REVIEW URRENT C OPINION
Update on cardiometabolic health effects of v-3 fatty acids Daan Kromhout and Janette de Goede
Purpose of review The fish fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may promote cardiometabolic health. This review summarizes the results of recent meta-analyses of prospective studies on cardiovascular diseases, diabetes type 2 and markers of atherosclerosis and thrombosis. Recent findings The results of recently published meta-analyses of prospective cohort studies showed that eating fish once a week was associated with a 16% lower risk of fatal coronary heart disease (CHD) and a 14% lower risk of stroke incidence, but was not related to heart failure. Fish consumption may be associated with a higher risk of diabetes in Western countries and a lower risk in Asian countries. Recent meta-analyses of randomized controlled trials showed that EPA–DHA supplementation reduced the risk of fatal CHD and sudden death by 10% of which the latter was not significant. Extra EPA–DHA did not reduce the risk of heart failure, stroke and cardiac arrhythmias. v-3 fatty acid (FA) supplementation did reduce markers of ventricular fibrillation, inflammation and endothelial dysfunction and platelet aggregation. Summary There is strong evidence for a protective effect of v-3 FA on fatal CHD and for some markers of atherosclerosis and thrombosis. Consistent results were not obtained for other vascular diseases and diabetes. v-3 FA reduced markers of ventricular fibrillation but did not reduce the risk of atrial fibrillation. Keywords cardiovascular diseases, cohort studies, meta-analysis, v-3 fatty acids, randomized controlled trials
INTRODUCTION More than 30 years ago, a comparison between the Inuit and the Danes showed that the incidence of acute myocardial infarction and diabetes was about 10 times lower in the Inuit than in the Danes [1]. The traditional diet of the Inuit was characterized by a very high intake of seafood of approximately 400 g/day compared with 60 g/day in the Danes. This corresponded to 10.5 g/day of v-3 fatty acids (FA) in the Inuit and 0.8 g/day in the Danes [2,3]. These results suggest that a high intake of the v-3 FA may protect against acute myocardial infarction and diabetes. After these cross-cultural research studies on v-3 FAs cardiovascular diseases (CVD) and diabetes became very popular. This update summarizes the most important recent research findings on v-3 FA and cardiometabolic health from meta-analyses of prospective cohort studies and randomized trials. The v-3 FAs in the diet are the fish fatty acids eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA), and the plant food-derived alphalinolenic acid (ALA). There is much more evidence
summarized in meta-analyses from prospective cohort studies and randomized trials about the effects of EPA–DHA on (markers of) cardiometabolic diseases than for ALA. We focus in the review on the effects of EPA–DHA on CVD and diabetes, and on markers of the underlying atherothrombotic process. We selected five major cardiometabolic diseases: fatal coronary heart disease (CHD), sudden cardiac death, heart failure, stroke and diabetes. Apart from the effects of EPA–DHA on these endpoints, we also review the effects of some biochemical and functional markers of atherosclerosis and thrombosis.
Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands Correspondence to Daan Kromhout, Division of Human Nutrition, PO Box 8129, 6700 EV Wageningen, The Netherlands. Tel: +31 317 483054; fax: +31 317 483342; e-mail: [email protected] Curr Opin Lipidol 2014, 25:85–90 DOI:10.1097/MOL.0000000000000041
0957-9672 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-lipidology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Nutrition and metabolism
current state-of-the-art drug treatment and the resulting low absolute risk of CVD [10].
KEY POINTS v-3 FA supplementation reduces the risk of fatal CHD by 10%. v-3 FA supplementation does not reduce the risk of cardiac arrhythmias. v-3 FA supplementation reduces markers of ventricular fibrillation, inflammation, endothelial dysfunction and platelet aggregation.
FATAL CORONARY HEART DISEASE Fish consumption and the intake of EPA and DHA are strongly correlated because fish consumption is the major source of EPA and DHA in the diet. The most recent meta-analysis on fish consumption and CHD included 17 cohort studies with more than 315 000 participants. Compared to persons with the lowest level of fish consumption, a fish consumption of once a week was associated with a 16% (relative risk, RR ¼ 0.84; 95%; CI: 0.75–0.95) lower risk of fatal CHD [4 ]. Similar RRs were obtained for those who ate 2–4 servings or more than five servings of fish per week. For the Western countries, the strongest associations were observed in the USA and the Netherlands. This was possibly because of the low level of fish consumption in these countries and to the relatively large number of persons who did not eat fish. Therefore, in these countries, the strongest contrast was obtained between persons who consumed fish once a week compared with nonfish eaters. An earlier meta-analysis including mainly prospective cohort studies and some randomized trials showed that eating fish once or twice a week, equal to approximately 250 mg/day EPA–DHA, was associated with a 36% lower risk of fatal CHD [5]. Three meta-analyses were recently published of randomized trials in which the effect was evaluated of EPA–DHA supplementation on fatal CHD [6–8] in patients with a history of CVD. The number of trials in each meta-analysis was 13 or 14 and there was a large overlap in the trials included in each meta-analysis. The number of patients was approximately 50 000 and about 75% was men. The additional daily dose of EPA–DHA ranged from 0.3 to 10 g/day. The reduction in relative risk of fatal CHD was approximately 10% and varied from 0.89 (95%; CI: 0.83–0.96) to 0.91 (95%; CI: 0.85–0.98). This is only half the risk (RR ¼ 0.80 95%; CI: 0.69–0.92) observed in a meta-analysis of 11 trials published before 2008 [9]. The smaller effect of EPA–DHA on fatal CHD observed in the recent meta-analyses may be the consequence of the &&
86
www.co-lipidology.com
SUDDEN CARDIAC DEATH Sudden cardiac death is defined as death within 1 h after the onset of symptoms in combination with sudden death with a history of myocardial infarction or fatal cardiac arrest. Sudden cardiac death is commonly preceded by ventricular arrhythmias. Basic research showed that enrichment of the myocardial membranes with the v-3 FAs ALA, EPA and DHA reduced the vulnerability to severe arrhythmias [11,12]. These results were supported by those of classic case–control studies showing strong inverse associations of the EPA–DHA content in the diet and in blood with the risk of cardiac arrest and sudden cardiac death [13,14]. The strongest effect in trials was observed in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico (GISSI)-Prevenzione trial in which an additional amount of 0.9 g EPA–DHA per day reduced sudden death by 45% (RR ¼ 0.55 95%; CI: 0.40–0.76) [15]. A meta-analysis based on five trials and more than 11 000 cardiac patients showed a 7% (RR ¼ 0.93 95%; CI: 0.66–1.30) lower risk of sudden death when EPA–DHA supplements of 0.9–2.6 g/day were given [16 ]. In another meta-analysis including seven trials and about 40 000 patients a 13% (RR ¼ 0.87 95%; CI: 0.75–1.01) lower risk was observed [8]. These reductions were not statistically significant but suggest an approximately 10% reduction in the risk of sudden death. This could be the consequence of the low power in the most recent trials because of the small number of sudden death cases. However, a subgroup analysis of the Alpha Omega Trial showed that in 1014 postmyocardial infarction patients who also had diabetes, an extra amount of 0.4 g/day EPA–DHA in combination with 1.9 g/day ALA reduced the composite endpoint of sudden death, cardiac arrest and placement of implanted cardio-defibrillators (ICD) by 84% (RR ¼ 0.16 95%; CI: 0.04–0.69) [17]. These results suggest that more powerful trials including high-risk patients are needed to establish the effect of v-3 FA on sudden cardiac death. &&
HEART FAILURE Three meta-analyses based on five prospective cohort studies with 145 000–170 000 participants were published on the association between fish consumption and heart failure [18–20]. Total fish consumption was not associated with heart failure (RR ¼ 1.00 95%; CI: 0.81–1.24) [18]. There was a Volume 25 Number 1 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Effects of v-3 fatty acids Kromhout and de Goede
suggestion for heterogeneity in the results because of the way the fish was prepared. However, only two cohort studies provided information on fish preparation. They suggest that nonfried fish was inversely and fried fish was positively associated with heart failure. More information is needed before we can draw a conclusion on the effect of preparation of fish on the incidence of heart failure. Secondary prevention trials with heart failure as primary endpoint have not been carried out but two meta-analyses provided information on heart failure as secondary endpoint. The meta-analyses with either three or six trials showed that an additional amount of EPA–DHA did not affect heart failure (RR ¼ 0.99 95%; CI: 0.93–1.06) and RR ¼ 0.92 95%; CI: 0.73–1.17) [8,21]. Results from larger trials are needed to get definitive information on the effect of EPA–DHA supplementation on heart failure.
