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Omega-3 fatty acids, thrombosis and vascular disease
International Congress Series 1262 (2004) 380 – 383
www.ics-elsevier.com
Omega-3 fatty acids, thrombosis and vascular disease William S. Harris * Lipid and Diabetes Research, Mid America Heart Institute, Saint Luke’s Hospital, 4320 Wornall Road, Suite 128, Kansas City, MO 64111, USA
Abstract. The cardioprotective effects of long-chain, marine omega-3 fatty acids (N3 FA) have been demonstrated in animal and human experimental studies, in epidemiological investigations and in randomized, controlled trials. In Western countries, effective intakes of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) appear to be in the 0.5 – 1 g/day range. The mechanism behind the N3 FA effect is not known with certainty, but appears to involve the prevention of fatal arrhythmias associated with myocardial ischemia. The extent to which this may be secondary to N3 FA-induced reductions in thrombotic tendencies is not known. Although the anti-thrombotic properties of larger quantities (>3 g/day) of N3 FA have been examined, the impact of < 1 g/day has not. Current evidence suggests that at very low intakes (150 mg/day of EPA) ex vivo platelet function may be inhibited, and individuals with higher blood levels of N3 FA have lower levels of tissue plasminogen activator. On the other hand, supplementation with 800 – 1600 mg/day of EPA + DHA had no effect on coagulation factors. Although further research is needed, these data imply that hemostatic processes may be beneficially impacted by low intakes of N3 FA, and CHD risk may thereby be reduced. D 2003 Published by Elsevier B.V. Keywords: Eicosapentaenoic acid; Docosahexaenoic acid; Fish oils; Platelet aggregation; Cardiovascular disease; Thrombosis; Hemostasis
1. Introduction The purpose of this review is to examine some of the evidence for an antithrombotic mechanism behind the cardioprotective effect of omega-3 fatty acids (N3 FA) derived from fish oils, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Evidence from several types of studies suggest that, especially in cultures with typically very low intakes of N3 FA such as the USA, increasing daily intakes by 500 –1000 mg of EPA + DHA may reduce risk of death from coronary heart disease (CHD). This evidence includes population studies [1 –4] and supplementation trials [5 –7].
* Tel.: +1-816-932-8235; fax: +1-816-932-8278. E-mail address: [email protected] (W.S. Harris). 0531-5131/ D 2003 Published by Elsevier B.V. doi:10.1016/j.ics.2003.12.097
W.S. Harris / International Congress Series 1262 (2004) 380–383
381
2. Clinical trial evidence of efficacy The best evidence for the cardioprotective effects of N3 FA comes from the GISSI Prevenzione study [7,8]. Here, supplementation with 850 mg/dayay of EPA + DHA reduced risk of death from any cause by 20% and risk of sudden death by 45% in postMI patients. 3. Potential cardioprotective mechanisms The mechanism(s) responsible for this beneficial effect are not known. Almost all the past studies that have explored ‘‘mechanistic’’ questions have used far greater intakes of N3 oils than were used in the GISSI and DART studies. Intakes of 3 to over 20 g of EPA + DHA have had effects on blood lipids (notably triglycerides), platelet function, blood pressure, blood vessel flexibility, and inflammation (reviewed in Ref. [9]). However, there is very little information on the biological effects of the low intakes (less than 1 g/day) as used in the major clinical trials and as suggested from epidemiological studies. At present, it appears that N3 FA feeding decreases risk for sudden cardiac death by reducing the susceptibility of the heart to malignant arrhythmias (see review, by Leaf et al. [10]). Whether there is a thrombotic element in the causal chain leading to this outcome is not presently known. 3.1. Effects of low intakes of x3 FA on platelet aggregation A supplementation experiment was conducted in elderly men from Lyon, France (average age 72) in which eleven were given 150 mg of EPA in capsule form and another eight were given placebo for four weeks [11]. Ex vivo platelet aggregation studies were carried out at the beginning and end of the study using several concentrations of three agonists: epinephrine, adenosine diphosphate (ADP), and collagen. Although a very small study, statistically significant reductions in platelet aggregation were found with all three agonists in the EPA group (Fig. 1). Interestingly, no change in platelet membrane FA
Fig. 1. Platelet aggregation. Effects of the indicated concentrations of three agonists on ex vivo platelet aggregation in 8 elderly subjects treated with placebo (Pla) or 11 treated with 150 mg/d of eicosapentaenoic acid (EPA). The bars represent the areas under the aggregation curves measured at baseline (black) and after four weeks of treatment (white). *p < 0.02. Adapted from Dolecek [12].
