti-inflammatory effects of dietary (n-3) PUFA in addition to their lipid-lowering effects. Fish oil supplementation suppresses proinflammatory cytokine production by human peripheral blood mononuclear cells (PBMC) (10–12) and inhibits lymphocyte proliferation (12,13). Docosahexaenoic acid (DHA) results in a dose-dependent inhibition of VCAM-1 and E-selectin, and to a lesser extent, ICAM-1 gene expression in cultured endothelial cells (14,15). Thus, (n-3) fatty acids appear to attenuate inflammatory responses that are important in the initiation of atherosclerosis.
Evidence from both epidemiologic studies and clinical trials demonstrate substantial cardioprotective effects of -linolenic acid (ALA) (16–21), despite modest or no changes in lipids and lipoproteins (17,21). Little is known about the effects of ALA on vascular inflammation and endothelial activation. Several studies reported that ALA has anti-inflammatory effects; however, a recent in vitro study reported that linoleic acid (LA) and to a lesser extent ALA, stimulated the development of a proinflammatory environment within the vascular endothelium (22). Given conflicting results, we designed a controlled feeding study to evaluate the effects of ALA on multiple CVD risk factors including CRP, markers of endothelial activation, and lipids and lipoproteins. Because analysis of serum fatty acids provides an objective measure of the dietary intake of fatty acids (23–25), we incorporated serum fatty acid biomarkers as exposure variables related to the outcome variables.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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140/90 mm Hg), or other systemic diseases. The 3 women were postmenopausal and not receiving hormone replacement therapy.
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3-wk break between diet periods to improve diet compliance. After each diet period, blood samples were taken on 2 consecutive days after a 12-h fast; 2-d means are reported.
Diets.
The 3 experimental diets provided comparable amounts of total fat [35% energy (en)], carbohydrate (50% en), protein (15% en), and cholesterol (300 mg/d). Each diet was developed at 8 energy levels (ranging from 7524 to 16,302 kJ), and a 6-d cycle menu for each energy level was planned using the Nutritionist V database (First DataBank Division). All diets were nutritionally adequate; the target and assayed macronutrient composition of the diets is shown in Table 2. The AAD provided 13% en from SFA, 13% en monounsaturated fatty acids (MUFA) and 9% en from PUFA. In the 2 high-PUFA diets, SFA was partially replaced with PUFA resulting in diets that provided 
8% en from SFA and 16–17% en from PUFA; MUFA were held constant. The 2 high-PUFA diets provided varying amounts of LA and ALA: 12.6% en from LA and 3.6% en from ALA for the LA Diet, and 10.5% en from LA and 6.5% en from ALA for the ALA Diet. In the 2 high-PUFA diets, half of the total fat was derived from walnuts and walnut oil because they are rich sources of PUFA and, particularly, ALA (100 g of walnuts provides 38 g of LA and 9 g of ALA; 100 g of walnut oil provides 53 g of LA and 10 g of ALA.). The daily consumption of walnuts and walnut oil was 37 and 15 g, respectively, when the energy intake was kept at 10,032 kJ/d. In addition, flaxseed oil, which is especially high in ALA (55 g/100 g oil), was used to increase the ALA content of the ALA Diet. The ratios of LA to ALA [(n-6) to (n-3)] were 10:1, 4:1, and 2:1, respectively, in the AAD, LA Diet, and ALA Diet.
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Serum CRP and cell adhesion molecules. Serum CRP levels were measured using a high-sensitivity ELISA assay developed in the Cytokine Core Laboratory of the Penn State General Clinical Research Center. Briefly, a 96-well plate was preincubated with a primary antibody against human CRP (Calbiochem) in a humidified container at 4°C overnight. The plate was washed and blocked with PBS containing 1% bovine serum albumin. After washing, 50 µL of serum or standards was added to each well followed immediately by 50 µL of biotinylated CRP and mixed thoroughly. The plate was incubated overnight at 4°C. The final color reaction was achieved by adding 100 µL of streptavidin conjugated with horseradish peroxidase (Pierce) to each well (incubated for 30 min), followed by the addition of 100 µL of substrate solution [2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid dissolved in 0.1 mol/L monohydrate citric acid at 0.03% (wt:v) (pH 4.35), Sigma] and incubated for another 1.5 h. The absorbent units were measured at a wavelength of 405 nm.