STROKE Three meta-analyses were published on fish consumption and the incidence of stroke in prospective cohort studies. A meta-analysis by Xun et al. [22] including 16 studies and more than 402 000 participants showed that eating fish once a week was associated with a 14% (RR ¼ 0.86 95%; CI: 0.80– 0.93) lower risk of stroke. Fish consumption up to less than five times per week was associated with similar RRs. These results were in accord with those of a meta-analysis of eight cohort studies published in 2004 [23]. The other recent two meta-analyses provided different information. Chowdhury et al. reported that an increase of two portions of fish per week was associated with a 4% (RR ¼ 0.96 95%; CI: 0.93–0.99) lower risk of stroke and Larsson et al. that an increase in three portions fish per week was related to a 6% (RR ¼ 0.94 95%; CI: 0.89–0.99) lower risk of stroke [24 ,25]. These results suggest that the contrast between eating fish once a week compared with nonfish was associated with the lowest relative risk. Stroke incidence was commonly registered in secondary prevention trials but was never a primary endpoint. In the meta-analyses of Chowdhury et al. [24 ] containing 12 trials with more than 60 000 patients, half the trials had less than 15 stroke cases and none showed a significant effect of EPA–DHA supplementation. In three meta-analyses of primary and secondary prevention trials extra EPA–DHA increased the risk of stroke nonsignificantly by 3–5% [8,21,24 ]. In three meta-analyses of secondary prevention trials with CVD patients, EPA–DHA increased the risk of stroke by 13% (RR ¼ 1.13 95%; CI: 0.77–1.66) to 17% (RR ¼ 1.17 95%; CI: &&
&&
&&
&&
&&
0.99–1.38) [8,16 ,24 ]. Although in cardiovascular patients the increased risk of stroke of approximately 15% was not statistically significant this warrants further study because of the substantially increased risk.
TYPE 2 DIABETES Four meta-analyses of prospective cohort studies were published on fish consumption and type 2 diabetes [26 ,27–29]. The number of cohorts varied between 11 and 13 and the total number of participants in these studies was more than 400 000. There were approximately 20 000 incident cases of diabetes. In these meta-analyses, fish consumption was not associated with diabetes but there was significant heterogeneity among populations. The studies from Europe and the USA observed positive and those from Asia inverse associations between fish consumption and the incidence of diabetes. In Western countries, the relative risks ranged from a 3% (RR ¼ 1.03 95% 0.96–1.11) to 38% (RR ¼ 1.38 95%; CI: 1.13–1.70) higher risk and in Asian countries from a 21% (RR ¼ 0.79 95%; CI: 0.66– 0.96) to a 2% (RR ¼ 0.98 95%; CI: 0.97- 1.00) lower risk. Randomized controlled trials on the effect of EPA–DHA supplementation on diabetes incidence have not been carried out. &
CARDIAC ARRHYTHMIAS Basic research showed that v-3 FA have potent effects on ion channels and calcium regulatory proteins that vary depending on the route of administration [30 ]. Circulating (acute administration) v-3 FA affect ion channels directly whereas incorporation (long-term supplementation) of these FAs in cell membranes indirectly alter cardiac electrical activity via alteration of membrane properties. Animal experimental studies demonstrated that v-3 FA reduce the risk of ventricular and atrial fibrillation. Ventricular fibrillation is a strong predictor of sudden cardiac death and atrial fibrillation of stroke. In three trials of patients with an implanted ICD, an additional amount of 0.9–2.8 g EPA–DHA per day reduced the risk of ventricular arrhythmias by 10% (RR ¼ 0.90 95%; CI: 0.67–1.22) [31]. For the subgroup of CHD patients, the relative risk was reduced by 21% (RR ¼ 0.79 95%; CI: 0.60–1.06). Also, in a substudy of the GISSI Heart Failure Trial, a nonsignificant trend toward a lower incidence of ventricular tachycardia/ fibrillation was observed in patients randomized to an additional amount of 0.9 g/day EPA–DHA [32]. These results are suggestive for a protective effect of EPA–DHA supplementation on ventricular
0957-9672 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&&
www.co-lipidology.com
87
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Nutrition and metabolism
arrhythmias but larger trials are needed before a conclusion can be drawn. Both heart rate and heart rate variability are well known predictors of ventricular arrhythmias and sudden cardiac death [30 ]. A previous metaanalysis including 30 randomized trials showed that EPA–DHA supplementation significantly decreased resting heart rate by 2.5 beats/min [33]. A recent meta-analysis of 15 randomized controlled trials showed that short-term EPA–DHA supplementation significantly increased the low-frequency domain of heart rate variability, as indicated by an increased vagal tone [34 ]. This suggests that vagal tone is an important mechanism underlying the antiarrhythmic effect of v-3 FA. The results of prospective cohort studies on fish consumption, v-3 FA in blood and the incidence of atrial fibrillation were inconsistent [35]. Recently, two large trials were published one in patients with recurrent atrial fibrillation, the FORwARD (randomized trial to assess efficacy of PUFA for the maintenance of sinus rhythm in persistent atrial fibrillation) trial with 586 patients, and the other one the v-3 fatty acids for prevention of postoperative atrial fibrillation (OPERA) trial in 1516 patients with postoperative atrial fibrillation [36,37]. Both trials did not observe an effect of EPA–DHA supplementation on atrial fibrillation. The most recently published meta-analysis included also the results of the FORwARD and the OPERA trial [38 ]. In this meta-analysis, the dose of EPA–DHA varied across studies from 0.6 to 4.5 g/day. The meta-analysis included eight trials of patients with reverted persistent or paroxysmal atrial fibrillation and eight trials of patients scheduled for cardiovascular surgery. The relative risk showed no significant effect on atrial fibrillation recurrence (RR ¼ 0.95 95%; CI: 0.79–1.13) or on postoperative atrial fibrillation (RR ¼ 0.86 95%; CI: 0.71–1.04). This meta-analysis showed that evidence is lacking for supplementation of v-3 FA in secondary prevention of atrial fibrillation and for the incidence of new atrial fibrillation in patients undergoing cardiovascular surgery. &&
&&
&&
MARKERS OF ATHEROSCLEROSIS AND THROMBOSIS Inflammation and endothelial dysfunction play a key role in the progression of atherosclerosis. Leukocyte adhesion and subsequent transendothelial migration into the arterial intima are critical pathogenic components involved in the initiation and progression of atherosclerotic lesions. Adhesion molecules such as intracellular adhesion molecule-1 and vascular adhesion molecule-1 mediate the adhesion of monocytes to endothelial cells, whereas E-selectin and P-selectin facilitate the transient 88
www.co-lipidology.com