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W.S. Harris / International Congress Series 1262 (2004) 380–383
composition (either arachidonic acid or EPA) was detected suggesting that EPA may be able to operate via a mechanism that does not depend on release of arachidonic acid or EPA from membrane phospholipids with subsequent conversion via cyclooxygenase to thromboxanes and other eicosanoids. This study implies that very small intakes of N3 FA may have physiological activity. This would be consistent with the reported reductions in risk for CHD death reported in several epidemiological studies in which fish intake, not supplements, were the source of N3 FA [1,12 –17]. 3.2. Effects of low intakes of x3 FA on coagulation and fibrinolytic factors Reduced thrombotic tendencies can arise not only from altered platelet function but also from changes in hemostatic factors. The effects of either low-dose, supplemental N3 FA and of background fish intake (assessed by a biomarker of intake, erythrocyte N3 FA levels) on several factors has been examined. The PRIME study (Prospective Epidemiological Study of Myocardial Infarction) [18] examined the relationship between erythrocyte FA composition and factor (F) VII coagulant activity (FVIIc) and antigen (FVIIag), von Willibrand’s factor, plasminogen activator inhibitor-1 (PAI-1), fibrinogen, D-dimer (fibrin degradation product), and tissue plasminogen activator (tPA). The latter was the only hemostatic marker related to RBC N3 FA levels in 283 men (average age 55 years with normal lipid profiles and body weights). There was an inverse correlation between these two factors such that a 10% increase in RBC N3 FA was associated with a 26% reduction in tPA ( p < 0.01). Lower tPA levels would suggest reduced systemic endothelial activation and thus lower risk for vascular disease [19]. These epidemiological findings were not supported, however, by the results of a recent intervention trial in 150 mildly hyperlipidemic but otherwise healthy men and women [20]. In this study, individuals were randomized to one of five treatment groups: placebo, EPA + DHA (800 or 1700 mg), or a-linolenic acid (4.5 or 9.5 g) for 6 months. The latter is an 18-carbon N3 FA found in certain plant oils. Compared with the changes observed in the placebo group, there was no effect on either coagulation factors (FVIIa, FVIIc, FVIIag, FXIIa, FXIIag, or fibrinogen) or fibrinolytic markers (PAI-1 or tPA). Whether the results would have been different for subjects at higher risk for CHD is not known. These studies provide too little data to make any firm statement regarding the effects of low intakes of N3 FA on either platelet function, or on coagulation or fibrinolytic factors. Nevertheless, future studies are clearly warranted in light of the impressive reduction in clinical events associated with these doses of N3 FA. 4. Conclusion At nutritionally achievable intakes of N3 FA, risk of death from cardiovascular is reduced. Because the vast majority of past studies on potential mechanisms have provided 3– 10 times more EPA + DHA than has been shown to be effective in reducing risk for clinical events, we cannot know whether the effects seen at those doses are responsible for the observed benefits associated with lower intakes. While some evidence suggests that N3 FA may have an anti-thrombotic effect at intakes of less than 1 g/day, much more research is needed at this intake level to sort out the relevant mechanisms of action.
W.S. Harris / International Congress Series 1262 (2004) 380–383
383
References [1] D.S. Siscovick, et al., Dietary intake and cell membrane levels of long-chain n 3 polyunsaturated fatty acids and the risk of primary cardiac arrest, J. Am. Med. Assoc. 274 (1995) 1363 – 1367. [2] C.M. Albert, et al., Blood levels of long-chain n 3 fatty acids and the risk of sudden death, N. Engl. J. Med. 346 (2002) 1113 – 1118. [3] T. Rissanen, et al., Fish oil-derived fatty acids, docosahexaenoic acid and docosapentaenoic acid, and the risk of acute coronary events. The Kuopio ischaemic heart disease risk factor study, Circulation 102 (2000) 2677 – 2679. [4] R.N. Lemaitre, et al., N-3 polyunsaturated fatty acids, fatal ischemic heart disease and non-fatal myocardial infarction in older adults. The cardiovascular health study, Am. J. Clin. Nutr. 76 (2002) 319 – 325. [5] M.L. Burr, et al., Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART), Lancet 2 (1989) 757 – 761. [6] C. von Schacky, et al., The effect of dietary N-3 fatty acids on coronary atherosclerosis. A