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American Journal of Clinical Nutrition, Vol. 81, No. 3, 583-589, March 2005
© 2005 American Society for Clinical Nutrition

ORIGINAL RESEARCH COMMUNICATION

Influence of long-term intervention with dietary counseling, long-chain n–3 fatty acid supplements, or both on circulating markers of endothelial activation in men with long-standing hyperlipidemia1,2,3

Elsa M Hjerkinn, Ingebjørg Seljeflot, Ingrid Ellingsen, Paula Berstad, Ingvar Hjermann, Leiv Sandvik and Harald Arnesen

1 From the Center for Clinical Research (EMH, IS, LS, and HA) and the Department of Preventive Cardiology (IE and IH), Ullevaal University Hospital, Oslo, and the Institute for Nutrition Research (PB), University of Oslo

2 Supported by the Norwegian Cardiovascular Council and by the Norwegian Retail Company RIMI. Vegetable oil and VITA margarine were supplied by the Norwegian Food Company Mills DA, and the n–3 PUFA and the placebo capsules used in the study were supplied by LUBE a/s DK.

3 Address reprint requests and correspondence to EM Hjerkinn, Center for Clinical Research (FUS), Ullevaal University Hospital, N-0407 Oslo, Norway. E mail: elsa.hjerkinn{at}ulleval.no


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Dietary factors and very-long-chain n–3 polyunsaturated fatty acids (n–3 PUFAs) may influence the atherothrombotic process. Elevated concentrations of circulating cell adhesion molecules, thrombomodulin (TM), von Willebrand factor (vWF), and tissue-type plasminogen activator antigen (tPAag) are related to atherothrombotic cardiovascular disease.

Objective: The randomized Diet and Omega-3 Intervention Trial (DOIT) targeted a comparison of the effect of 3-y dietary counseling, n–3 PUFA supplementation (2.4 g/d), or both on circulating markers of endothelial activation.

Design: The study included 563 elderly men with long-standing hyperlipidemia. The men were randomly assigned by factorial design into 4 groups: control (no dietary counseling and placebo capsules), dietary counseling (and placebo capsules), n–3 PUFA supplementation (no dietary counseling), and dietary counseling and n–3 PUFA supplementation.

Results: Serum concentrations of fatty acids reflected good compliance. Dietary counseling was followed by significantly reduced concentrations of soluble intercellular adhesion molecule 1 (sICAM-1; P < 0.001), sTM (P = 0.004), and tPAag (P < 0.001) than in subjects without dietary counseling. After n–3 PUFA supplementation, significantly reduced concentrations of sICAM-1 (P < 0.001) and sTM (P = 0.006) were observed when compared with subjects receiving placebo capsules. An increase in tPAag was not significantly different from that observed in subjects receiving placebo capsules. For sICAM-1, a significant effect was observed for both interventions combined.

Conclusions: Each intervention (dietary counseling or n–3 PUFA supplements) reduced sTM and sICAM-1 concentrations, indicating decreased endothelial activation. The tPAag increase in the groups not receiving dietary counseling (pooled), which indicates progression of atherosclerosis, was significantly counteracted by dietary counseling.

Key Words: Dietary intervention • n–3 PUFA supplementation • adhesion molecules • endothelial activation • tissue-type plasminogen activator antigen • tPAag • hyperlipidemia


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Inflammatory mechanisms play a central role in all phases of atherosclerosis, from initiation, during progression, and through clinical manifestations of cardiovascular diseases (CVDs) (1). Activated endothelial cells express selective adhesion molecules (CAMs) such as E-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) that recruit circulating leukocytes to the arterial wall. Thus, these molecules are central in the recruitment of inflammatory cells to the site of atheroma development, and they reflect an underlying vascular inflammation. Soluble forms of these molecules (sCAMs) are thought to reflect the amount of molecules expressed on the endothelial surface (2). The concentrations of sCAMs were used in different studies to elucidate the inflammatory state of the endothelium, and several studies showed that patients with manifest or future CVD have an elevated serum concentration of these inflammatory markers (3–5).

Elevated concentrations of hemostatic endothelial-related molecules such as thrombomodulin (TM), von Willebrand factor (vWF), and tissue plasminogen activator measured as antigen (t-PAag) were also found in the plasma from patients with atherosclerotic disease (6–8). These molecules are, therefore, viewed as hemostatic markers of endothelial activation in atherosclerosis, although their exact roles in the prothrombotic state of the endothelium are not clearly defined.

