Hostname: page-component-cd9895bd7-dzt6s Total loading time: 0 Render date: 2024-12-26T07:46:35.920Z Has data issue: false hasContentIssue false
  • English
  • Français

n-3 PUFA in CVD: influence of cytokine polymorphism

Published online by Cambridge University Press:  30 April 2007

C. von Schacky
C. von Schacky*
Affiliation:
Preventive Cardiology, Medizinische Klinik und Poliklinik Innenstadt, University of Munich, Ziemssenstraße 1, D-80336 München, Germany
*
Corresponding author: Professor C. von Schacky, fax +49 89 4423 6949, email Clemens.vonschacky@med.uni-muenchen.de
Rights & Permissions [Opens in a new window]

Abstract

In their current guidelines cardiac societies recommend the consumption of the two n-3 fatty acids EPA and DHA to prevent cardiovascular complications. Cardiovascular events are reduced by EPA and DHA, because they are antiarrhythmic, mitigate the course of atherosclerosis and stabilise plaque. As atherosclerosis is considered an inflammatory disorder a number of studies have investigated the anti-inflammatory mechanisms of EPA and DHA in a cardiovascular context in human dietary intervention studies. Pro-inflammatory cytokines, or cytokines reflecting inflammatory processes, e.g. IL-1β, IL-2, IL-6, TNFα, platelet-derived growth factor (PDGF)-A and -B and monocyte chemoattractant protein-1 (MCP-1), are reduced by ingestion of EPA and DHA by human subjects. Interestingly, C-reactive protein remains largely unaltered. However, in in vitro and animal models, but less so in human subjects, soluble cytokines reflecting interactions between blood cells and the vessel wall, such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, are reduced. Moreover, in contrast to common expectations, oxidative stress seems to be reduced after ingestion of EPA and DHA, at least as indicated by measurement of urinary F2 isoprostane excretion. Notably, for PDGF-A and -B and for MCP-1 the reduction has been demonstrated to occur at the gene expression level, which indicates that a deliberate change in diet can alter gene expression quantitatively. The precise underlying mechanism, however, remains to be clarified, but might involve PPAR, NF-κB and/or the eicosanoid system. The same holds true for the mechanisms by which levels of other cytokines are altered by EPA and DHA.

Keywords

CytokinesGrowth factorsCoronary artery disease
Type
Research Article
Information
Proceedings of the Nutrition Society , Volume 66 , Issue 2 , May 2007 , pp. 166 - 170
Copyright
Copyright © The Author 2007

Abbreviations:
ICAM

intercellular adhesion molecule

MCP-1

monocyte chemoattractant protein-1

PDGF

platelet-derived growth factor

s

soluble

VCAM

vascular cell adhesion molecule

The World's most important cardiac societies have issued guidelines that recommend the intake of the two marine n-3 fatty acids EPA and DHA at 1 g/d for CVD prevention, treatment after a myocardial infarction and prevention of sudden death and secondary disease (De Backer et al. Reference De Backer, Ambrosioni, Borch-Johnsen, Brotons, Cifkova and Dallongeville2003; Priori et al. Reference Priori, Aliot, Blomstrom-Lundqvist, Bossaert, Breithardt and Brugada2003; Van der Werf et al. Reference Van der Werf, Ardissino, Betriu, Cokkinos, Falk and Fox2003; Smith et al. Reference Smith, Allen, Blair, Bonow, Brass and Fonarow2006). National cardiac societies have followed suit (Wirth & Gohlke, Reference Wirth and Gohlke2005). These recommendations are based not only on intervention trials with these n-3 fatty acids (Burr et al. Reference Burr, Fehily, Gilbert, Rogers, Holliday, Sweetnam, Elwood and Deadman1989, Reference Burr, Ashfield-Watt, Dunstan, Fehily, Breay, Ashton, Zotos, Haboubi and Elwood2003; The GISSI Prevenzione Group, 1999; Marchioli et al. Reference Marchioli, Barzi, Bomba, Chieffo, Di Gregorio and Di Mascio2002; Yokoyama et al. Reference Yokoyama and Origasea2003), but also on a wealth of literature describing mechanisms of actions, animal models, studies with surrogate and intermediate factors and other aspects (von Schacky, Reference von Schacky1987, Reference von Schacky2003). Taken together, the scientific basis of the current guidelines is so strong that they have been established despite a null result in a recent Cochrane analysis (Hooper et al. Reference Hooper, Thompson, Harrison, Summerbell, Ness and Moore2006).