Serum ICAM-1, VCAM-1, and E-selectin were measured using quantitative sandwich enzyme immunoassay kits (R&D Systems) following protocols provided by the manufacturer. Murine monoclonal antibodies against human ICAM-1, VCAM-1, and E-selectin were precoated onto microplates. Diluted conjugates (100 µL; antibodies against recombinant human ICAM-1, VCAM-1, and E-selectin conjugated to horseradish peroxidase) were added to each well. Then, 100 µL of standards (recombinant human ICAM-1, VCAM-1, and E-selectin), controls (lyophilized human serum containing natural and recombinant human cell adhesion molecules), or diluted serum samples were added to each well. The plates were sealed and incubated at room temperature for 1.5 h. After washing (6 times) to remove any unbound substances and/or antibody-enzyme reagent, 100 µL of a stabilized substrate solution (tetramethylbenzidine) was added to each well and the plates were sealed and incubated at room temperature for 30 min. Color development was stopped by adding 100 µL of stop solution to each well. The optical density of each well was determined at a wavelength of 450 nm with the wavelength corrected at 620 nm. The minimal detectable levels of ICAM, VCAM-1, and E-selectin were 0.35, 2, and 0.1 µg/L, respectively.
Lipids, lipoproteins and apolipoproteins. Assays for serum TC, HDL cholesterol (HDL-C) and triglycerides (TG) were conducted at the Mary Imogene Bassett Research Institute, using an enzymatic method as described by Yu-Poth et al. (26). LDL-C levels were calculated by Friedewald’s equation: LDL-C = TC – (HDL-C + TG/5) (27). Apolipoprotein (apo) AI and apo B were determined by rate immunonephelometry on a Beckman Array (Beckman Instruments).
Serum fatty acid profile. Serum fatty acid composition was determined using GC. Serum total lipids were extracted using a chloroform:methanol mixture (1:1, v:v) containing BHT (Sigma) and heptadecanoic acid (used as an internal standard, Nu-Chek-Prep). FAME were separated on a SP-2330 capillary column (30 m x 0.25 mm with 0.2 µm film, Supelco) on a Hewlett-Packard 5890 II gas chromatograph equipped with a flame-ionization detector. The column was programmed to set the initial temperature at 150°C for 8 min, then raise the temperature from 150 to 190°C at 2°C/min with the final temperature held at 190°C for 20 min. Helium was used as a carrier and make-up gas at a flow rate of 40 mL/min and a split ratio of 1:100. The temperatures for injector and detector were set at 250 and 265°C, respectively. Peak areas were integrated as relative weight using Hewlett-Packard ChemStation software. The percentage of individual fatty acids was calculated according to the peak areas relative to the total area (total fatty acid was set at 100%).
Statistical analyses.
Statistical analyses were performed using SAS v8.2 (SAS Institute). ANOVA was used to test for difference among the 3 experimental diets. For all other outcome variables, data from men and women were pooled because the women were postmenopausal. Results are expressed as means ± SEM unless otherwise noted. For variables with nonnormal distributions (i.e., CRP), medians and geometric means ± SEM are reported, and statistical analyses were conducted after a logarithmic (base 10) transformation. The mixed procedure (PROC MIXED) was used to test for effects of diet, order (the sequence of the 3 diets given to each subject), and their interactive effects on outcome variables. Significant diet effects were examined with Tukey’s least significant difference test. Pearson correlation analyses were conducted to test associations between lipid/lipoprotein variables and novel CVD risk factors. Probability values 0.05 were considered significantly different; a P-value 0.1 denoted a trend. For all outcome variables reported in the Results, none of the order effects or the interactions of diets with orders were significant; therefore, only diet effects are presented.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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75% when subjects consumed the ALA Diet (P < 0.01, Fig. 3), and 45% when subjects consumed the LA Diet (P = 0.08) compared with the AAD. However, CRP levels did not differ after subjects consumed the LA and ALA Diets.