As observed in epidemiologic studies and in clinical trials certain food patterns reduce the risk of CVD. However, several short- and long-term trials with dietary intervention on healthy and diseased populations have shown some diverging results (9–12).

Alimentary factors such as total fat and different fatty acids were shown to influence the concentrations of serum lipoproteins as well as the development of CVD (13, 14). Dietary patterns may also influence hemostasis through effects on lipoproteins (15).

Clinical trials have reported that the very-long-chain polyunsaturated n–3 fatty acids (n–3 PUFAs) favorably affect coronary artery disease and mortality (9, 16). The n–3 PUFAs from fish oils are thought to be antiatherogenic and antithrombogenic (17) especially when substituted for saturated fatty acids (18–20), and evidence suggests the favorable effects of the marine n–3 fatty acids on endothelial function (21, 22), although conflicting results exist (23). The aim of the present randomized Diet and Omega-3 Intervention Trial (DOIT) was to compare the possible modulating effect of a 3-y diet counseling with that of supplementation with marine n–3 PUFA on some markers of endothelial activation.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
The basis for recruitment into the present study was a long-term follow-up of the participants from the diet and smoking part of the Oslo study (24), comprising 1232 men (born 1923–1932) with high risk of CVD. Subjects in this cohort were originally included in 1972 if they had serum cholesterol concentrations of 6.9–9.0 mmol/L and systolic blood pressure <150 mm Hg. In 1997 the 910 survivors were contacted to participate in the DOIT study.

Altogether, 655 subjects attended a screening visit. Subjects were excluded if they lacked willingness to participate, had specific disease states thought to influence longevity or study compliance, or had long travel distances or other practical causes for not being enrolled in the study.

Study design
The DOIT study was actuated to evaluate the effects of a 3-y intervention with dietary counseling, n–3 PUFA supplementation, or both. It was placebo controlled for the n–3 PUFA, in a randomized 2 x 2 factorial design on the progress of atherosclerosis in a high-risk population.

A total of 563 men aged between 65 and 75 y were randomly assigned according to a factorial design into 4 groups: 1) control (no dietary counseling and placebo capsules), 2) dietary counseling (and placebo capsules), 3) n–3 PUFA capsules (and no dietary counseling), and 4) dietary counseling and n–3 PUFA capsules combined. The men were followed for 3 y. The DOIT study was approved by the regional Ethics Committee, and all subjects gave their informed written consent to participate.

Intervention principles
Altogether, 282 subjects were randomly assigned to receive 2.4 g n–3 PUFA daily (Pikasol; Lube, Denmark), and 281 subjects received placebo (corn oil), each as 2 capsules twice daily for 3 y. The n–3 PUFA capsules contained about 35% eicosapentaenoic acid (EPA; C20:5n–3), 20% docosahexaenoic acid (DHA; C22:6n–3), and 3.5 mg tocopherols/g to prevent fatty acid peroxidation. The placebo capsules contained 56% linoleic acid (18:2n–6), 32% oleic acid (18:1n–9), 10% palmitic acid (16:0), and 4 mg tocopherols/g.

A total of 281 subjects were randomly assigned to dietary intervention. The dietary counseling was undertaken on an individual basis and consisted of advice to increase the use of vegetable oils and margarines (rapeseed oil, olive oil, and sunflower oil), vegetables, fruit, and fish and to decrease the use of meat and fat from animal sources. Special oil and margarine (VITA margarine; Norwegian Food Company Mills DA, Oslo) were specifically supplied to these participants at all visits. Overweight subjects were encouraged to adopt a calorie-restricted diet. The dietary advice was given by a clinical nutritionist on the basis of a food-frequency questionnaire that was obtained from all participants at baseline. Dietary counseling was given for 30–45 min at randomization and for 30 min after 3 mo. Thereafter, the subjects visited or had telephone contact with the nutritionist every 6 mo. Additional follow-up was offered in 7% of the participants because of poor adherence. The food-frequency questionnaire was repeated at the final visit in all participants. The intake of saturated fat and monounsaturated fat (oleic acid, 18:1n–9) was calculated from the food registration forms together with other nutrients. This method was previously validated and described in detail (25).

Laboratory methods
Blood samples were drawn after an overnight fast (≥10 h). Serum was separated within 1 h and used for determination of sE-selectin, sICAM-1, and sVCAM-1. Simultaneously, serum was prepared for analysis of total cholesterol, HDL cholesterol, triacylglycerols, glucose, and fatty acids.