rolling of monocytes along the endothelial. The cellular adhesion molecules (CAMs) exist not only as membrane-bound forms but also in plasma soluble forms. The plasma concentrations of these soluble adhesion molecules are potential biomarkers of CVD [39]. A growing body of evidence from animal and human studies suggests that v-3 FA have antiinflammatory properties and may suppress the soluble adhesion molecules [39]. A meta-analysis of randomized controlled trials investigated the effects of v-3 FA supplementation on the plasma concentration of the four soluble molecules. Eighteen studies were included with 1840 participants. The dose of the v-3 FA ranged from 0.3 to 6.6 g/day and the interventions lasted 6 weeks to 36 months. The v-3 FA supplementation did not reduce plasma concentrations of soluble Vascular Cell Adhesion Molecule (sVCAM), sP-selectin and sE-selectin. v-3 FA reduced soluble InterCellular Adhesion Molecule (sICAM) significantly in both healthy and dyslipidemic patients. The results for sICAM suggest that v-3 FA supplementation could be relevant in preventing both the development and the progression of atherosclerosis. Recently, a meta-analysis was published on the effect of v-3 FA supplementation on endothelial function [40 ]. Sixteen studies were eligible with a total of 901 participants. Five studies included healthy participants and 11 studies comprised patients with dyslipidemia, type 2 diabetes and CVD. The dose of v-3 FA ranged from 0.45 to 4.7 g/day and the treatment duration varied from 2 weeks to 12 months. Endothelial function was measured by flow-mediated dilatation (FMD) and endothelial-independent vasodilatation (EIV). Daily v-3 FA supplementation increased FMD significantly by 2.3% (95%; CI: 0.89–3.72%) compared with placebo and the effect estimate was similar in healthy individuals and patients. Individuals with a higher dose of v-3 FA benefited more than those with a lower dose. No significant changes in EIV were observed after v-3 FA supplementation. Arterial stiffness, the elastic properties of the arteries, is a functional marker of atherosclerosis and is an important predictor of cardiovascular events [41]. Arterial stiffness is generally measured by arterial compliance or pulse wave velocity, which is considered the gold standard. Evidence from randomized controlled trials suggested that fish oil may reduce arterial stiffness; however, a quantitative estimate of the effect was lacking. Ten trials with a total of 550 participants met the inclusion criteria for this meta-analysis. With the exception of a trial with 64 healthy young men, the others were patients with either overweight, diabetes or &&
Volume 25 Number 1 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Effects of v-3 fatty acids Kromhout and de Goede
dyslipidemia [42]. The dose of EPA–DHA ranged from 0.6 to 3 g/day and the duration varied from 6 to 105 weeks. Four trials used pulse wave velocity and six arterial compliance as outcome. v-3 FA supplementation improved significantly both pulse wave velocity and arterial compliance. Platelets are involved in thrombus formation and platelet aggregation is critical for thrombosis. Agents that physiologically activate platelets in vivo include adenosine diphosphate (ADP), thromboxane A2, collagen, arachidonic acid, epinephrine, thrombin and serotonin. Randomized controlled trials on the effect of v-3 FA on platelet aggregation yielded equivocal results. A meta-analysis explored the quantitative effect of v-3 FA supplementation on platelet aggregation [43]. Fifteen studies were included with a total of 742 participants. Seven trials included healthy participants and eight trials patients with type 2 diabetes, dyslipidemia, CHD or end-stage renal disease. The dose of v-3 FA ranged from 0.8 to 6.8 g/day and the duration varied from 2 to 16 weeks. Nine studies with 409 participants demonstrated that daily supplementation with v-3 FA reduced significantly ADP-induced platelet aggregation and platelet aggregation units. However, there was significant heterogeneity in the results. High-risk patients but not healthy participants benefited from v-3 FA supplementation. v-3 FA did not reduce collagen-induced and arachidonic acid-induced platelet aggregation. Larger trials are needed to confirm these results.
CONCLUSION Prospective cohort studies and randomized controlled trials provide strong evidence that EPA and DHA reduce the risk of fatal CHD. EPA–DHA supplementation did also reduce heart rate and heart rate variability, markers of ventricular arrhythmias, but only suggestive evidence was obtained for a reduced risk of ventricular fibrillation and sudden death. EPA–DHA supplementation did not reduce atrial fibrillation. Fish consumption was inversely related to the incidence of stroke but not to the incidence of heart failure. EPA–DHA supplementation did not reduce heart failure and stroke. Fish consumption may be inversely associated with diabetes incidence in Asian countries and positively in Western countries. EPA and DHA may favourably influence atherosclerosis and thrombosis. EPA–DHA supplementation did reduce some markers of inflammation, endothelial dysfunction and platelet aggregation. Acknowledgements The authors gratefully acknowledge the constructive comments of Dr Peter Hollman of Wageningen University on
an earlier version of the manuscript. The work of D.K. was supported by grants from the Dutch Heart Foundation, Netherlands Prevention Foundation, Royal Netherlands Academy of Arts and Sciences and the National Institutes of Health, USA. He obtained an unrestricted grant from Unilever Research and Development for the development, production and distribution of margarines in the Alpha Omega Trial. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Kromann N, Green A. Epidemiological studies in the Upernavik district, Greenland. Incidence of some chronic diseases 1950-1974. Acta Med Scand 1980; 208:401–406. 2. Bang HO, Dyerberg J. Plasma lipids and lipoproteins in Greenlandic west coast Eskimos. Acta Med Scand 1972; 192:2657–2661. 3. Bang HO, Dyerberg J, Sinclair HM. The composition of the Eskimo food in north western Greenland. Am J Clin Nutr 1980; 33:2567–2661. 4. Zheng J, Huang T, Yu Y, et al. Fish consumption and CHD mortality: an updated && meta-analysis of seventeen cohorts. Publ Hlth Nutr 2012; 15:725–737. This is the most recent and largest meta-analysis of prospective cohort studies on fish consumption and fatal CHD in primary prevention. Also the results are presented of stratified analyses to, for example region, dietary assessment etc. 5. Mozaffarian D, Rimm EB. Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA 2006; 296:1885–1899. 6. Delgado-Lista J, Perez-Martinez P, Lopez-Mirada J, Perez-Jimenez F. Long chain omega-3 fatty acids and cardiovascular disease: a systematic review. Br J Nutr 2012; 107 (Suppl 2):S201–S213. 7. Trikalinos TA, Lee J, Moorthy D, et al. Effects of eicosapentaenoic acid and docosahexaenoic acid on mortality across diverse settings: systematic review and meta-analysis of randomized trials and prospective cohorts. Tech Rev 17, vol. 4. (Prepared by the Tufts medical center evidence-based practice center under contract no. HHSA 290–2007-10055-1.) AHRQ publication no. 12-EHC040-EF. Rockville, MD: Agency for Healthcare Research and Quality; February 2012. 8. Rizos EC, Ntzani EE, Bika E, et al. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA 2012; 308:1024–1033. 9. Le´on H, Shibata MC, Sivakumaran S, et al. Effect of fish oil on arrhythmias and mortality: systematic review. BMJ 2008; 337:a2931. 10. Saravanan P, Davidson NC, Schmidt EB, Calder PC. Cardiovascular effects of marine omega-3 fatty acids. Lancet 2010; 376:540–550. 11. McLennan PL, Owen AJ, Slee EL, Theiss ML. Myocardial function, ischaemia and n-3 polyunsaturated fatty acids: a membrane basis. J Cardiovasc Med (Hagerstown) 2007; 8 (Suppl 1):S15–S18. 12. London B, Albert C, Anderson ME, et al. Omega-3 fatty acids and cardiac arrhythmias: prior studies and recommendations for future research: a report from the National Heart, Lung, and Blood Institute and Office of Dietary Supplements. Omega-3 fatty acids and their role in cardiac arrhythmogenesis workshop. Circulation 2007; 116:e320–e335. 13. Siscovick DS, Raghunathan TE, King I, et al. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. JAMA 1995; 274:1363–1367. 14. Albert CM, Campos H, Stampfer MJ, et al. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N Engl J Med 2002; 346:1113– 1118. 15. GISSI Investigators. 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; 354:447–455. 16. Kwak SM, Myung S-K, Lee YJ, Seo HG for the Korean Meta-analysis Study && Group. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in secondary prevention of cardiovascular disease. Arch Intern Med 2012; 172:686–694. This is the first meta-analysis that included only high-quality randomized, doubleblind, placebo-controlled trials on the efficacy of EPA and DHA supplementation in secondary prevention. Also the results are presented of subgroup analyses to duration of treatment, dosage of EPA or DHA, and so on.