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2 mg/L), subjects with lower CRP levels had a greater reduction in LDL-C levels after they consumed the 2 high-PUFA diets (vs. AAD) than those with higher CRP levels (–0.51 ± 0.06 vs. –0.36 ± 0.06 mmol/L, P = 0.068). However, other lipid variables as well as the serum fatty acid profile did not differ between the 2 groups, i.e., those with high vs. low CRP levels. Serum cell adhesion molecule concentrations. For cell adhesion molecules, individual responses to the 3 experimental diets appear in Figure 4. The 2 high-PUFA Diets significantly decreased serum ICAM-1 and E-selectin compared with the AAD (P < 0.01; Fig. 5). The ALA Diet also reduced VCAM-1 levels compared with the AAD (P < 0.01); however, VCAM-1 levels did not differ after subjects consumed the LA Diet and the AAD. In addition, the ALA Diet resulted in greater decreases in both VCAM-1 and E-selectin levels compared with the LA Diet [decreased by 12.9% (P < 0.01) and 7.2% (P < 0.01), respectively].
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Changes in serum CRP and VCAM-1 predicted by changes in serum (n-3) fatty acids. After subjects consumed the ALA Diet, changes in serum CRP and VCAM-1 were inversely associated with changes in serum EPA (vs. AAD, r = –0.496, P = 0.016 and r = –0.418, P = 0.047, respectively, Table 3). A trend for inverse correlations also existed between changes in CRP and VCAM-1 and changes in serum EPA+DPA, and between changes in CRP and changes in serum ALA+EPA+DPA (P < 0.1 for all, Table 3). In addition, when subjects consumed the LA Diet, similar inverse correlations were observed between changes in CRP and changes in serum EPA (r = –0.353, P = 0.099) and EPA+DPA (r = –0.386, P = 0.069). However, changes in ICAM-1 and E-selectin were not significantly associated with changes in any of the serum (n-3) fatty acids. Taken together, these data suggest that serum EPA appears to play a role in regulating CRP and VCAM-1 levels.
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Walnut supplementation, as a way of enriching serum lipids with LA and ALA, was shown to have a favorable effect on plasma lipids and lipoproteins (30–34). Our results are similar and demonstrate that a diet low in saturated fat and cholesterol, and high in PUFA, regardless of (n-3) or (n-6) series, significantly decreases serum lipid and lipoprotein levels. Higher levels of (n-3) fatty acids did not elicit more favorable effects on lipid risk factors. In addition, the diet high in PUFA and ALA decreased serum HDL-C and apo AI levels, an effect that was reported in some studies (17,33,35,36), but not in others (31,32,34). Nevertheless, the 2 high-PUFA diets in the present study significantly decreased TC:HDL-C ratios.
CRP and proinflammatory cytokines play an important role in atherogenesis (2,5). Increased CRP levels exhibit synergy with concurrent hypercholesterolemia to increase CVD risk in both men and women (37,38). Several studies reported that CRP is inversely associated with EPA and DHA in both healthy subjects and in patients with stable coronary artery disease (39,40). Consistent with this finding, our results demonstrate that a diet high in PUFA and ALA significantly decreased CRP levels, and the changes in serum EPA and EPA+DPA were inversely associated with changes in CRP. However, the magnitude of this response was variable among subjects; it will be important to determine whether there is a genetic basis for different CRP responses to diet because recent studies showed that CRP gene polymorphism influences CRP levels (41,42). Erlinger et al. (43) reported that increased CRP levels are associated with smaller decreases in TC and LDL-C in response to a reduced-fat/low-cholesterol diet. The present study also demonstrated that subjects with higher CRP levels had a diminished cholesterol-lowering response to the 2 high-PUFA diets that was reduced by 29% compared with subjects with lower CRP levels. Therefore, decreasing CRP levels by dietary and/or other interventions can improve the lipid responses, thereby reducing overall CVD risk.
Endothelial activation and enhanced expression of cell adhesion molecules are early events in atherogenesis (44). Several studies showed that DHA or oleic acid decreases the expression of cell adhesion molecules in the endothelium (14,15,45) and in PBMC (46), thereby reducing adhesion of monocytoid cells to the endothelium. Consistent with these findings, we found that ICAM-1 and E-selectin decreased after subjects consumed the 2 high-PUFA diets. Moreover, markedly favorable effects on VCAM-1 and E-selectin were elicited only by a diet high in ALA. These results suggest that diets high in PUFA and (n-3) fatty acids exert their cardioprotective effects in part via effects on endothelial function, and that a higher dose of ALA may have the largest beneficial effects on the markers of endothelial activation. Interestingly, we found that the changes in VCAM-1 could be predicted by the changes in serum EPA and DPA, suggesting that these are bioactive components that inhibit vascular endothelial activation. Although in vitro cell culture studies demonstrated that DHA decreases cell adhesion molecule expression in the endothelium (14,15), the present study did not replicate this effect, perhaps because we observed no significant changes in serum DHA after subjects consumed the 3 experimental diets. This may be explained by the low efficiency of ALA conversion to DHA (28,29).