Citrated blood (evacuated tubes containing 0.129 mol/L trisodium citrate in dilution 1:10; Becton Dickinson, Plymouth, United Kingdom) was collected, and platelet-poor plasma was obtained within 30 min by centrifugation at 2500g for 20 min at 4°C to determine tPAag, vWF, and sTM. All samples, except for lipid analyses, were kept frozen at –70°C until analyzed.

Serum lipids and glucose were determined by conventional enzymatic methods. LDL cholesterol was calculated according to Friedewald’s formula (26). Commercial enzyme immunoassays were used throughout for the endothelial cell markers: the soluble CAMs with kits from R&D Systems Europe (Abingdon, Oxon, United Kingdom), vWF and TM by Asserachrom (Stago Diagnostica, Asnieres, France), and tPAag by TintElize tPA, measuring both free tPAag and in complex with plasminogen activator inhibitor type 1 (Biopool AB, Umeaa, Sweden). The interassay CVs were 5.3% for E-selectin, 4.8% for sICAM-1, 5.2% for sVCAM-1, 8.0% for vWF, 7.6% for sTM, and 3.5% for tPAag.

In a random subset of participants (n = 278), fatty acid composition was analyzed by gas-liquid chromatography as described (27, 28). Pooled serum samples were used as control. The interassay CVs for fatty acid peaks were 13% for linoleic acid, 24% for {alpha}-linolenic acid, 20% for arachidonic acid, 18% for EPA, and 29% for DHA. The values are presented as percentage of total fatty acid in serum. We analyzed the total fat in serum for fatty acids and especially the essential long-chain fatty acids assumed to reflect oral fat intake.

Statistical analyses
To compare the control and 3 intervention groups with regard to baseline values, one-factor analysis of variance was used for all continuous variables, whereas a chi-square test was applied for the categorical variables. Triacylglycerol values were loge transformed throughout all analyses. According to the 2 x 2 factorial study design, intervention effects were investigated by using a multiple linear regression model (analysis of covariance). The 36-mo values were used as the dependent variable, and the baseline values, dietary counseling code, n–3 PUFA supplementation code, and dietary counseling by n–3 PUFA supplementation interaction, were included as independent variables. If a significant interaction was found between dietary counseling and n–3 PUFA supplementation (P < 0.05), the changes in each of the 3 intervention groups were compared separately with the changes in the placebo and no dietary counseling group (3 comparisons in total) by using Tukey’s test for multiple comparisons. When no significant interaction effect was observed, the interaction term was removed from the model. For analyses of nutrient patterns only baseline values and dietary counseling code were included as covariates. Changes from baseline to 36 mo were analyzed by a two-sided paired t test. Correlation analyses were performed with Spearman’s method. A significance level of 5% was used. The statistical analyses were performed with SPSS software, version 11.0 (SPSS Inc, Chicago).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Clinical characteristics, use of medication, and some laboratory variables in the study population are presented in Table 1Go. No significant differences were observed between the treatment groups at baseline, with the exception for age (69 y in the control group and 70 y in the intervention groups; P = 0.01) and mean glucose values (6.3 mmol/L in the control group and 5.9 mmol/L in the dietary counseling group, 5.8 mmol/L in the n–3 PUFA supplementation group, and 5.9 mmol/L in the combined dietary counseling and n–3 PUFA supplementation group; P = 0.01).


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  		TABLE 1 Clinical characteristics, use of medication, and fasting laboratory variables in the study population1

 
After 3 y, 487 subjects completed the study, 38 had died, 29 dropped out because of disease states interfering with study follow-up, and 9 individuals were unwilling to complete the study period. According to analyses of the food-frequency questionnaire as listed in Table 2Go, dietary intervention was followed by a significantly greater decrease in intake of saturated fat when compared with the change in the group with no dietary counseling. In addition, the change in intake of polyunsaturated fat was greater and the decrease in n–3 fatty acids was lesser. Most impressively, the increase in polyunsaturated-to-saturated fat ratio was significantly greater in the dietary counseling group than in the control group. The total fatty acid concentrations in serum at baseline and after 36 mo are shown in Table 3Go. In subjects receiving dietary counseling (pooled groups 2 and 4) a significant elevation was observed in {alpha} linolenic acid and EPA when compared with subjects not receiving dietary counseling (pooled groups 1 and 3).