0957-9672 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-lipidology.com
89
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Nutrition and metabolism 17. Kromhout D, Geleijnse JM, de Goede J, et al. n-3 fatty acids, ventricular arrhythmia-related events, and fatal myocardial infarction in postmyocardial infarction patients with diabetes. Diabetes Care 2011; 34:2515–2520. 18. Hou LN, Li F, Pei HJ, et al. Fish intake and risk of heart failure: a meta-analysis. Exp Ther Med 2012; 4:481–486. 19. Djousse L, Akinkuolie AO, Wu JH, et al. Fish consumption omega-3 fatty acids and risk of heart failure: a meta-analysis. Clin Nutr 2012; 31:846–853. 20. Li YH, Zhou CH, Pei HJ, et al. Fish consumption and incidence of heart failure: a meta-analysis of prospective cohort studies. Chin Med J (Engl) 2012; 126:942–948. 21. Kotwal S, Jun M, Sullivan D, et al. Omega-3 fatty acids and cardiovascular outcomes: systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes 2012; 5:808–818. 22. Xun P, Qin B, Song Y, et al. Fish consumption and the risk of stroke and its subtypes: accumulative evidence from a meta-analysis of prospective cohort studies. Eur J Clin Nutr 2012; 66:1199–1207. 23. He K, Song Y, Daviglus ML, et al. Fish consumption and incidence of stroke: a meta-analysis of cohort studies. Stroke 2004; 35:1538–1542. 24. Chowdhury R, Stevens S, Gorman D, et al. Association between fish con&& sumption, long chain omega-3 fatty acids, and risk of cerebrovascular disease: systematic review and meta-analysis. BMJ 2012; 345:e6698. This is a comprehensive review and meta-analysis of 21 prospective cohort studies on fish consumption and stroke and of 12 randomized trials on EPA–DHA supplementation and stroke. 25. Larsson SC, Orsini N. Fish consumption and the risk of stroke: a doseresponse meta-analysis. Stroke 2011; 42:3621–3623. 26. Wu JH, Micha R, Imamura F, et al. Omega-3 fatty acids and incident & type 2 diabetes: a systematic review and meta-analysis. Br J Nutr 2012; 107 (Suppl 2):S214–S227. This is one of the largest meta-analysis of prospective cohort studies showing a significant positive association between fish consumption and the incidence of diabetes in Western countries and an inverse association in Asian countries. 27. Wallin A, Giuseppe D, Orsini N, et al. Fish consumption, dietary long-chain n-3 fatty acids, and risk of type 2 diabetes: systematic review and meta-analysis of prospective studies. Diabetes Care 2012; 35:918–929. 28. Zheng JS, Huang T, Yang J, et al. Marine N-3 polyunsaturated fatty acids are inversely associated with risk of type 2 diabetes in Asians: a systematic review and meta-analysis. PLoS One 2012; 7:e44525. 29. Xun P, He K. Fish consumption and incidence of diabetes: meta-analysis of data from 438 000 individuals in 12 independent prospective cohort studies with an average 11-year follow-up. Diabetes Care 2012; 35:930– 938. 30. Billman GE. The effects of omega-3 polyunsaturated fatty acids on cardiac && rhythm: a critical reassessment. Pharmacol Ther 2013; 140:53–80. This is a very comprehensive review that addresses the effects of EPA–DHA on heart rate and heart rate variability, and provides a critical evaluation of the effects of EPA–DHA on atrial fibrillation and ventricular arrhythmias/sudden cardiac death.
90
www.co-lipidology.com
31. Brouwer IA, Raitt MH, Dullemeijer C, et al. Effect of fish oil on ventricular tachyarrhythmia in three studies in patients with implantable cardioverter defibrillators. Eur Hear J 2009; 30:820–826. 32. Finzi AA, Latini R, Barlera S, et al. Effects of n-3 polyunsaturated fatty acids on malignant ventricular arrhythmias in patients with chronic heart failure and implantable cardioverter-defibrillators: a substudy of the Gruppo Italiano per lo Studio della Sopravvivenza nell‘Insufficienza Cardiaca (GISSI-HF) trial. Am Heart J 2011; 161:338–343. 33. Mozaffarian D, Geelen A, Brouwer IA, et al. Effect of fish oil on heart rate in humans: meta-analysis of randomized controlled trials. Circulation 2005; 112:1945–1952. 34. Xin W, Wei W, Li X-Y. Short-term effects of fish oil supplementation on heart && rate variability in humans: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2013; 97:926–935. This meta-analysis shows that short-term EPA–DHA supplementation may favourably influence heart rate variability, an important mechanism underlying the antiarrhythmic effect of EPA–DHA. 35. Rix TA, Christensen JH, Schmidt EB. Omega-3 fatty acids and cardiac arrhythmias. Curr Opin Nutr Metab Care 2013; 16:168–173. 36. Macchia A, Grancelli H, Varini S, et al. Omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: results of the FORwARD (randomized trial to assess efficacy of PUFA for the maintenance of sinus rhythm in persistent atrial fibrillation) Trial. J Am Coll Cardiol 2013; 61:463–468. 37. Mozaffarian D, Marchioli R, Macchia A, et al. Fish oil and postoperative atrial fibrillation: the omega-3 fatty acids for prevention of postoperative atrial fibrillation (OPERA) randomized trial. JAMA 2012; 308:2001–2011. 38. Mariani J, Doval H, Nul D, et al. N-3 fatty acids to prevent atrial fibrillation: && updated systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc 2013; 2:e005033. This meta-analysis shows convincingly that omega-3 FA supplementation does not have antiarrhythmic effects on atrial fibrillation. 39. Yang Y, Lu N, Chen D, et al. Effects of n-3 PUFA supplementation on plasma soluble adhesion molecules: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2012; 95:972–980. 40. Wang Q, Liang X, Wang L, et al. Effect of omega-3 fatty acids supplementa&& tion on endothelial function: a meta-analysis of randomized controlled trials. Atherosclerosis 2012; 221:536–543. This meta-analysis of 16 randomized controlled trials showed that EPA–DHA supplementation significantly increased FMD, a marker of endothelial function. 41. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness. A systematic review and meta-analysis. J Am Coll Cardiol 2010; 55:1318–1327. 42. Pase MP, Grima NA, Sarris J. Do long-chain n-3 fatty acids reduce arterial stiffness? A meta-analysis of randomised controlled trials. Br J Nutr 2011; 106:974–980. 43. Gao L-g, Cao J, Mao Q-x, et al. Influence of omega-3 polyunsaturated fatty acid-supplementation on platelet aggregation in humans: a meta-analysis of randomized trials. Atherosclerosis 2013; 226:328–334.