Ridker et al. (37,38) showed that CRP elicits an additive value to lipid testing in assessing risk for future CVD events. Other studies reported that changes in CRP were inversely correlated with changes in HDL-C and apo AI (47), and positively correlated with serum TG (48). In addition, ICAM-1, but not VCAM-1 or E-selectin, was significantly associated with serum TC (49). In general, arterial wall lipids are susceptible to oxidation, and oxidized LDL can activate leukocytes (including monocytes and macrophages) and endothelial cells, inducing a chronic inflammatory response (50,51). On the other hand, an increase in cholesterol reverse transport by HDL (i.e., increased HDL-C) would be expected to decrease lipid accumulation in the artery wall, thereby decreasing the vascular inflammatory response. This may explain the associations between lipid risk factors and novel inflammatory markers. In the present study, we did observe an inverse association between CRP and HDL-C when subjects consumed the LA Diet and AAD. In contrast, we found both CRP and HDL-C levels decreased when subjects consumed the ALA Diet. The underlying mechanisms require further study. Nevertheless, the findings that CRP and ICAM-1 are positively correlated with TC:HDL-C ratios in the present study are of great importance given that the TC:HDL-C ratio is a significant predictor of CVD risk (37,38). Because the diet high in ALA beneficially affected both lipids/lipoproteins and CRP/cell adhesion molecules, this suggests that ALA acts via multiple mechanisms to reduce CVD risk.
On the basis of in vitro data, there has been some concern that (n-6) fatty acids, primarily LA, stimulate a proinflammatory environment within the vascular endothelium (22), promoting endothelial dysfunction. However, the present study demonstrated that a diet high in LA decreased ICAM-1 and E-selectin levels, and tended to decrease CRP. Of note is that ALA also increased in this diet, resulting in lower LA:ALA or (n-6):(n-3) ratios. Given that (n-3) fatty acids exert anti-inflammatory responses, the addition of (n-3) fatty acids to a diet rich in (n-6) fatty acids might counteract the potentially adverse effect of LA on endothelial function.
In conclusion, a diet high in PUFA, especially ALA, elicits cardioprotective effects by decreasing lipid and lipoprotein levels and by eliciting vascular anti-inflammatory effects. The fact that ALA has marked, beneficial effects on multiple CVD risk factors further underscores its potentially important role in CVD risk reduction. These findings provide additional support for the importance of ensuring adequate PUFA and ALA intake as a strategy to markedly lower CVD risk.
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FOOTNOTES |
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3 Abbreviations used: AA, arachidonic acid; AAD, average American diet; ALA, -linolenic acid; apo, apolipoprotein; CRP, C-reactive protein; CVD, cardiovascular disease; DHA, docosahexaenoic acid; DPA, docosapentaenoic acid; en, energy; EPA, eicosapentaenoic acid; HDL-C, HDL cholesterol; ICAM-1, intercellular cell adhesion molecule-1; IL, interleukin; LA, linoleic acid; LDL-C, LDL cholesterol; MUFA, monounsaturated fatty acids; PBMC, peripheral blood mononuclear cells; TC, total cholesterol; TG, triglycerides; VCAM-1, vascular cell adhesion molecule-1.
Manuscript received 21 May 2004. Initial review completed 28 June 2004. Revision accepted 9 August 2004.
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LITERATURE CITED |
|---|
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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1. Gimbrone, M. A., Jr, Topper, J. N., Nagel, T., Anderson, K. R. & Garcia-Cardena, G. (2000) Endothelial dysfunction, hemodynamic forces, and atherogenesis. Ann. N.Y. Acad. Sci. 902:230-239.