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  		TABLE 2 Nutrient pattern and some dietary fatty acids (g/d) recorded in the no diet advice group and the dietary advice group at baseline and after 36 mo1

 

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  		TABLE 3 Serum fatty acids, lipids, and body mass index at baseline and after 36 mo in the control and intervention groups1

 
As expected after n–3 PUFA supplementation, we observed a highly significant elevation of EPA and DHA and a significant reduction in the n–6-to-n–3 ratio when compared with placebo supplementation. We also observed a smaller increase in arachidonic acid and a reduction in linoleic acid and total fatty acids after n–3 PUFA supplements compared with placebo capsules.

Effect of treatment on lipids and body mass index (BMI) are also presented in Table 3Go. Dietary counseling was followed by significant reductions in the concentration of triacylglycerols (P = 0.003) and in BMI (P = 0.005), but no significant changes in concentrations of total cholesterol or HDL cholesterol were noted when compared with subjects not receiving dietary counseling. For the individuals receiving n–3 PUFA supplementation, concentrations of triacylglycerols (P < 0.001) and the ratio of total cholesterol to HDL cholesterol (P = 0.046) were significantly reduced compared with subjects receiving placebo capsules.

The effects of treatment on the circulating markers of endothelial activation are shown in Table 4Go. The concentrations of sVCAM-1, sE-selectin, and vWF did not change in the intervention groups during the study period when compared with the respective control subjects. In subjects receiving dietary counseling, concentrations of sTM and tPAag were significantly reduced compared with no dietary counseling. As for sICAM-1, a significant interaction (P = 0.038) between diet and n–3 PUFA was observed. Accordingly, the dietary counseling and placebo group (group 2) was separately compared with the no dietary counseling and placebo group (group 1), and a highly significant reduction in concentrations of sICAM-1 was observed in group 2 (P < 0.001).


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  		TABLE 4 Circulating concentrations of endothelial markers at baseline and after 36 mo in the control and intervention groups1

 
The sICAM-1 reduction in the group receiving n–3 PUFA supplements alone (group 3) was also significantly different from the increase in the control group (group 1) (P < 0.001). Concentrations of tPAag after n–3 PUFA supplementation were not different from those after placebo capsules, whereas the sTM reduction was significantly different from changes after the placebo capsules (P = 0.006). When both interventions were given in combination, a significant effect was also observed for sICAM-1.

In the total study population, poor correlations between changes in serum concentrations of essential very-long-chain n–3 PUFAs and changes in markers of endothelial activation during the study period were found. However, changes in BMI and serum triacylglycerols (r = 0.288; P < 0.001) correlated significantly with changes in tPAag (r = 0.141; P < 0.01).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study we observed a highly significant reduction in the concentrations of sICAM-1, both for dietary counseling and for n–3 PUFA supplementation, whereas the concentrations of sICAM-1 in the control group increased significantly during the 3-y study period, indicating a beneficial effect of the intervention principles on endothelial activation. This effect was possibly also reflected in the significant reduction in sTM observed with both interventions. The concentrations of tPAag also increased during the study period, probably reflecting a progress of the atherosclerotic process (29, 30). Individuals who received dietary counseling experienced a reduction in tPAag concentrations in comparison with subjects who did not receive dietary counseling. However, the increase in tPAag after n–3 PUFA supplementation was not different from that observed after placebo capsules.

The elderly population in the present trial is highly selected, having had a CVD risk profile with hypercholesterolemia for 25 y. Of the initial population of 1232, 26% had died, and of the participants recruited in this trial 28% had verified CVD. Furthermore, 30% received treatment for hypertension and 27% were on statin treatment. Although the present population by selection may have some cardioprotective traits, they should still be considered as high-risk subjects.

It is of particular interest that key markers of atherosclerosis may be modified by dietary counseling, n–3 PUFA supplementation, or both in this selected population of elderly high-risk men. The subjects in this trial initially had a high intake of n–3 PUFA because 55% had previously used some supplement regularly. Participants were asked to discontinue n–3 PUFA at least 1 mo before random assignment. However, at baseline they had a relatively low n–6 PUFA:n–3 PUFA compared with other trial populations (31, 32). The changes in EPA and arachidonic acid in the control group during the study period are probably caused by discontinuation of previously used n–3 PUFA supplementation. Subjects in the control group showed a slight improvement in their lipid profile. This improvement was probably caused by the focus on diet and prevention of CVDs at the screening visit, because all participants were informed of their higher-risk profile and given general information about lifestyle and diet.