EPA and DHA have been demonstrated not only to have an antiarrhythmic effect (Leaf et al. Reference Leaf, Albert, Josephson, Steinhaus, Kluger, Kang, Cox, Zhang and Schoenfeld2005; Raitt et al. Reference Raitt, Connor, Morris, Kron, Halperin and Chugh2005), but also to mitigate the course of coronary atherosclerosis (von Schacky et al. Reference von Schacky, Angerer, Kothny, Theisen and Mudra1999) and to stabilize unstable plaque, e.g. in carotid arteries (Thies et al. Reference Thies, Garry, Yaqoob, Rerkasem, Williams, Shearman, Gallagher, Calder and Grimble2003). These two findings are manifestations of an anti-inflammatory effect of EPA and DHA, currently used in the treatment of inflammatory disorders such as rheumatoid arthritis (Kremer, Reference Kremer2000). For some time atherosclerosis has been considered to be a disease with an inflammatory component (for example, see Ross, Reference Ross1999). The present review considers investigations aimed at unravelling the mechanisms by which EPA and DHA exert their anti-inflammatory effects through alterations of cytokine metabolism. Since differences exist in cytokine metabolism in vitro v. in vivo and in experimental animals v. in human subjects the present review will largely focus on work done in human subjects.

Cytokines related to inflammation and atherosclerosis

IL-1β

IL-1β is an important cytokine that has a plethora of actions, including a pronounced pro-inflammatory effect and increasing the expression of adhesion molecules (Dinarello, Reference Dinarello2006). Levels of IL-1β decrease by 61–90% when healthy volunteers and patients with rheumatoid arthritis ingest doses of between 2·7 and 5·8 g EPA and DHA/d (for review, see James et al. Reference James, Gibson and Cleland2000). Furthermore, IL-1β levels associated with stimulation by strenuous exercise (a marathon run) are not influenced by previous ingestion of 3·6 g EPA and DHA/d (Toft et al. Reference Toft, Thorn, Ostrowski, Asp, Moller, Iversen, Hermann, Sondergaard and Pedersen2000), which suggests that IL-1β levels clearly respond to a strong stimulus. These findings might partially explain why infectious complications are not seen more frequently in large-scale intervention trials using EPA and DHA (von Schacky & Harris, Reference von Schacky and Harris2006).

IL-6

IL-6 is a cytokine that together with a soluble IL-6 receptor plays an important role in perpetuating an inflammatory state (Scheller et al. Reference Scheller, Ohnesorge and Rose-John2006). IL-6 is generally reduced, as assessed ex vivo, after supplementation of the human diet with n-3 fatty acids (for review, see Calder, Reference Calder2005). In the supernatant fraction of unstimulated mononuclear cells the reduction is more pronounced after 0·3 g EPA and DHA/d than after 1·0 or 2·0 g EPA and DHA/d (Trebble et al. Reference Trebble, Arden, Stroud, Wootton, Burdge, Miles, Ballinger, Thompson and Calder2003). However, in the supernatant fraction of stimulated mononuclear cells the reduction is clearly dose-related (Trebble et al. Reference Trebble, Arden, Stroud, Wootton, Burdge, Miles, Ballinger, Thompson and Calder2003).

IL-10

An epidemiological study (Ferrucci et al. Reference Ferrucci, Cherubini, Bandinelli, Bartali, Corsi, Lauretani, Ma, Andres-Lacueva, Senin and Gualnik2006) has shown that low levels of this anti-inflammatory compound are associated with low levels of DHA. After treatment for 1 year with 3·4 g EPA and DHA/d, the IL-10 levels of forty-five recipients of heart transplants were found to be decreased (Holm et al. Reference Holm, Berge, Anderassen, Ueland, Kjekshus, Simonsen, Froland, Gullestad and Aukrust2001). In healthy volunteers after supplementation with 7 g EPA and DHA/d for 4 weeks IL-10 mRNA steady-state levels were found to be unaltered in either unstimulated mononuclear cells or monocytes that had been adherence-activated ex vivo (Baumann et al. Reference Baumann, Hessel, Larass, Müller, Angerer, Kiefl and von Schacky1999). There have been no other reports of studies in human subjects. Thus, there is at present no clear picture of the effects of EPA and DHA on levels of IL-10.