2. Libby, P., Ridker, P. M. & Maseri, A. (2002) Inflammation and atherosclerosis. Circulation 105:1135-1143.
3. Ross, R. (1999) Atherosclerosis—an inflammatory disease. N. Engl. J. Med. 340:115-126.
4. Rifai, N. & Ridker, P. M. (2002) Inflammatory markers and coronary heart disease. Curr. Opin. Lipidol. 13:383-389.[Medline]
5. Tracy, R. P. (1999) Inflammation markers and coronary heart disease. Curr. Opin. Lipidol. 10:435-441.[Medline]
6. Pasceri, V., Willerson, J. T. & Yeh, E. T. (2000) Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 102:2165-2168.
7. Seino, Y., Ikeda, U., Ikeda, M., Yamamoto, K., Misawa, Y., Hasegawa, T., Kano, S. & Shimada, K. (1994) Interleukin 6 gene transcripts are expressed in human atherosclerotic lesions. Cytokine 6:87-91.[Medline]
8. Glass, C. K. & Witztum, J. L. (2001) Atherosclerosis. the road ahead. Cell 104:503-516.[Medline]
9. Plutzky, J. (2001) Inflammatory pathways in atherosclerosis and acute coronary syndromes. Am. J. Cardiol. 88:10K-15K.[Medline]
10. Endres, S., Ghorbani, R., Kelley, V. E., Georgilis, K., Lonnemann, G., van der Meer, J. W., Cannon, J. G., Rogers, T. S., Klempner, M. S. & Weber, P. C. (1989) The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N. Engl. J. Med. 320:265-271.[Abstract]
11. James, M. J., Gibson, R. A. & Cleland, L. G. (2000) Dietary polyunsaturated fatty acids and inflammatory mediator production. Am. J. Clin. Nutr. 71:343S-348S.
12. Meydani, S. N., Endres, S., Woods, M. M., Goldin, B. R., Soo, C., Morrill-Labrode, A., Dinarello, C. A. & Gorbach, S. L. (1991) Oral (n-3) fatty acid supplementation suppresses cytokine production and lymphocyte proliferation: comparison between young and older women. J. Nutr. 121:547-555.
13. Thies, F., Nebe-von-Caron, G., Powell, J. R., Yaqoob, P., Newsholme, E. A. & Calder, P.C. (2001) Dietary supplementation with 
-linolenic acid or fish oil decreases T lymphocyte proliferation in healthy older humans. J. Nutr. 131:1918-1927.
14. De Caterina, R., Cybulsky, M. I., Clinton, S. K., Gimbrone, M. A., Jr & Libby, P. (1994) The omega-3 fatty acid docosahexaenoate reduces cytokine-induced expression of proatherogenic and proinflammatory proteins in human endothelial cells. Arterioscler. Thromb. 14:1829-1836.[Abstract]
15. De Caterina, R., Cybulsky, M. A., Clinton, S. K., Gimbrone, M. A., Jr & Libby, P. (1995) Omega-3 fatty acids and endothelial leukocyte adhesion molecules. Prostaglandins Leukot. Essent. Fatty Acids 52:191-195.[Medline]
16. Ascherio, A., Rimm, E. B., Giovannucci, E. L., Spiegelman, D., Stampfer, M. & Willett, W. C. (1996) Dietary fat and risk of coronary heart disease in men: cohort follow up study in the United States. Br. Med. J. 313:84-90.
17. de Lorgeril, M., Renaud, S., Mamelle, N., Salen, P., Martin, J. L., Monjaud, I., Guidollet, J., Touboul, P. & Delaye, J. (1994) Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 343:1454-1459.[Medline]
18. Djousse, L., Pankow, J. S., Eckfeldt, J. H., Folsom, A. R., Hopkins, P. N., Province, M. A., Hong, Y. & Ellison, R. C. (2001) Relation between dietary linolenic acid and coronary artery disease in the National Heart, Lung, and Blood Institute Family Heart Study. Am. J. Clin. Nutr. 74:612-619.
19. Dolecek, T. A. (1992) Epidemiological evidence of relationships between dietary polyunsaturated fatty acids and mortality in the multiple risk factor intervention trial. Proc. Soc. Exp. Biol. Med. 200:177-182.[Abstract]
20. Hu, F. B., Stampfer, M. J., Manson, J. E., Rimm, E. B., Wolk, A., Colditz, G. A., Hennekens, C. H. & Willett, W. C. (1999) Dietary intake of alpha-linolenic acid and risk of fatal ischemic heart disease among women. Am. J. Clin. Nutr. 69:890-897.