After dietary counseling, the concentrations of sTM and sICAM-1 were reduced, reflecting reduced endothelial activation. The concentrations of tPAag were also reduced, possibly indicating an antiatherosclerotic effect of the dietary counseling. These findings are in accordance with systematically reviewed epidemiologic data, having reported beneficial effects from dietary intervention on CVD (14). Especially the advice of low-energy intake and the use of fish, unsaturated vegetable oil, fiber-rich bread along with an increase in fruit and vegetables are thought to be important for the present results of the dietary counseling. After dietary counseling we found no changes in total cholesterol, whereas a slight increase in HDL cholesterol and a reduction in triacylglycerols might have contributed to the reduced expression of sICAM-1 over the 3 y. Because dietary intervention is known to alter several risk factors simultaneously, it is more likely that the beneficial effect observed is caused by the combination of several interactions. A significant reduction of BMI emerged during dietary intervention. Evidence seems to support the notion that weight loss is associated with reduced endothelial activation (33–35). In the present trial, changes in BMI were also significantly associated with changes in tPAag concentrations.

After n–3 PUFA supplementation, a significant reduction was observed in triacylglycerols as well as a slight reduction in the total cholesterol:HDL cholesterol. The increase in serum concentrations of n–3 PUFA was highly significant, and the ratio of n–6 to n–3 fatty acids was substantially decreased. However, correlation analyses did not provide any clues to the possible relation between changes in the fatty acid profile and the reduction of sICAM-1 and sTM after n–3 PUFA supplementation.

The effect of n–3 PUFA on markers of activated endothelium has been studied extensively both in vitro and in vivo. De Caterina et al (21) found reduced cytokine-induced expression of VCAM-1, ICAM-1, and E-selectin in their in vitro studies on cultured human endothelial cells exposed to DHA. Miles et al (32) found no significant effects on sICAM-1 or sE-selectin of 1.2 g/d over 12 wk in 12 elderly healthy subjects, whereas sVCAM-1 was significantly reduced when compared with control subjects. In accordance with the present results, Abe et al (36) could demonstrate reduction of sICAM-1 after ≥7-mo supplementation with 4 g n–3 PUFA/d in hypertriglyceridemic men. In their population with 30% diabetics, they could demonstrate a reduction in sE-selectin, which was more pronounced in subjects with diabetes, and a reduction in sVCAM-1 was observed only in subjects with diabetes. Although 15% were diabetics in our population, no changes in sE-selectin or sVCAM-1 were observed. Thus, the dose of n–3 PUFA and selection of patients seem to be of significant importance.

Multiple regulatory mechanisms are apparently involved in the pathogenesis of endothelial activation. It has been assumed that the greater number of double bonds seem critical for the greater activity of marine n–3 compared with n–6 fatty acids in this respect (21). However, a great number of pathways are suggested that concern the influence of polyunsaturated fatty acids on the expression of these cell markers, including properties of the membrane lipid layer, the production of reactive oxygen species, and activation of nuclear transcription factors such as nuclear factor {kappa}B and peroxisome proliferator-activated receptor {alpha} (21, 37–39). In the present study no changes in vitamin E or in thiobarbituric acid reactive substances could be observed in the participants who took n–3 PUFA supplementation when compared with subjects who did not (data not shown). Thus, oxidative or antioxidative mechanisms possibly were not involved in the present results. However, the similar effect of the dietary intervention with small changes in the serum fatty acid pattern point to more complicated regulatory mechanisms (40).

In terms of clinical value, the reduction of sICAM-1 by each intervention is thought to be important. ICAM-1 is considered to be critical in the initiation and progression of atherosclerosis and may reflect inflammatory activity. According to the Physicians’ Health Study (4), subjects in the highest quartile (>260 ng/mL) of sICAM-1 had a substantially increased risk of future myocardial infarction, and in the PRIME study (41) concentrations of ICAM-1 served as risk markers for future acute coronary events. This may indicate that intervention principles which reduce the concentrations of ICAM-1 may be important in diminishing the risk and incidence of atherosclerotic disease. Likewise, however, studies of patients with CVD pinpointed the relation between concentrations of tPAag and future events (29, 30). The present results seem to indicate that dietary intervention by reducing sICAM-1, sTM, and tPAag concentrations is more favorable than more specific supplementation with n–3 PUFA. Because the present study focused on markers of endothelial activation, circulatory markers of inflammation and hemostasis such as tissue plasminogen activator and plasminogen activator inhibitor type I complex and C-reactive protein were not examined. These markers would be of interest to include in future research.