Volume 25 Number 1 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Update on cardiometabolic health effects of v-3 fatty acids Daan Kromhout and Janette de Goede
Purpose of review The fish fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may promote cardiometabolic health. This review summarizes the results of recent meta-analyses of prospective studies on cardiovascular diseases, diabetes type 2 and markers of atherosclerosis and thrombosis. Recent findings The results of recently published meta-analyses of prospective cohort studies showed that eating fish once a week was associated with a 16% lower risk of fatal coronary heart disease (CHD) and a 14% lower risk of stroke incidence, but was not related to heart failure. Fish consumption may be associated with a higher risk of diabetes in Western countries and a lower risk in Asian countries. Recent meta-analyses of randomized controlled trials showed that EPA–DHA supplementation reduced the risk of fatal CHD and sudden death by 10% of which the latter was not significant. Extra EPA–DHA did not reduce the risk of heart failure, stroke and cardiac arrhythmias. v-3 fatty acid (FA) supplementation did reduce markers of ventricular fibrillation, inflammation and endothelial dysfunction and platelet aggregation. Summary There is strong evidence for a protective effect of v-3 FA on fatal CHD and for some markers of atherosclerosis and thrombosis. Consistent results were not obtained for other vascular diseases and diabetes. v-3 FA reduced markers of ventricular fibrillation but did not reduce the risk of atrial fibrillation. Keywords cardiovascular diseases, cohort studies, meta-analysis, v-3 fatty acids, randomized controlled trials
INTRODUCTION More than 30 years ago, a comparison between the Inuit and the Danes showed that the incidence of acute myocardial infarction and diabetes was about 10 times lower in the Inuit than in the Danes [1]. The traditional diet of the Inuit was characterized by a very high intake of seafood of approximately 400 g/day compared with 60 g/day in the Danes. This corresponded to 10.5 g/day of v-3 fatty acids (FA) in the Inuit and 0.8 g/day in the Danes [2,3]. These results suggest that a high intake of the v-3 FA may protect against acute myocardial infarction and diabetes. After these cross-cultural research studies on v-3 FAs cardiovascular diseases (CVD) and diabetes became very popular. This update summarizes the most important recent research findings on v-3 FA and cardiometabolic health from meta-analyses of prospective cohort studies and randomized trials. The v-3 FAs in the diet are the fish fatty acids eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA), and the plant food-derived alphalinolenic acid (ALA). There is much more evidence
summarized in meta-analyses from prospective cohort studies and randomized trials about the effects of EPA–DHA on (markers of) cardiometabolic diseases than for ALA. We focus in the review on the effects of EPA–DHA on CVD and diabetes, and on markers of the underlying atherothrombotic process. We selected five major cardiometabolic diseases: fatal coronary heart disease (CHD), sudden cardiac death, heart failure, stroke and diabetes. Apart from the effects of EPA–DHA on these endpoints, we also review the effects of some biochemical and functional markers of atherosclerosis and thrombosis.
Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands Correspondence to Daan Kromhout, Division of Human Nutrition, PO Box 8129, 6700 EV Wageningen, The Netherlands. Tel: +31 317 483054; fax: +31 317 483342; e-mail: [email protected] Curr Opin Lipidol 2014, 25:85–90 DOI:10.1097/MOL.0000000000000041
0957-9672 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-lipidology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Nutrition and metabolism
current state-of-the-art drug treatment and the resulting low absolute risk of CVD [10].
KEY POINTS v-3 FA supplementation reduces the risk of fatal CHD by 10%. v-3 FA supplementation does not reduce the risk of cardiac arrhythmias. v-3 FA supplementation reduces markers of ventricular fibrillation, inflammation, endothelial dysfunction and platelet aggregation.
FATAL CORONARY HEART DISEASE Fish consumption and the intake of EPA and DHA are strongly correlated because fish consumption is the major source of EPA and DHA in the diet. The most recent meta-analysis on fish consumption and CHD included 17 cohort studies with more than 315 000 participants. Compared to persons with the lowest level of fish consumption, a fish consumption of once a week was associated with a 16% (relative risk, RR ¼ 0.84; 95%; CI: 0.75–0.95) lower risk of fatal CHD [4 ]. Similar RRs were obtained for those who ate 2–4 servings or more than five servings of fish per week. For the Western countries, the strongest associations were observed in the USA and the Netherlands. This was possibly because of the low level of fish consumption in these countries and to the relatively large number of persons who did not eat fish. Therefore, in these countries, the strongest contrast was obtained between persons who consumed fish once a week compared with nonfish eaters. An earlier meta-analysis including mainly prospective cohort studies and some randomized trials showed that eating fish once or twice a week, equal to approximately 250 mg/day EPA–DHA, was associated with a 36% lower risk of fatal CHD [5]. Three meta-analyses were recently published of randomized trials in which the effect was evaluated of EPA–DHA supplementation on fatal CHD [6–8] in patients with a history of CVD. The number of trials in each meta-analysis was 13 or 14 and there was a large overlap in the trials included in each meta-analysis. The number of patients was approximately 50 000 and about 75% was men. The additional daily dose of EPA–DHA ranged from 0.3 to 10 g/day. The reduction in relative risk of fatal CHD was approximately 10% and varied from 0.89 (95%; CI: 0.83–0.96) to 0.91 (95%; CI: 0.85–0.98). This is only half the risk (RR ¼ 0.80 95%; CI: 0.69–0.92) observed in a meta-analysis of 11 trials published before 2008 [9]. The smaller effect of EPA–DHA on fatal CHD observed in the recent meta-analyses may be the consequence of the &&
86
www.co-lipidology.com
SUDDEN CARDIAC DEATH Sudden cardiac death is defined as death within 1 h after the onset of symptoms in combination with sudden death with a history of myocardial infarction or fatal cardiac arrest. Sudden cardiac death is commonly preceded by ventricular arrhythmias. Basic research showed that enrichment of the myocardial membranes with the v-3 FAs ALA, EPA and DHA reduced the vulnerability to severe arrhythmias [11,12]. These results were supported by those of classic case–control studies showing strong inverse associations of the EPA–DHA content in the diet and in blood with the risk of cardiac arrest and sudden cardiac death [13,14]. The strongest effect in trials was observed in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico (GISSI)-Prevenzione trial in which an additional amount of 0.9 g EPA–DHA per day reduced sudden death by 45% (RR ¼ 0.55 95%; CI: 0.40–0.76) [15]. A meta-analysis based on five trials and more than 11 000 cardiac patients showed a 7% (RR ¼ 0.93 95%; CI: 0.66–1.30) lower risk of sudden death when EPA–DHA supplements of 0.9–2.6 g/day were given [16 ]. In another meta-analysis including seven trials and about 40 000 patients a 13% (RR ¼ 0.87 95%; CI: 0.75–1.01) lower risk was observed [8]. These reductions were not statistically significant but suggest an approximately 10% reduction in the risk of sudden death. This could be the consequence of the low power in the most recent trials because of the small number of sudden death cases. However, a subgroup analysis of the Alpha Omega Trial showed that in 1014 postmyocardial infarction patients who also had diabetes, an extra amount of 0.4 g/day EPA–DHA in combination with 1.9 g/day ALA reduced the composite endpoint of sudden death, cardiac arrest and placement of implanted cardio-defibrillators (ICD) by 84% (RR ¼ 0.16 95%; CI: 0.04–0.69) [17]. These results suggest that more powerful trials including high-risk patients are needed to establish the effect of v-3 FA on sudden cardiac death. &&
HEART FAILURE Three meta-analyses based on five prospective cohort studies with 145 000–170 000 participants were published on the association between fish consumption and heart failure [18–20]. Total fish consumption was not associated with heart failure (RR ¼ 1.00 95%; CI: 0.81–1.24) [18]. There was a Volume 25 Number 1 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Effects of v-3 fatty acids Kromhout and de Goede
suggestion for heterogeneity in the results because of the way the fish was prepared. However, only two cohort studies provided information on fish preparation. They suggest that nonfried fish was inversely and fried fish was positively associated with heart failure. More information is needed before we can draw a conclusion on the effect of preparation of fish on the incidence of heart failure. Secondary prevention trials with heart failure as primary endpoint have not been carried out but two meta-analyses provided information on heart failure as secondary endpoint. The meta-analyses with either three or six trials showed that an additional amount of EPA–DHA did not affect heart failure (RR ¼ 0.99 95%; CI: 0.93–1.06) and RR ¼ 0.92 95%; CI: 0.73–1.17) [8,21]. Results from larger trials are needed to get definitive information on the effect of EPA–DHA supplementation on heart failure.