TNFα

TNFα is a pro-inflammatory cytokine that has a large number of effects, among them increased body temperature, reduced appetite and stimulation of other immunmodulatory cytokines (Grimble, Reference Grimble1996). TNF is thought to be a propagator of atherosclerosis (Ross, Reference Ross1999). The effects of fish oil on TNFα production by peripheral blood mononuclear cells have been investigated in eleven studies of healthy volunteers, of which six studies have demonstrated a suppressive effect (for review, see Grimble et al. Reference Grimble, Howell, O'Reilly, Turner, Markovic, Hirrell, East and Calder2002). These apparently discrepant findings can be explained by the effects of inherent TNFα production and by polymorphisms in the TNFα and lymphotoxin α genes (Grimble et al. Reference Grimble, Howell, O'Reilly, Turner, Markovic, Hirrell, East and Calder2002). These polymorphisms might also explain an unexpected increase in TNF in recipients of heart transplants after supplementation with 3·4 g EPA and DHA/d for 1 year (Holm et al. Reference Holm, Berge, Anderassen, Ueland, Kjekshus, Simonsen, Froland, Gullestad and Aukrust2001). In a dose–response study of healthy volunteers levels of TNFα in the supernatant fraction of unstimulated and stimulated mononuclear cells was shown to decrease (Trebble et al. Reference Trebble, Arden, Stroud, Wootton, Burdge, Miles, Ballinger, Thompson and Calder2003). Interestingly, the decrease was found to be less pronounced after consuming 2·0 g EPA and DHA/d than after consuming 1·0 g EPA and DHA/d.

DHA, but not EPA, reduces the expression of pro-inflammatory IL-1, IL-6 and TNFα in vitro (De Caterina et al. Reference De Caterina, Zampolli, Del Turco, Madonna and Massaro2006).

Platelet-derived growth factor

Platelet-derived growth factor (PDGF) stimulates smooth muscle cell proliferation and plays a role in the migration of these cells into neointima following injury and in atherosclerosis (Raines, Reference Raines2004). PDGF is thought to play a major role in the proliferation of atherosclerotic lesions (Ross, Reference Ross1999). In volunteers ingesting 7 g EPA and DHA/d levels of mRNA coding for PDGF-A and -B were found to be reduced by 58% after 1 week and by 70% after 6 weeks, with these levels remaining constant in controls on an unaltered Western diet (Kaminski et al. Reference Kaminski, Jendraschak, Kiefl and von Schacky1993). This finding was the first demonstration that a deliberate change in diet can alter gene expression quantitatively. In a subsequent study, with the same dose of EPA and DHA but comparing it with 7 g n-6 fatty acids/d and 7 g n-9 fatty acids/d (Baumann et al. Reference Baumann, Hessel, Larass, Müller, Angerer, Kiefl and von Schacky1999), the reduction in the levels of PDGF-A and -B mRNA was found to be quantitatively less pronounced (for PDGF-A −25 (sd 10) %, for PDGF-B −31 (sd 13) %) in non-stimulated mononuclear cells. However, after cell adherence for 4 h or 20 h the reduction was found to persist to a quantitatively similar extent (Baumann et al. Reference Baumann, Hessel, Larass, Müller, Angerer, Kiefl and von Schacky1999). Lower doses of EPA and DHA (0·3, 0·6 or 0·9 g n-3 fatty acids/d) have no effect on serum mitogenic activity or serum PDGF levels (Wallace et al. Reference Wallace, McCabe, Roche, Higgins, Robson, Gilmore, McGlynn and Strain2000).

Monocyte chemoattractant protein-1

Monocyte chemoattractant protein-1 (MCP-1), acting through its receptor chemokine (C–C motif) receptor 2, appears to play an early and important role in the recruitment of monocytes to atherosclerotic lesions and in the formation of intimal hyperplasia after intimal injury (Charo & Taubman, Reference Charo and Taubman2004). Supplementation with dietary n-3 fatty acids (EPA and DHA), but not n-6 or n-9 fatty acids, at 7 g /d for 4 weeks reduces MCP-1 mRNA levels in unstimulated mononuclear cells ex vivo by 40% (Baumann et al. Reference Baumann, Hessel, Larass, Müller, Angerer, Kiefl and von Schacky1999). After stimulation of the cells by adherence for 4 h and 20 h MCP-1 mRNA levels are reduced by 35 (sd 20) % and 30 (sd 8) % respectively (Baumann et al. Reference Baumann, Hessel, Larass, Müller, Angerer, Kiefl and von Schacky1999). It is quite likely that the reductions in gene expression translate into reduced levels of MCP-1 before and after stimulation in vivo, although the direct proof will be quite difficult to obtain. Evidence from in vitro studies (De Caterina & Massaro, Reference De Caterina and Massaro2005) indicates that both EPA and DHA decrease agonist-induced activation of NF-κB and increase PPAR. This effect might very well play a role in the reduced gene expression for PDGF-A and -B and for MCP-1 in vivo after EPA and DHA.