We conclude that in the DOIT population it was feasible and possible to modify the dietary habits and serum fatty acid profile by intervention with dietary counseling, n–3 PUFA supplementation, or both. Both intervention principles influenced the endothelial markers sICAM-1 and sTM in a favorable manner. However, the influence on tPAag was divergent with a reduced concentration being obtained with dietary counseling but not with n–3 PUFA supplementation.


   ACKNOWLEDGMENTS
 
We gratefully thank the participants of the study, and we acknowledge the administrative contribution of Liv Breivik and the technical assistance of Hanne Kleven.

HA, IH, and EMH designed and conducted the study. EMH wrote the manuscript in collaboration with IS, IH, and HA. IE conducted the dietary intervention. PB was responsible for the analyses of fatty acids and IS for the circulating endothelial markers. LS assisted with the statistical analyses. None of the authors had any conflict of interest.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med 1999;340:115–26.[Free Full Text]
  2. Adams DH, Mainolfi E, Elias E, Neuberger JM, Rothlein R. Detection of circulating intercellular adhesion molecule-1 after liver transplantation–evidence of local release within the liver during graft rejection. Transplantation 1993;55:83–7.[Medline]
  3. Morisaki N, Saito I, Tamura K, et al. New indices of ischemic heart disease and aging: studies on the serum levels of soluble intercellular adhesion molecule-1 (ICAM-1) and soluble vascular cell adhesion molecule-1 (VCAM-1) in patients with hypercholesterolemia and ischemic heart disease. Atherosclerosis 1997;131:43–8.[Medline]
  4. Ridker PM, Hennekens CH, Roitman-Johnson B, Stampfer MJ, Allen J. Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet 1998;351:88–92.[Medline]
  5. Schumacher A, Seljeflot I, Sommervoll L, Christensen B, Otterstad JE, Arnesen H. Increased levels of markers of vascular inflammation in patients with coronary heart disease. Scand J Clin Lab Invest 2002;62:59–68.[Medline]
  6. Badimon L, Badimon JJ, Chesebro JH, Fuster V. von Willebrand factor and cardiovascular disease. Thromb Haemost 1993;70:111–8.[Medline]
  7. Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo JC. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med 1995;332:635–41.[Abstract/Free Full Text]
  8. Blann AD, Amiral J, McCollum CN. Circulating endothelial cell/leucocyte adhesion molecules in ischaemic heart disease. Br J Haematol 1996;95:263–5.[Medline]
  9. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet 1989;2:757–61.[Medline]
  10. de Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994;343:1454–9.[Medline]
  11. Marckmann P, Gronbaek M. Fish consumption and coronary heart disease mortality. A systematic review of prospective cohort studies. Eur J Clin Nutr 1999;53:585–90.[Medline]
  12. Bemelmans WJ, Broer J, Feskens EJ, et al. 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 2002;75:221–7.[Abstract/Free Full Text]
  13. Brown AA, Hu FB. Dietary modulation of endothelial function: implications for cardiovascular disease. Am J Clin Nutr 2001;73:673–86.[Abstract/Free Full Text]
  14. Hooper L, Summerbell CD, Higgins JP, et al. Dietary fat intake and prevention of cardiovascular disease: systematic review. BMJ 2001;322:757–63.[Abstract/Free Full Text]
  15. Stiko-Rahm A, Wiman B, Hamsten A, Nilsson J. Secretion of plasminogen activator inhibitor-1 from cultured human umbilical vein endothelial cells is induced by very low density lipoprotein. Arteriosclerosis 1990;10:1067–73.[Abstract/Free Full Text]
  16. Dietary supplementation with n–3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet 1999;354:447–55.[Medline]
  17. Eritsland J, Arnesen H, Gronseth K, Fjeld NB, Abdelnoor M. Effect of dietary supplementation with n–3 fatty acids on coronary artery bypass graft patency. Am J Cardiol 1996;77:31–6.[Medline]
  18. Ulbricht TL, Southgate DA. Coronary heart disease: seven dietary factors. Lancet 1991;338:985–92.[Medline]