STROKE Three meta-analyses were published on fish consumption and the incidence of stroke in prospective cohort studies. A meta-analysis by Xun et al. [22] including 16 studies and more than 402 000 participants showed that eating fish once a week was associated with a 14% (RR ¼ 0.86 95%; CI: 0.80– 0.93) lower risk of stroke. Fish consumption up to less than five times per week was associated with similar RRs. These results were in accord with those of a meta-analysis of eight cohort studies published in 2004 [23]. The other recent two meta-analyses provided different information. Chowdhury et al. reported that an increase of two portions of fish per week was associated with a 4% (RR ¼ 0.96 95%; CI: 0.93–0.99) lower risk of stroke and Larsson et al. that an increase in three portions fish per week was related to a 6% (RR ¼ 0.94 95%; CI: 0.89–0.99) lower risk of stroke [24 ,25]. These results suggest that the contrast between eating fish once a week compared with nonfish was associated with the lowest relative risk. Stroke incidence was commonly registered in secondary prevention trials but was never a primary endpoint. In the meta-analyses of Chowdhury et al. [24 ] containing 12 trials with more than 60 000 patients, half the trials had less than 15 stroke cases and none showed a significant effect of EPA–DHA supplementation. In three meta-analyses of primary and secondary prevention trials extra EPA–DHA increased the risk of stroke nonsignificantly by 3–5% [8,21,24 ]. In three meta-analyses of secondary prevention trials with CVD patients, EPA–DHA increased the risk of stroke by 13% (RR ¼ 1.13 95%; CI: 0.77–1.66) to 17% (RR ¼ 1.17 95%; CI: &&
&&
&&
&&
&&
0.99–1.38) [8,16 ,24 ]. Although in cardiovascular patients the increased risk of stroke of approximately 15% was not statistically significant this warrants further study because of the substantially increased risk.
TYPE 2 DIABETES Four meta-analyses of prospective cohort studies were published on fish consumption and type 2 diabetes [26 ,27–29]. The number of cohorts varied between 11 and 13 and the total number of participants in these studies was more than 400 000. There were approximately 20 000 incident cases of diabetes. In these meta-analyses, fish consumption was not associated with diabetes but there was significant heterogeneity among populations. The studies from Europe and the USA observed positive and those from Asia inverse associations between fish consumption and the incidence of diabetes. In Western countries, the relative risks ranged from a 3% (RR ¼ 1.03 95% 0.96–1.11) to 38% (RR ¼ 1.38 95%; CI: 1.13–1.70) higher risk and in Asian countries from a 21% (RR ¼ 0.79 95%; CI: 0.66– 0.96) to a 2% (RR ¼ 0.98 95%; CI: 0.97- 1.00) lower risk. Randomized controlled trials on the effect of EPA–DHA supplementation on diabetes incidence have not been carried out. &
CARDIAC ARRHYTHMIAS Basic research showed that v-3 FA have potent effects on ion channels and calcium regulatory proteins that vary depending on the route of administration [30 ]. Circulating (acute administration) v-3 FA affect ion channels directly whereas incorporation (long-term supplementation) of these FAs in cell membranes indirectly alter cardiac electrical activity via alteration of membrane properties. Animal experimental studies demonstrated that v-3 FA reduce the risk of ventricular and atrial fibrillation. Ventricular fibrillation is a strong predictor of sudden cardiac death and atrial fibrillation of stroke. In three trials of patients with an implanted ICD, an additional amount of 0.9–2.8 g EPA–DHA per day reduced the risk of ventricular arrhythmias by 10% (RR ¼ 0.90 95%; CI: 0.67–1.22) [31]. For the subgroup of CHD patients, the relative risk was reduced by 21% (RR ¼ 0.79 95%; CI: 0.60–1.06). Also, in a substudy of the GISSI Heart Failure Trial, a nonsignificant trend toward a lower incidence of ventricular tachycardia/ fibrillation was observed in patients randomized to an additional amount of 0.9 g/day EPA–DHA [32]. These results are suggestive for a protective effect of EPA–DHA supplementation on ventricular
0957-9672 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&&
www.co-lipidology.com
87
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Nutrition and metabolism
arrhythmias but larger trials are needed before a conclusion can be drawn. Both heart rate and heart rate variability are well known predictors of ventricular arrhythmias and sudden cardiac death [30 ]. A previous metaanalysis including 30 randomized trials showed that EPA–DHA supplementation significantly decreased resting heart rate by 2.5 beats/min [33]. A recent meta-analysis of 15 randomized controlled trials showed that short-term EPA–DHA supplementation significantly increased the low-frequency domain of heart rate variability, as indicated by an increased vagal tone [34 ]. This suggests that vagal tone is an important mechanism underlying the antiarrhythmic effect of v-3 FA. The results of prospective cohort studies on fish consumption, v-3 FA in blood and the incidence of atrial fibrillation were inconsistent [35]. Recently, two large trials were published one in patients with recurrent atrial fibrillation, the FORwARD (randomized trial to assess efficacy of PUFA for the maintenance of sinus rhythm in persistent atrial fibrillation) trial with 586 patients, and the other one the v-3 fatty acids for prevention of postoperative atrial fibrillation (OPERA) trial in 1516 patients with postoperative atrial fibrillation [36,37]. Both trials did not observe an effect of EPA–DHA supplementation on atrial fibrillation. The most recently published meta-analysis included also the results of the FORwARD and the OPERA trial [38 ]. In this meta-analysis, the dose of EPA–DHA varied across studies from 0.6 to 4.5 g/day. The meta-analysis included eight trials of patients with reverted persistent or paroxysmal atrial fibrillation and eight trials of patients scheduled for cardiovascular surgery. The relative risk showed no significant effect on atrial fibrillation recurrence (RR ¼ 0.95 95%; CI: 0.79–1.13) or on postoperative atrial fibrillation (RR ¼ 0.86 95%; CI: 0.71–1.04). This meta-analysis showed that evidence is lacking for supplementation of v-3 FA in secondary prevention of atrial fibrillation and for the incidence of new atrial fibrillation in patients undergoing cardiovascular surgery. &&
&&
&&
MARKERS OF ATHEROSCLEROSIS AND THROMBOSIS Inflammation and endothelial dysfunction play a key role in the progression of atherosclerosis. Leukocyte adhesion and subsequent transendothelial migration into the arterial intima are critical pathogenic components involved in the initiation and progression of atherosclerotic lesions. Adhesion molecules such as intracellular adhesion molecule-1 and vascular adhesion molecule-1 mediate the adhesion of monocytes to endothelial cells, whereas E-selectin and P-selectin facilitate the transient 88
www.co-lipidology.com