C-reactive protein

C-reactive protein is a marker of systemic inflammation that is currently considered to be a risk factor for CVD (Tsimikas et al. Reference Tsimikas, Willerson and Ridker2006). Given the anti-inflammatory and anti-atherosclerotic effects of EPA and DHA, reduced levels of C-reactive protein would be expected to occur after supplementation. While an epidemiological study (Pischon et al. Reference Pischon, Hankinson, Hotamisligil, Rifai, Willett and Rimm2003) has shown an inverse relationship between the intake of EPA and DHA and levels of C-reactive protein, human intervention studies (for review, see Mori & Beilin, Reference Mori and Beilin2004) have not found a reduction in C-reactive protein levels after ingestion of EPA and DHA. Thus at present no clear picture of the relationship between EPA and DHA and C-reactive protein has emerged.

Cytokines related to endothelial activation

Vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule-1 (ICAM-1) and E-selectin have a role in the pathogenesis of atherosclerosis (Hope & Meredith, Reference Hope and Meredith2003). Plasma levels can be measured because soluble (s) VCAM and sICAM are shed from the cell surface. Plasma levels of sE-selectin can also be measured (Roldan et al. Reference Roldan, Marin, Lip and Blann2003). Levels of VCAM and ICAM correlate to some extent with the presence of clinical atherosclerosis (Hope & Meredith, Reference Hope and Meredith2003). However, VCAM-1 and ICAM-1 have a role in the early phase of the development of the atherosclerotic lesion, i.e. in monocyte recruitment by endothelial cells, before the appearance of macrophages (foam cells) in the intima (De Caterina & Massaro, Reference De Caterina and Massaro2005). E-selectin is expressed on the endothelial surface slightly earlier in the sequence of events (Roldan et al. Reference Roldan, Marin, Lip and Blann2003). sVCAM-1, sICAM-1 and sE-selectin are considered to be markers of endothelial activation (Hope & Meredith, Reference Hope and Meredith2003; Roldan et al. Reference Roldan, Marin, Lip and Blann2003). Whether they are risk factors for atherosclerosis or its clinical events is a matter of debate.

Stimulated endothelial cells express less sVCAM, sICAM or sE-selectin in the presence of n-3 fatty acids, with DHA being more potent than EPA (De Caterina et al. Reference De Caterina, Madonna and Massaro2004). DHA reduces mRNA levels by inhibition of the activation of the NF-κB system of transcription factors (De Caterina et al. Reference De Caterina, Madonna and Massaro2004). Corresponding findings from studies in experimental animals have been published (for review, see Calder, Reference Calder2004).

Studies in human subjects have yielded less clear results. In a randomized study of forty-one male smokers with hyperlipidaemia (Seljeflot et al. Reference Seljeflot, Arnesen, Brude, Nenseter, Drevon and Hjermann1998) 4·8 g EPA and DHA/d was shown to increase levels of sVCAM-1 and sE-selectin. In middle-aged healthy volunteers (Thies et al. Reference Thies, Miles, Nebe-von-Caron, Powell, Hurst, Newsholme and Calder2001) supplementation with 1 g EPA and DHA/d for 12 weeks was found to reduce levels of sVCAM-1 (–28%) and sE-selectin (−17%), while levels of sICAM-1 were unaltered. In another 12-week randomized double-blind study of healthy subjects by the same group (Miles et al. Reference Miles, Thies, Wallace, Powell, Hurst, Newsholme and Calder2001) levels of all three compounds were found to be unaltered after fish oil supplementation. In a 1-year double-blind study of 300 patients after a myocardial infarction (Grundt et al. Reference Grundt, Nilsen, Mansoor, Hetland and Nordoy2003) treatment with EPA and DHA was not found to reduce levels of sICAM or sE-selectin. In individuals with type 2 diabetes, however, levels of sE-selectin are reduced after treatment with EPA or DHA (Nomura et al. Reference Nomura, Kanazawa and Fukuhara2003; Woodman et al. Reference Woodman, Mori, Burke, Puddey, Barden, Watts and Beilin2003). Administration of 2·4 g EPA and DHA/d to 171 elderly men at risk for coronary artery disease has been shown to increase sVCAM (Berstad et al. Reference Berstad, Seljeflot, Veierod, Hjerkinn, Arnesen and Pedersen2003). A randomized study (Eschen et al. Reference Eschen, Christensen, De Caterina and Schmidt2004) comparing EPA and DHA at doses of 2·0 g/d and 6·6 g/d in healthy subjects has shown a decrease in sE-selectin only when fed at a dose of 6·6 g/d. In a large (563 elderly subjects) 3-year randomized study that compared (using a factorial design) dietary advice, 2·4 g EPA and DHA/d and no treatment (Hjerkinn et al. Reference Hjerkinn, Seljeflot, Ellingsen, Berstad, Berstad, Hjermann, Sandvik and Arnesen2005) EPA and DHA was found to reduce levels of sICAM.