randomized double-blind placebo-controlled trial, Ann. Intern. Med. 130 (1999) 554 – 562. [7] R. Marchioli, et al., 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’Infarto Miocardico (GISSI)-Prevenzione, Circulation 105 (2002) 1897 – 1903. [8] GISSI-Prevenzione Investigators, Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E in 11,324 patients with myocardial infarction: results of the GISSI-Prevenzione trial, Lancet 354 (1999) 447 – 455. [9] P.M. Kris-Etherton, et al., Fish consumption, fish oil omega-3 fatty acids and cardiovascular disease, Circulation 106 (2002) 2747 – 2757. [10] A. Leaf, et al., Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils, Circulation 107 (2003) 2646 – 2652. [11] F. Driss, et al., Inhibition of platelet aggregration and thromboxane synthesis after intake of small amounts of icosapentaenoic acid, Thromb. Res. 36 (1984) 389 – 396. [12] T.A. Dolecek, Epidemiological evidence of relationships between dietary polyunsaturated fatty acids and mortality in the multiple risk factor intervention trial, Proc. Soc. Exp. Biol. Med. 200 (1992) 177 – 182. [13] C.M. Albert, et al., Fish consumption and risk of sudden cardiac death, JAMA 279 (1998) 23 – 28. [14] F.B. Hu, et al., Fish and omega-3 fatty acid intake and risk of coronary heart disease in women, JAMA 287 (2002) 1815 – 1821. [15] D. Mozaffarian, et al., Cardiac benefits of fish consumption may depend on the type of fish meal consumed: the cardiovascular health study, Circulation 107 (2003) 1372 – 1377. [16] F.B. Hu, et al., Fish and long-chain omega-3 fatty acid intake and risk of coronary heart disease and total mortality in diabetic women, Circulation 107 (2003) 1852 – 1857. [17] A. Ascherio, et al., Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men, N. Engl. J. Med. 332 (1995) 977 – 982. [18] P.Y. Scarabin, et al., Haemostasis in relation to dietary fat as estimated by erythrocyte fatty acid composition: the prime study, Thromb. Res. 102 (2001) 285 – 293. [19] I. Juhan-Vague, et al., Fibrinolytic function and coronary risk, Curr. Cardiol. Rep. 1 (1999) 119 – 124. [20] Y.E. Finnegan, et al., Plant and marine-derived (n-3) polyunsaturated fatty acids do not affect blood coagulation and fibrinolytic factors in moderately hyperlipidemic humans, J. Nutr. 133 (2003) 2210 – 2213.
www.ics-elsevier.com
Omega-3 fatty acids, thrombosis and vascular disease William S. Harris * Lipid and Diabetes Research, Mid America Heart Institute, Saint Luke’s Hospital, 4320 Wornall Road, Suite 128, Kansas City, MO 64111, USA
Abstract. The cardioprotective effects of long-chain, marine omega-3 fatty acids (N3 FA) have been demonstrated in animal and human experimental studies, in epidemiological investigations and in randomized, controlled trials. In Western countries, effective intakes of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) appear to be in the 0.5 – 1 g/day range. The mechanism behind the N3 FA effect is not known with certainty, but appears to involve the prevention of fatal arrhythmias associated with myocardial ischemia. The extent to which this may be secondary to N3 FA-induced reductions in thrombotic tendencies is not known. Although the anti-thrombotic properties of larger quantities (>3 g/day) of N3 FA have been examined, the impact of < 1 g/day has not. Current evidence suggests that at very low intakes (150 mg/day of EPA) ex vivo platelet function may be inhibited, and individuals with higher blood levels of N3 FA have lower levels of tissue plasminogen activator. On the other hand, supplementation with 800 – 1600 mg/day of EPA + DHA had no effect on coagulation factors. Although further research is needed, these data imply that hemostatic processes may be beneficially impacted by low intakes of N3 FA, and CHD risk may thereby be reduced. D 2003 Published by Elsevier B.V. Keywords: Eicosapentaenoic acid; Docosahexaenoic acid; Fish oils; Platelet aggregation; Cardiovascular disease; Thrombosis; Hemostasis
1. Introduction The purpose of this review is to examine some of the evidence for an antithrombotic mechanism behind the cardioprotective effect of omega-3 fatty acids (N3 FA) derived from fish oils, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Evidence from several types of studies suggest that, especially in cultures with typically very low intakes of N3 FA such as the USA, increasing daily intakes by 500 –1000 mg of EPA + DHA may reduce risk of death from coronary heart disease (CHD). This evidence includes population studies [1 –4] and supplementation trials [5 –7].