rolling of monocytes along the endothelial. The cellular adhesion molecules (CAMs) exist not only as membrane-bound forms but also in plasma soluble forms. The plasma concentrations of these soluble adhesion molecules are potential biomarkers of CVD [39]. A growing body of evidence from animal and human studies suggests that v-3 FA have antiinflammatory properties and may suppress the soluble adhesion molecules [39]. A meta-analysis of randomized controlled trials investigated the effects of v-3 FA supplementation on the plasma concentration of the four soluble molecules. Eighteen studies were included with 1840 participants. The dose of the v-3 FA ranged from 0.3 to 6.6 g/day and the interventions lasted 6 weeks to 36 months. The v-3 FA supplementation did not reduce plasma concentrations of soluble Vascular Cell Adhesion Molecule (sVCAM), sP-selectin and sE-selectin. v-3 FA reduced soluble InterCellular Adhesion Molecule (sICAM) significantly in both healthy and dyslipidemic patients. The results for sICAM suggest that v-3 FA supplementation could be relevant in preventing both the development and the progression of atherosclerosis. Recently, a meta-analysis was published on the effect of v-3 FA supplementation on endothelial function [40 ]. Sixteen studies were eligible with a total of 901 participants. Five studies included healthy participants and 11 studies comprised patients with dyslipidemia, type 2 diabetes and CVD. The dose of v-3 FA ranged from 0.45 to 4.7 g/day and the treatment duration varied from 2 weeks to 12 months. Endothelial function was measured by flow-mediated dilatation (FMD) and endothelial-independent vasodilatation (EIV). Daily v-3 FA supplementation increased FMD significantly by 2.3% (95%; CI: 0.89–3.72%) compared with placebo and the effect estimate was similar in healthy individuals and patients. Individuals with a higher dose of v-3 FA benefited more than those with a lower dose. No significant changes in EIV were observed after v-3 FA supplementation. Arterial stiffness, the elastic properties of the arteries, is a functional marker of atherosclerosis and is an important predictor of cardiovascular events [41]. Arterial stiffness is generally measured by arterial compliance or pulse wave velocity, which is considered the gold standard. Evidence from randomized controlled trials suggested that fish oil may reduce arterial stiffness; however, a quantitative estimate of the effect was lacking. Ten trials with a total of 550 participants met the inclusion criteria for this meta-analysis. With the exception of a trial with 64 healthy young men, the others were patients with either overweight, diabetes or &&
Volume 25 Number 1 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Effects of v-3 fatty acids Kromhout and de Goede
dyslipidemia [42]. The dose of EPA–DHA ranged from 0.6 to 3 g/day and the duration varied from 6 to 105 weeks. Four trials used pulse wave velocity and six arterial compliance as outcome. v-3 FA supplementation improved significantly both pulse wave velocity and arterial compliance. Platelets are involved in thrombus formation and platelet aggregation is critical for thrombosis. Agents that physiologically activate platelets in vivo include adenosine diphosphate (ADP), thromboxane A2, collagen, arachidonic acid, epinephrine, thrombin and serotonin. Randomized controlled trials on the effect of v-3 FA on platelet aggregation yielded equivocal results. A meta-analysis explored the quantitative effect of v-3 FA supplementation on platelet aggregation [43]. Fifteen studies were included with a total of 742 participants. Seven trials included healthy participants and eight trials patients with type 2 diabetes, dyslipidemia, CHD or end-stage renal disease. The dose of v-3 FA ranged from 0.8 to 6.8 g/day and the duration varied from 2 to 16 weeks. Nine studies with 409 participants demonstrated that daily supplementation with v-3 FA reduced significantly ADP-induced platelet aggregation and platelet aggregation units. However, there was significant heterogeneity in the results. High-risk patients but not healthy participants benefited from v-3 FA supplementation. v-3 FA did not reduce collagen-induced and arachidonic acid-induced platelet aggregation. Larger trials are needed to confirm these results.
CONCLUSION Prospective cohort studies and randomized controlled trials provide strong evidence that EPA and DHA reduce the risk of fatal CHD. EPA–DHA supplementation did also reduce heart rate and heart rate variability, markers of ventricular arrhythmias, but only suggestive evidence was obtained for a reduced risk of ventricular fibrillation and sudden death. EPA–DHA supplementation did not reduce atrial fibrillation. Fish consumption was inversely related to the incidence of stroke but not to the incidence of heart failure. EPA–DHA supplementation did not reduce heart failure and stroke. Fish consumption may be inversely associated with diabetes incidence in Asian countries and positively in Western countries. EPA and DHA may favourably influence atherosclerosis and thrombosis. EPA–DHA supplementation did reduce some markers of inflammation, endothelial dysfunction and platelet aggregation. Acknowledgements The authors gratefully acknowledge the constructive comments of Dr Peter Hollman of Wageningen University on
an earlier version of the manuscript. The work of D.K. was supported by grants from the Dutch Heart Foundation, Netherlands Prevention Foundation, Royal Netherlands Academy of Arts and Sciences and the National Institutes of Health, USA. He obtained an unrestricted grant from Unilever Research and Development for the development, production and distribution of margarines in the Alpha Omega Trial. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Kromann N, Green A. Epidemiological studies in the Upernavik district, Greenland. Incidence of some chronic diseases 1950-1974. Acta Med Scand 1980; 208:401–406. 2. Bang HO, Dyerberg J. Plasma lipids and lipoproteins in Greenlandic west coast Eskimos. Acta Med Scand 1972; 192:2657–2661. 3. Bang HO, Dyerberg J, Sinclair HM. The composition of the Eskimo food in north western Greenland. Am J Clin Nutr 1980; 33:2567–2661. 4. Zheng J, Huang T, Yu Y, et al. Fish consumption and CHD mortality: an updated && meta-analysis of seventeen cohorts. Publ Hlth Nutr 2012; 15:725–737. This is the most recent and largest meta-analysis of prospective cohort studies on fish consumption and fatal CHD in primary prevention. Also the results are presented of stratified analyses to, for example region, dietary assessment etc. 5. Mozaffarian D, Rimm EB. Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA 2006; 296:1885–1899. 6. Delgado-Lista J, Perez-Martinez P, Lopez-Mirada J, Perez-Jimenez F. Long chain omega-3 fatty acids and cardiovascular disease: a systematic review. Br J Nutr 2012; 107 (Suppl 2):S201–S213. 7. Trikalinos TA, Lee J, Moorthy D, et al. Effects of eicosapentaenoic acid and docosahexaenoic acid on mortality across diverse settings: systematic review and meta-analysis of randomized trials and prospective cohorts. Tech Rev 17, vol. 4. (Prepared by the Tufts medical center evidence-based practice center under contract no. HHSA 290–2007-10055-1.) AHRQ publication no. 12-EHC040-EF. Rockville, MD: Agency for Healthcare Research and Quality; February 2012. 8. Rizos EC, Ntzani EE, Bika E, et al. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA 2012; 308:1024–1033. 9. Le´on H, Shibata MC, Sivakumaran S, et al. Effect of fish oil on arrhythmias and mortality: systematic review. BMJ 2008; 337:a2931. 10. Saravanan P, Davidson NC, Schmidt EB, Calder PC. Cardiovascular effects of marine omega-3 fatty acids. Lancet 2010; 376:540–550. 11. McLennan PL, Owen AJ, Slee EL, Theiss ML. Myocardial function, ischaemia and n-3 polyunsaturated fatty acids: a membrane basis. J Cardiovasc Med (Hagerstown) 2007; 8 (Suppl 1):S15–S18. 12. London B, Albert C, Anderson ME, et al. Omega-3 fatty acids and cardiac arrhythmias: prior studies and recommendations for future research: a report from the National Heart, Lung, and Blood Institute and Office of Dietary Supplements. Omega-3 fatty acids and their role in cardiac arrhythmogenesis workshop. Circulation 2007; 116:e320–e335. 13. Siscovick DS, Raghunathan TE, King I, et al. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. JAMA 1995; 274:1363–1367. 14. Albert CM, Campos H, Stampfer MJ, et al. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N Engl J Med 2002; 346:1113– 1118. 15. GISSI Investigators. 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; 354:447–455. 16. Kwak SM, Myung S-K, Lee YJ, Seo HG for the Korean Meta-analysis Study && Group. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in secondary prevention of cardiovascular disease. Arch Intern Med 2012; 172:686–694. This is the first meta-analysis that included only high-quality randomized, doubleblind, placebo-controlled trials on the efficacy of EPA and DHA supplementation in secondary prevention. Also the results are presented of subgroup analyses to duration of treatment, dosage of EPA or DHA, and so on.