Thus, while a clear picture has emerged in vitro and in animal studies, demonstrating reductions in plasma levels of sVCAM, sICAM and sE-selectin, investigations in human subjects have yielded mixed results. This disparity may be related to differences in populations studied and doses used.

Oxidative stress

The measurement of urinary F2 isoprostane excretion by GC–MS is currently thought to best reflect oxidative stress in vivo (Mori & Beilin, Reference Mori and Beilin2004). In contrast to theoretical concerns and earlier observations with less-refined methodology, oxidative stress has been consistently shown to be reduced after ingestion of EPA and DHA both in combination and individually (Mori & Beilin, Reference Mori and Beilin2004). Reduced oxidative stress is thought to contribute to the anti-atherosclerotic actions of n-3 fatty acids, possibly through immunomodulation and decreased leucocyte activation (Mori & Beilin, Reference Mori and Beilin2004).

Conclusion

Taken together EPA and DHA reduce levels of the pro-inflammatory cytokines IL-1β, IL-6 and TNFα in human subjects. Moreover, mRNA levels of pro-atherosclerotic growth factors, such as PDGF-A and -B, and MCP-1 are reduced in mononuclear cells after supplementing the human diet with EPA and DHA. The cytokines and growth factors mentioned play a role in the propagation of the atherosclerotic lesion. In vitro the levels of sICAM, sVCAM and sE-selectin are reduced by the presence of EPA or DHA. These cytokines reflect endothelial activation. Data from human studies are less clear cut, probably because endothelial activation is transient. It is currently thought that the effects of EPA and DHA on cytokines and growth factors are the mechanisms responsible for the anti-atherosclerotic action of these n-3 fatty acids.