21. Singh, R. B., Niaz, M. A., Sharma, J. P., Kumar, R., Rastogi, V. & Moshiri, M. (1997) Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival–4. Cardiovasc. Drugs Ther. 11:485-491.[Medline]
22. Toborek, M., Lee, Y. W., Garrido, R., Kaiser, S. & Hennig, B. (2002) Unsaturated fatty acids selectively induce an inflammatory environment in human endothelial cells. Am. J. Clin. Nutr. 75:119-125.
23. Ma, J., Folsom, A. R., Shahar, E. & Eckfeldt, J. H. (1995) Plasma fatty acid composition as an indicator of habitual dietary fat intake in middle-aged adults. The Atherosclerosis Risk in Communities (ARIC) Study Investigators. Am. J. Clin. Nutr. 62:564-571.
24. Lemaitre, R. N., King, I. B., Mozaffarian, D., Kuller, L. H., Tracy, R. P. & Siscovick, D. S. (2003) n-3 Polyunsaturated fatty acids, fatal ischemic heart disease, and nonfatal myocardial infarction in older adults: the Cardiovascular Health Study. Am. J. Clin. Nutr. 77:319-325.
25. Erkkila, A. T., Lehto, S., Pyorala, K. & Uusitupa, M. I. (2003) n-3 Fatty acids and 5-y risks of death and cardiovascular disease events in patients with coronary artery disease. Am. J. Clin. Nutr. 78:65-71.
26. Yu-Poth, S., Etherton, T. D., Reddy, C. C., Pearson, T. A., Reed, R., Zhao, G., Jonnalagadda, S., Wan, Y. & Kris-Etherton, P. M. (2000) Lowering dietary saturated fat and total fat reduces the oxidative susceptibility of LDL in healthy men and women. J. Nutr. 130:2228-2237.
27. Friedewald, W. T., Levy, R. I. & Fredrickson, D. S. (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin. Chem. 18:499-502.[Abstract]
28. Pawlosky, R. J., Hibbeln, J. R., Novotny, J. A. & Salem, N., Jr (2001) Physiological compartmental analysis of alpha-linolenic acid metabolism in adult humans. J. Lipid Res. 42:1257-1265.
29. Pawlosky, R. J., Hibbeln, J. R., Lin, Y., Goodson, S., Riggs, P., Sebring, N., Brown, G. L. & Salem, N., Jr (2003) Effects of beef- and fish-based diets on the kinetics of n-3 fatty acid metabolism in human subjects. Am. J. Clin. Nutr. 77:565-572.
30. Almario, R. U., Vonghavaravat, V., Wong, R. & Kasim-Karakas, S. E. (2001) Effects of walnut consumption on plasma fatty acids and lipoproteins in combined hyperlipidemia. Am. J. Clin. Nutr. 74:72-79.
31. Chisholm, A., Mann, J., Skeaff, M., Frampton, C., Sutherland, W., Duncan, A. & Tiszavari, S. (1998) A diet rich in walnuts favourably influences plasma fatty acid profile in moderately hyperlipidaemic subjects. Eur. J. Clin. Nutr. 52:12-16.[Medline]
32. Iwamoto, M., Imaizumi, K., Sato, M., Hirooka, Y., Sakai, K., Takeshita, A. & Kono, M. (2002) Serum lipid profiles in Japanese women and men during consumption of walnuts. Eur. J. Clin. Nutr. 56:629-637.[Medline]
33. Sabate, J., Fraser, G. E., Burke, K., Knutsen, S. F., Bennett, H. & Lindsted, K. D. (1993) Effects of walnuts on serum lipid levels and blood pressure in normal men. N. Engl. J. Med. 328:603-607.
34. Zambon, D., Sabate, J., Munoz, S., Campero, B., Casals, E., Merlos, M., Laguna, J. C. & Ros, E. (2000) Substituting walnuts for monounsaturated fat improves the serum lipid profile of hypercholesterolemic men and women. Ann. Intern. Med. 132:538-546.
35. Bemelmans, W. J., Broer, J., Feskens, E. J., Smit, A. J., Muskiet, F. A., Lefrandt, J. D., Bom, V. J., May, J. F. & Meyboom-de Jong, B. (2002) Effect of an increased intake of alpha-linolenic acid and group nutritional education on cardiovascular risk factors: the Mediterranean Alpha-linolenic Enriched Groningen Dietary Intervention (MARGARIN) study. Am. J. Clin. Nutr. 75:221-227.