  19. Bucher HC, Hengstler P, Schindler C, Meier G. n–3 Polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials. Am J Med 2002;112:298–304.[Medline]
  20. Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002;106:2747–57.[Free Full Text]
  21. De Caterina R, Liao JK, Libby P. Fatty acid modulation of endothelial activation. Am J Clin Nutr 2000;71:213S–23S.[Abstract/Free Full Text]
  22. Goodfellow J, Bellamy MF, Ramsey MW, Jones CJ, Lewis MJ. Dietary supplementation with marine omega-3 fatty acids improve systemic large artery endothelial function in subjects with hypercholesterolemia. J Am Coll Cardiol 2000;35:265–70.[Abstract/Free Full Text]
  23. Johansen O, Seljeflot I, Hostmark AT, Arnesen H. The effect of supplementation with omega-3 fatty acids on soluble markers of endothelial function in patients with coronary heart disease. Arterioscler Thromb Vasc Biol 1999;19:1681–6.[Abstract/Free Full Text]
  24. Hjermann I, Velve BK, Holme I, Leren P. Effect of diet and smoking intervention on the incidence of coronary heart disease. Report from the Oslo Study Group of a randomised trial in healthy men. Lancet 1981;2:1303–10.[Medline]
  25. Andersen LF, Solvoll K, Johansson LR, Salminen I, Aro A, Drevon CA. Evaluation of a food frequency questionnaire with weighed records, fatty acids, and alpha-tocopherol in adipose tissue and serum. Am J Epidemiol 1999;150:75–87.[Abstract/Free Full Text]
  26. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge. Clin Chem 1972;18:499–502.[Abstract]
  27. Folch J, Lees M, Sloane Stanley GH. A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 1957;226:497–509.[Free Full Text]
  28. Hoshi M, Williams M, Kishimoto Y. Esterification of fatty acids at room temperature by chloroform-methanolic HCl-cupric acetate. J Lipid Res 1973;14:599–601.[Abstract]
  29. Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 1993;341:1165–8.[Medline]
  30. Jansson JH, Olofsson BO, Nilsson TK. Predictive value of tissue plasminogen activator mass concentration on long-term mortality in patients with coronary artery disease. A 7-year follow-up. Circulation 1993;88:2030–4.[Abstract/Free Full Text]
  31. de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation 1999;99:779–85.[Abstract/Free Full Text]
  32. Miles EA, Thies F, Wallace FA, et al. Influence of age and dietary fish oil on plasma soluble adhesion molecule concentrations. Clin Sci (Lond) 2001;100:91–100.[Medline]
  33. Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 1999;19:972–8.[Abstract/Free Full Text]
  34. Ito H, Ohshima A, Inoue M, et al. Weight reduction decreases soluble cellular adhesion molecules in obese women. Clin Exp Pharmacol Physiol 2002;29:399–404.[Medline]
  35. Ziccardi P, Nappo F, Giugliano G, et al. Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 2002;105:804–9.[Abstract/Free Full Text]
  36. Abe Y, El Masri B, Kimball KT, et al. Soluble cell adhesion molecules in hypertriglyceridemia and potential significance on monocyte adhesion. Arterioscler Thromb Vasc Biol 1998;18:723–31.[Abstract/Free Full Text]
  37. Neve BP, Fruchart JC, Staels B. Role of the peroxisome proliferator-activated receptors (PPAR) in atherosclerosis. Biochem Pharmacol 2000;60:1245–50.[Medline]
  38. James MJ, Gibson RA, Cleland LG. Dietary polyunsaturated fatty acids and inflammatory mediator production. Am J Clin Nutr 2000;71:343S–8S.[Abstract/Free Full Text]
  39. Toborek M, Lee YW, Garrido R, Kaiser S, Hennig B. Unsaturated fatty acids selectively induce an inflammatory environment in human endothelial cells. Am J Clin Nutr 2002;75:119–25.[Abstract/Free Full Text]
  40. Vorster HH, Cummings JH, Veldman FJ. Diet and haemostasis: time for nutrition science to get more involved. Br J Nutr 1997;77:671–84.[Medline]
  41. Luc G, Arveiler D, Evans A, et al. Circulating soluble adhesion molecules ICAM-1 and VCAM-1 and incident coronary heart disease: the PRIME Study. Atherosclerosis 2003;170:169–76.[Medline]
Received for publication February 17, 2004. Accepted for publication November 2, 2004.




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