References

Baumann, KH, Hessel, F, Larass, I, Müller, T, Angerer, P, Kiefl, R & von Schacky, C (1999) Dietary omega-3, omega-6, and omega-9 unsaturated fatty acids and growth factor and cytokine gene expression in unstimulated and stimulated monocytes. A randomized volunteer study. Arteriosclerosis, Thrombosis, and Vascular Biology 19, 59–66.CrossRefGoogle ScholarPubMed
Berstad, P, Seljeflot, I, Veierod, MB, Hjerkinn, EM, Arnesen, H & Pedersen, JH (2003) Supplementation with fish oil affects the association between very long-chain polyunsaturated fatty acids in serum non-esterified fatty acids and soluble vascular cell adhesion molecule-1. Clinical Science 105, 13–20.CrossRefGoogle ScholarPubMed
Burr, ML, Ashfield-Watt, PAL, Dunstan, FDJ, Fehily, AM, Breay, P, Ashton, T, Zotos, PC, Haboubi, NAA & Elwood, PC (2003) Lack of benefit of dietary advice to men with angina, results of a controlled trial. European Journal of Clinical Nutrition 57, 193–200.CrossRefGoogle ScholarPubMed
Burr, ML, Fehily, AM, Gilbert, JF, Rogers, S, Holliday, RM, Sweetnam, PM, Elwood, PC & Deadman, NM (1989) Effects of changes in fat, fish, and fibre intakes on death and myocardial infarction: diet and reinfarction trial (DART). Lancet ii, 757–761.CrossRefGoogle Scholar
Calder, PC (2004) n-3 fatty acids and cardiovascular disease: evidence explained and mechanisms explored. Clinical Science 107, 1–11.CrossRefGoogle ScholarPubMed
Calder, PC (2005) Polyunsaturated fatty acids and inflammation. Biochemical Society Transactions 33, 423–427.CrossRefGoogle ScholarPubMed
Charo, IF & Taubman, MB (2004) Chemokines in the pathogenesis of vascular disease. Circulation Research 95, 858–866.CrossRefGoogle ScholarPubMed
De Backer, G, Ambrosioni, E, Borch-Johnsen, K, Brotons, C, Cifkova, R, Dallongeville, J et al. (2003) European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. European Heart Journal 24, 1601–1610.CrossRefGoogle ScholarPubMed
De Caterina, R, Madonna, R & Massaro, M (2004) Effects of omega-3 fatty acids on cytokines and adhesion molecules. Current Atherosclerosis Reports 6, 485–491.CrossRefGoogle ScholarPubMed
De Caterina, R & Massaro, M (2005) Omega-3 fatty acids and the regulation of expression of endothelial pro-atherogenic and pro-inflammatory genes. Journal of Membrane Biology 206, 103–116.CrossRefGoogle ScholarPubMed
De Caterina, R, Zampolli, A, Del Turco, S, Madonna, R & Massaro, M (2006) Nutritional mechanisms that influence cardiovascular disease. American Journal of Clinical Nutrition 83, Suppl., 421S–426S.CrossRefGoogle ScholarPubMed
Dinarello, CA (2006) Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. American Journal of Clinical Nutrition 83, Suppl., 447S–455S.CrossRefGoogle ScholarPubMed
Eschen, O, Christensen, JH, De Caterina, R & Schmidt, EB (2004) Soluble adhesion molecules in healthy subjects: a dose response study using n-3 fatty acids. Nutrition and Metabolism in Cardiovascular Disease 14, 180–185.CrossRefGoogle ScholarPubMed
Ferrucci, L, Cherubini, A, Bandinelli, S, Bartali, B, Corsi, A, Lauretani, F, Ma, A, Andres-Lacueva, C, Senin, U & Gualnik, JM (2006) Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers. Journal of Clinical Endocrinology and Metabolism 91, 398–400.CrossRefGoogle ScholarPubMed
Grimble, RF (1996) Interaction between nutrients, pro-inflammatory cytokines and inflammation. Clinical Science 91, 121–130.CrossRefGoogle ScholarPubMed
Grimble, RF, Howell, WM, O'Reilly, G, Turner, SJ, Markovic, O, Hirrell, S, East, JM & Calder, PC (2002) The ability of fish oil to suppress tumor necrosis factor α production by peripheral blood mononuclear cells in healthy men is associated with polymorphisms in genes that influence tumor necrosis factor α production. American Journal of Clinical Nutrition 76, 454–459.CrossRefGoogle ScholarPubMed
Grundt, H, Nilsen, DW, Mansoor, MA, Hetland, O & Nordoy, A (2003) Reduction in homocysteine by n-3 polyunsaturated fatty acids after 1 year in a randomised double-blind study following an acute myocardial infarction: no effect on endothelial adhesion properties. Pathophysiology in Haemostasis and Thrombosis 33, 88–95.CrossRefGoogle Scholar
Hjerkinn, EM, Seljeflot, I, Ellingsen, I, Berstad, I, Berstad, P, Hjermann, I, Sandvik, L & Arnesen, H (2005) 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 hyperlipidemia. American Journal of Clinical Nutrition 81, 583–589.CrossRefGoogle ScholarPubMed