* Tel.: +1-816-932-8235; fax: +1-816-932-8278. E-mail address: [email protected] (W.S. Harris). 0531-5131/ D 2003 Published by Elsevier B.V. doi:10.1016/j.ics.2003.12.097
W.S. Harris / International Congress Series 1262 (2004) 380–383
381
2. Clinical trial evidence of efficacy The best evidence for the cardioprotective effects of N3 FA comes from the GISSI Prevenzione study [7,8]. Here, supplementation with 850 mg/dayay of EPA + DHA reduced risk of death from any cause by 20% and risk of sudden death by 45% in postMI patients. 3. Potential cardioprotective mechanisms The mechanism(s) responsible for this beneficial effect are not known. Almost all the past studies that have explored ‘‘mechanistic’’ questions have used far greater intakes of N3 oils than were used in the GISSI and DART studies. Intakes of 3 to over 20 g of EPA + DHA have had effects on blood lipids (notably triglycerides), platelet function, blood pressure, blood vessel flexibility, and inflammation (reviewed in Ref. [9]). However, there is very little information on the biological effects of the low intakes (less than 1 g/day) as used in the major clinical trials and as suggested from epidemiological studies. At present, it appears that N3 FA feeding decreases risk for sudden cardiac death by reducing the susceptibility of the heart to malignant arrhythmias (see review, by Leaf et al. [10]). Whether there is a thrombotic element in the causal chain leading to this outcome is not presently known. 3.1. Effects of low intakes of x3 FA on platelet aggregation A supplementation experiment was conducted in elderly men from Lyon, France (average age 72) in which eleven were given 150 mg of EPA in capsule form and another eight were given placebo for four weeks [11]. Ex vivo platelet aggregation studies were carried out at the beginning and end of the study using several concentrations of three agonists: epinephrine, adenosine diphosphate (ADP), and collagen. Although a very small study, statistically significant reductions in platelet aggregation were found with all three agonists in the EPA group (Fig. 1). Interestingly, no change in platelet membrane FA
Fig. 1. Platelet aggregation. Effects of the indicated concentrations of three agonists on ex vivo platelet aggregation in 8 elderly subjects treated with placebo (Pla) or 11 treated with 150 mg/d of eicosapentaenoic acid (EPA). The bars represent the areas under the aggregation curves measured at baseline (black) and after four weeks of treatment (white). *p < 0.02. Adapted from Dolecek [12].
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W.S. Harris / International Congress Series 1262 (2004) 380–383
composition (either arachidonic acid or EPA) was detected suggesting that EPA may be able to operate via a mechanism that does not depend on release of arachidonic acid or EPA from membrane phospholipids with subsequent conversion via cyclooxygenase to thromboxanes and other eicosanoids. This study implies that very small intakes of N3 FA may have physiological activity. This would be consistent with the reported reductions in risk for CHD death reported in several epidemiological studies in which fish intake, not supplements, were the source of N3 FA [1,12 –17]. 3.2. Effects of low intakes of x3 FA on coagulation and fibrinolytic factors Reduced thrombotic tendencies can arise not only from altered platelet function but also from changes in hemostatic factors. The effects of either low-dose, supplemental N3 FA and of background fish intake (assessed by a biomarker of intake, erythrocyte N3 FA levels) on several factors has been examined. The PRIME study (Prospective Epidemiological Study of Myocardial Infarction) [18] examined the relationship between erythrocyte FA composition and factor (F) VII coagulant activity (FVIIc) and antigen (FVIIag), von Willibrand’s factor, plasminogen activator inhibitor-1 (PAI-1), fibrinogen, D-dimer (fibrin degradation product), and tissue plasminogen activator (tPA). The latter was the only hemostatic marker related to RBC N3 FA levels in 283 men (average age 55 years with normal lipid profiles and body weights). There was an inverse correlation between these two factors such that a 10% increase in RBC N3 FA was associated with a 26% reduction in tPA ( p < 0.01). Lower tPA levels would suggest reduced systemic endothelial activation and thus lower risk for vascular disease [19]. These epidemiological findings were not supported, however, by the results of a recent intervention trial in 150 mildly hyperlipidemic but otherwise healthy men and women [20]. In this study, individuals were randomized to one of five treatment groups: placebo, EPA + DHA (800 or 1700 mg), or a-linolenic acid (4.5 or 9.5 g) for 6 months. The latter is an 18-carbon N3 FA found in certain plant oils. Compared with the changes observed in the placebo group, there was no effect on either coagulation factors (FVIIa, FVIIc, FVIIag, FXIIa, FXIIag, or fibrinogen) or fibrinolytic markers (PAI-1 or tPA). Whether the results would have been different for subjects at higher risk for CHD is not known. These studies provide too little data to make any firm statement regarding the effects of low intakes of N3 FA on either platelet function, or on coagulation or fibrinolytic factors. Nevertheless, future studies are clearly warranted in light of the impressive reduction in clinical events associated with these doses of N3 FA. 4. Conclusion At nutritionally achievable intakes of N3 FA, risk of death from cardiovascular is reduced. Because the vast majority of past studies on potential mechanisms have provided 3– 10 times more EPA + DHA than has been shown to be effective in reducing risk for clinical events, we cannot know whether the effects seen at those doses are responsible for the observed benefits associated with lower intakes. While some evidence suggests that N3 FA may have an anti-thrombotic effect at intakes of less than 1 g/day, much more research is needed at this intake level to sort out the relevant mechanisms of action.