36. Rallidis, L. S., Paschos, G., Liakos, G. K., Velissaridou, A. H., Anastasiadis, G. & Zampelas, A. (2003) Dietary -linolenic acid decreases C-reactive protein, serum amyloid A and interleukin-6 in dyslipidaemic patients. Atherosclerosis 167:237-242.[Medline]
37. Ridker, P. M., Glynn, R. J. & Hennekens, C. H. (1998) C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 97:2007-2011.[Medline]
38. Ridker, P. M. (2001) High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 103:1813-1818.[Medline]
39. Pischon, T., Hankinson, S. E., Hotamisligil, G. S., Rifai, N., Willett, W. C. & Rimm, E. B. (2003) Habitual dietary intake of n-3 and n-6 fatty acids in relation to inflammatory markers among US men and women. Circulation 108:155-160.[Medline]
40. Madsen, T., Skou, H. A., Hansen, V. E., Fog, L., Christensen, J. H., Toft, E. & Schmidt, E. B. (2001) C-reactive protein, dietary n-3 fatty acids, and the extent of coronary artery disease. Am. J. Cardiol. 88:1139-1142.[Medline]
41. Kluft, C. & de Maat, M. P. (2003) Genetics of C-reactive protein: new possibilities and complications. Arterioscler. Thromb. Vasc. Biol. 23:1956-1959.
42. Brull, D. J., Serrano, N., Zito, F., Jones, L., Montgomery, H. E., Rumley, A., Sharma, P., Lowe, G. D., World, M. J., Humphries, S. E. & Hingorani, A. D. (2003) Human CRP gene polymorphism influences CRP levels: implications for the prediction and pathogenesis of coronary heart disease. Arterioscler. Thromb. Vasc. Biol. 23:2063-2069.
43. Erlinger, T. P., Miller, E. R., 3rd, Charleston, J. & Appel, L. J. (2003) Inflammation modifies the effects of a reduced-fat low-cholesterol diet on lipids: results from the DASH-sodium trial. Circulation 108:150-154.[Medline]
44. Cybulsky, M. I. & Gimbrone, M. A., Jr (1991) Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 251:788-791.
45. Carluccio, M. A., Massaro, M., Bonfrate, C., Siculella, L., Maffia, M., Nicolardi, G., Distante, A., Storelli, C. & De Caterina, R. (1999) Oleic acid inhibits endothelial activation: A direct vascular antiatherogenic mechanism of a nutritional component in the Mediterranean diet. Arterioscler. Thromb. Vasc. Biol. 19:220-228.
46. Yaqoob, P., Knapper, J. A., Webb, D. H., Williams, C. M., Newsholme, E. A. & Calder, P. C. (1998) Effect of olive oil on immune function in middle-aged men. Am. J. Clin. Nutr. 67:129-135.[Abstract]
47. Strandberg, T. E., Vanhanen, H. & Tikkanen, M. J. (2000) Associations between change in C-reactive protein and serum lipids during statin treatment. Ann. Med. 32:579-583.[Medline]
48. Muscari, A., Bastagli, L., Poggiopollini, G., Tomassetti, V., Massarelli, G., Cappelletti, O., Plate, L., Boni, P. & Puddu, P. (2002) Different associations of C-reactive protein, fibrinogen and C3 with traditional risk factors in middle-aged men. Int. J. Cardiol. 83:63-71.[Medline]
49. Schumacher, A., Seljeflot, I., Sommervoll, L., Christensen, B., Otterstad, J. E. & Arnesen, H. (2002) Increased levels of markers of vascular inflammation in patients with coronary heart disease. Scand. J. Clin. Lab. Investig. 62:59-68.[Medline]
50. Liao, F., Andalibi, A., Lusis, A. J. & Fogelman, A. M. (1995) Genetic control of the inflammatory response induced by oxidized lipids. Am. J. Cardiol. 75:65B-66B.[Medline]
51. Rajavashisth, T. B., Andalibi, A., Territo, M. C., Berliner, J. A., Navab, M., Fogelman, A. M. & Lusis, A. J. (1990) Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins. Nature (Lond.) 344:254-257.[Medline]
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