Holm, T, Berge, RK, Anderassen, AK, Ueland, T, Kjekshus, J, Simonsen, S, Froland, S, Gullestad, L & Aukrust, P (2001) Omega-3 fatty acids enhance tumor necrosis factor-alpha levels in heart transplant recipients. Transplantation 72, 706–711.CrossRefGoogle ScholarPubMed
Hooper, L, Thompson, RL, Harrison, RA, Summerbell, CD, Ness, AR, Moore, HJ et al. (2006) Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review. British Medical Journal 332, 752–760.CrossRefGoogle ScholarPubMed
Hope, SA & Meredith, IT (2003) Cellular adhesion molecules and cardiovascular disease. Part II. Their association with conventional and emerging risk factors, acute coronary events and cardiovascular risk prediction. Internal Medical Journal 33, 450–462.CrossRefGoogle ScholarPubMed
James, MJ, Gibson, RA & Cleland, LG (2000) Dietary polyunsaturated fatty acids and inflammatory mediator production. American Journal of Clinical Nutrition 71, Suppl., 343S–348S.CrossRefGoogle ScholarPubMed
Kaminski, WE, Jendraschak, E, Kiefl, R & von Schacky, C (1993) Dietary ω-3 fatty acids lower levels of PDGF mRNA in human mononuclear cells. Blood 81, 1871–1879.CrossRefGoogle ScholarPubMed
Kremer, JM (2000) n-3 fatty acid supplements in rheumatoid arthritis. American Journal of Clinical Nutrition 71, Suppl., 349S–351S.CrossRefGoogle ScholarPubMed
Leaf, A, Albert, CM, Josephson, M, Steinhaus, D, Kluger, J, Kang, JX, Cox, B, Zhang, H & Schoenfeld, D for the Fatty Acid Antiarrhythmia Trial Investigators (2005) Prevention of fatal arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake. Circulation 112, 2762–2768.CrossRefGoogle ScholarPubMed
Marchioli, R, Barzi, F, Bomba, E, Chieffo, C, Di Gregorio, D, Di Mascio, R et al. (2002) Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction. Time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarcto Miocardio (GISSI) Prevenzione. Circulation 105, 1897–1903.CrossRefGoogle Scholar
Miles, EA, Thies, F, Wallace, FA, Powell, JR, Hurst, TL, Newsholme, EA & Calder, PC (2001) Influence of age and dietary fish oil on plasma soluble adhesion molecule concentrations. Clinical Science 100, 91–100.CrossRefGoogle ScholarPubMed
Mori, TA & Beilin, LJ (2004) Omega-3 fatty acids and inflammation. Current Atherosclerosis Reports 6, 461–467.CrossRefGoogle ScholarPubMed
Mori, TA, Woodman, RJ, Burke, V, Puddey, IB, Croft, KD & Beilin, LJ (2003) Effect of eicosapentaenoic acid and docosahexaenoic acid in oxidative stress and inflammatory markers in treated type 2 diabetic subjects. Free Radical Biology and Medicine 7, 772–781.CrossRefGoogle Scholar
Nomura, S, Kanazawa, S & Fukuhara, S (2003) Effects of eicosapentaenoic acid on platelet activation markers and cell adhesion molecules in hyperlipidemic patients with type 2 diabetes. Journal of Diabetes and its Complications 17, 153–159.CrossRefGoogle ScholarPubMed
Pischon, T, Hankinson, SE, Hotamisligil, GS, Rifai, N, Willett, WC & Rimm, EB (2003) Habitual dietary intake of n-3 and n-3 fatty acids in relation to inflammatory markers among US men and women. Circulation 108, 155–160.CrossRefGoogle ScholarPubMed
Priori, SG, Aliot, E, Blomstrom-Lundqvist, C, Bossaert, L, Breithardt, G, Brugada, P et al. (2003) European Society of Cardiology update of the guidelines on sudden cardiac death of the European Society of Cardiology. European Heart Journal 24, 13–15.CrossRefGoogle Scholar
Raines, EW (2004) PDGF and cardiovascular disease. Cytokine and Growth Factor Reviews 15, 237–254.CrossRefGoogle ScholarPubMed
Raitt, MJ, Connor, WE, Morris, C, Kron, J, Halperin, B, Chugh, SS et al. (2005) Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators. Journal of the American Medical Association 293, 2884–2891.CrossRefGoogle ScholarPubMed
Roldan, V, Marin, F, Lip, GY & Blann, AD (2003) Soluble E-selectin in cardiovascular disease and its risk factors. A review of the literature. Thrombosis and Haemostasis 90, 1007–1020.CrossRefGoogle ScholarPubMed
Ross, R (1999) Atherosclerosis – an inflammatory disease. New England Journal of Medicine 340, 115–126.CrossRefGoogle ScholarPubMed
Scheller, J, Ohnesorge, N & Rose-John, S (2006) Interleukin-6 trans-signaling in chronic inflammation and cancer. Scandinavian Journal of Immunology 63, 321–329.CrossRefGoogle Scholar