W.S. Harris / International Congress Series 1262 (2004) 380–383
383
References [1] D.S. Siscovick, et al., Dietary intake and cell membrane levels of long-chain n 3 polyunsaturated fatty acids and the risk of primary cardiac arrest, J. Am. Med. Assoc. 274 (1995) 1363 – 1367. [2] C.M. Albert, et al., Blood levels of long-chain n 3 fatty acids and the risk of sudden death, N. Engl. J. Med. 346 (2002) 1113 – 1118. [3] T. Rissanen, et al., Fish oil-derived fatty acids, docosahexaenoic acid and docosapentaenoic acid, and the risk of acute coronary events. The Kuopio ischaemic heart disease risk factor study, Circulation 102 (2000) 2677 – 2679. [4] R.N. Lemaitre, et al., N-3 polyunsaturated fatty acids, fatal ischemic heart disease and non-fatal myocardial infarction in older adults. The cardiovascular health study, Am. J. Clin. Nutr. 76 (2002) 319 – 325. [5] M.L. Burr, et al., Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART), Lancet 2 (1989) 757 – 761. [6] C. von Schacky, et al., The effect of dietary N-3 fatty acids on coronary atherosclerosis. A randomized double-blind placebo-controlled trial, Ann. Intern. Med. 130 (1999) 554 – 562. [7] R. Marchioli, et al., 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’Infarto Miocardico (GISSI)-Prevenzione, Circulation 105 (2002) 1897 – 1903. [8] GISSI-Prevenzione Investigators, Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E in 11,324 patients with myocardial infarction: results of the GISSI-Prevenzione trial, Lancet 354 (1999) 447 – 455. [9] P.M. Kris-Etherton, et al., Fish consumption, fish oil omega-3 fatty acids and cardiovascular disease, Circulation 106 (2002) 2747 – 2757. [10] A. Leaf, et al., Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils, Circulation 107 (2003) 2646 – 2652. [11] F. Driss, et al., Inhibition of platelet aggregration and thromboxane synthesis after intake of small amounts of icosapentaenoic acid, Thromb. Res. 36 (1984) 389 – 396. [12] T.A. Dolecek, Epidemiological evidence of relationships between dietary polyunsaturated fatty acids and mortality in the multiple risk factor intervention trial, Proc. Soc. Exp. Biol. Med. 200 (1992) 177 – 182. [13] C.M. Albert, et al., Fish consumption and risk of sudden cardiac death, JAMA 279 (1998) 23 – 28. [14] F.B. Hu, et al., Fish and omega-3 fatty acid intake and risk of coronary heart disease in women, JAMA 287 (2002) 1815 – 1821. [15] D. Mozaffarian, et al., Cardiac benefits of fish consumption may depend on the type of fish meal consumed: the cardiovascular health study, Circulation 107 (2003) 1372 – 1377. [16] F.B. Hu, et al., Fish and long-chain omega-3 fatty acid intake and risk of coronary heart disease and total mortality in diabetic women, Circulation 107 (2003) 1852 – 1857. [17] A. Ascherio, et al., Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men, N. Engl. J. Med. 332 (1995) 977 – 982. [18] P.Y. Scarabin, et al., Haemostasis in relation to dietary fat as estimated by erythrocyte fatty acid composition: the prime study, Thromb. Res. 102 (2001) 285 – 293. [19] I. Juhan-Vague, et al., Fibrinolytic function and coronary risk, Curr. Cardiol. Rep. 1 (1999) 119 – 124. [20] Y.E. Finnegan, et al., Plant and marine-derived (n-3) polyunsaturated fatty acids do not affect blood coagulation and fibrinolytic factors in moderately hyperlipidemic humans, J. Nutr. 133 (2003) 2210 – 2213.