Seljeflot, I, Arnesen, H, Brude, IR, Nenseter, MS, Drevon, CA & Hjermann, I (1998) Effects of omega-3 fatty acids and/or antioxidants on endothelial cell markers. European Journal of Clinical Investigation 28, 629–635.CrossRefGoogle ScholarPubMed
Smith, SC, Allen, J, Blair, SN, Bonow, RO, Brass, LM, Fonarow, GC et al. (2006) AHA/ACC Guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update. Circulation 113, 2363–2372.CrossRefGoogle ScholarPubMed
The GISSI Prevenzione Group (1999) 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 354, 447–455.CrossRefGoogle Scholar
Thies, F, Garry, JM, Yaqoob, P, Rerkasem, K, Williams, J, Shearman, CP, Gallagher, PJ, Calder, PC & Grimble, RF (2003) Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial. Lancet 361, 477–485.CrossRefGoogle ScholarPubMed
Thies, F, Miles, EA, Nebe-von-Caron, G, Powell, JR, Hurst, TL, Newsholme, EA & Calder, PC (2001) Influence of dietary supplementation with long-chain n-3 or n-6 polyunsaturated fatty acids on blood inflammatory cell populations and functions and on plasma soluble adhesion molecules in healthy adults. Lipids 36, 1183–1193.CrossRefGoogle ScholarPubMed
Toft, AD, Thorn, M, Ostrowski, K, Asp, S, Moller, K, Iversen, S, Hermann, C, Sondergaard, SR & Pedersen, BK (2000) N-3 polyunsaturated fatty acids do not affect cytokine response to strenuous exercise. Journal of Applied Physiology 89, 2401–2406.CrossRefGoogle Scholar
Trebble, T, Arden, NK, Stroud, MA, Wootton, SA, Burdge, GC, Miles, EA, Ballinger, AB, Thompson, RL & Calder, PC (2003) Inhibition of tumour necrosis factor-α and interleukin 6 production by mononuclear cells following dietary fish-oil supplementation in healthy men and response to antioxidant co-supplementation. British Journal of Nutrition 90, 405–412.CrossRefGoogle ScholarPubMed
Tsimikas, S, Willerson, JT & Ridker, PM (2006) C-reactive protein and other emerging blood markers to optimize risk stratification of vulnerable patients. Journal of the American College of Cardiology 47, Suppl., C19–C31.CrossRefGoogle Scholar
Van der Werf, F, Ardissino, D, Betriu, A, Cokkinos, DV, Falk, E, Fox, KA et al. (2003) Management of acute myocardial infarction in patients presenting with ST-segment elevation. The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. European Heart Journal 24, 28–66.CrossRefGoogle Scholar
von Schacky, C (1987) Prophylaxis of atherosclerosis with marine omega-3 fatty acids – a comprehensive strategy. Annals of Internal Medicine 107, 890–899.CrossRefGoogle ScholarPubMed
von Schacky, C (2003) The role of omega-3 fatty acids in cardiovascular disease. Current Atherosclerosis Reports 5, 139–145.CrossRefGoogle ScholarPubMed
von Schacky, C, Angerer, P, Kothny, W, Theisen, K & Mudra, H (1999) The effect of dietary omega-3 fatty acids on coronary atherosclerosis. A randomized, double-blind, placebo-controlled trial. Annals of Internal Medicine 130, 554–562.CrossRefGoogle ScholarPubMed
von Schacky, C & Harris, WS (2007) Beneficial cardiovascular effects of omega-3 fatty acids. Cardiovascular Research 72, 310–315.CrossRefGoogle Scholar
Wallace, JM, McCabe, AJ, Roche, HM, Higgins, S, Robson, PJ, Gilmore, WS, McGlynn, H & Strain, JJ (2000) The effect of low-dose fish oil supplementation on serum growth factors in healthy humans. European Journal of Clinical Nutrition 54, 690–694.CrossRefGoogle ScholarPubMed
Wirth, A & Gohlke, H (2005) Rolle des Korpergewichts fur die Pravention der koronaren Herzkrankheit (Role of body weight for the prevention of coronary heart disease). Zeitschrift für Kardiologie 94, Suppl. 3, III/22–III/29.CrossRefGoogle ScholarPubMed
Woodman, RJ, Mori, TA, Burke, V, Puddey, IB, Barden, A, Watts, GF & Beilin, LJ (2003) Effects of purified eicosapentaenoic acid and docosahexaenoic acid on platelet, fibrinolytic and vascular function in hypertensive type 2 diabetic patients. Atherosclerosis 166, 85–93.CrossRefGoogle ScholarPubMed
Yokoyama, M & Origasea, H for the JELIS Investigators (2003) Effects of eicosapentaenoic acid on cardiovascular events in Japanese patients with hypercholesterolemia: Rationale, design, and baseline characteristics of the Japan EPA Lipid Intervention Study (JELIS). American Heart Journal 146, 613–620.CrossRefGoogle ScholarPubMed