0957-9672 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-lipidology.com
89
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Nutrition and metabolism 17. Kromhout D, Geleijnse JM, de Goede J, et al. n-3 fatty acids, ventricular arrhythmia-related events, and fatal myocardial infarction in postmyocardial infarction patients with diabetes. Diabetes Care 2011; 34:2515–2520. 18. Hou LN, Li F, Pei HJ, et al. Fish intake and risk of heart failure: a meta-analysis. Exp Ther Med 2012; 4:481–486. 19. Djousse L, Akinkuolie AO, Wu JH, et al. Fish consumption omega-3 fatty acids and risk of heart failure: a meta-analysis. Clin Nutr 2012; 31:846–853. 20. Li YH, Zhou CH, Pei HJ, et al. Fish consumption and incidence of heart failure: a meta-analysis of prospective cohort studies. Chin Med J (Engl) 2012; 126:942–948. 21. Kotwal S, Jun M, Sullivan D, et al. Omega-3 fatty acids and cardiovascular outcomes: systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes 2012; 5:808–818. 22. Xun P, Qin B, Song Y, et al. Fish consumption and the risk of stroke and its subtypes: accumulative evidence from a meta-analysis of prospective cohort studies. Eur J Clin Nutr 2012; 66:1199–1207. 23. He K, Song Y, Daviglus ML, et al. Fish consumption and incidence of stroke: a meta-analysis of cohort studies. Stroke 2004; 35:1538–1542. 24. Chowdhury R, Stevens S, Gorman D, et al. Association between fish con&& sumption, long chain omega-3 fatty acids, and risk of cerebrovascular disease: systematic review and meta-analysis. BMJ 2012; 345:e6698. This is a comprehensive review and meta-analysis of 21 prospective cohort studies on fish consumption and stroke and of 12 randomized trials on EPA–DHA supplementation and stroke. 25. Larsson SC, Orsini N. Fish consumption and the risk of stroke: a doseresponse meta-analysis. Stroke 2011; 42:3621–3623. 26. Wu JH, Micha R, Imamura F, et al. Omega-3 fatty acids and incident & type 2 diabetes: a systematic review and meta-analysis. Br J Nutr 2012; 107 (Suppl 2):S214–S227. This is one of the largest meta-analysis of prospective cohort studies showing a significant positive association between fish consumption and the incidence of diabetes in Western countries and an inverse association in Asian countries. 27. Wallin A, Giuseppe D, Orsini N, et al. Fish consumption, dietary long-chain n-3 fatty acids, and risk of type 2 diabetes: systematic review and meta-analysis of prospective studies. Diabetes Care 2012; 35:918–929. 28. Zheng JS, Huang T, Yang J, et al. Marine N-3 polyunsaturated fatty acids are inversely associated with risk of type 2 diabetes in Asians: a systematic review and meta-analysis. PLoS One 2012; 7:e44525. 29. Xun P, He K. Fish consumption and incidence of diabetes: meta-analysis of data from 438 000 individuals in 12 independent prospective cohort studies with an average 11-year follow-up. Diabetes Care 2012; 35:930– 938. 30. Billman GE. The effects of omega-3 polyunsaturated fatty acids on cardiac && rhythm: a critical reassessment. Pharmacol Ther 2013; 140:53–80. This is a very comprehensive review that addresses the effects of EPA–DHA on heart rate and heart rate variability, and provides a critical evaluation of the effects of EPA–DHA on atrial fibrillation and ventricular arrhythmias/sudden cardiac death.
90
www.co-lipidology.com
31. Brouwer IA, Raitt MH, Dullemeijer C, et al. Effect of fish oil on ventricular tachyarrhythmia in three studies in patients with implantable cardioverter defibrillators. Eur Hear J 2009; 30:820–826. 32. Finzi AA, Latini R, Barlera S, et al. Effects of n-3 polyunsaturated fatty acids on malignant ventricular arrhythmias in patients with chronic heart failure and implantable cardioverter-defibrillators: a substudy of the Gruppo Italiano per lo Studio della Sopravvivenza nell‘Insufficienza Cardiaca (GISSI-HF) trial. Am Heart J 2011; 161:338–343. 33. Mozaffarian D, Geelen A, Brouwer IA, et al. Effect of fish oil on heart rate in humans: meta-analysis of randomized controlled trials. Circulation 2005; 112:1945–1952. 34. Xin W, Wei W, Li X-Y. Short-term effects of fish oil supplementation on heart && rate variability in humans: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2013; 97:926–935. This meta-analysis shows that short-term EPA–DHA supplementation may favourably influence heart rate variability, an important mechanism underlying the antiarrhythmic effect of EPA–DHA. 35. Rix TA, Christensen JH, Schmidt EB. Omega-3 fatty acids and cardiac arrhythmias. Curr Opin Nutr Metab Care 2013; 16:168–173. 36. Macchia A, Grancelli H, Varini S, et al. Omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: results of the FORwARD (randomized trial to assess efficacy of PUFA for the maintenance of sinus rhythm in persistent atrial fibrillation) Trial. J Am Coll Cardiol 2013; 61:463–468. 37. Mozaffarian D, Marchioli R, Macchia A, et al. Fish oil and postoperative atrial fibrillation: the omega-3 fatty acids for prevention of postoperative atrial fibrillation (OPERA) randomized trial. JAMA 2012; 308:2001–2011. 38. Mariani J, Doval H, Nul D, et al. N-3 fatty acids to prevent atrial fibrillation: && updated systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc 2013; 2:e005033. This meta-analysis shows convincingly that omega-3 FA supplementation does not have antiarrhythmic effects on atrial fibrillation. 39. Yang Y, Lu N, Chen D, et al. Effects of n-3 PUFA supplementation on plasma soluble adhesion molecules: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2012; 95:972–980. 40. Wang Q, Liang X, Wang L, et al. Effect of omega-3 fatty acids supplementa&& tion on endothelial function: a meta-analysis of randomized controlled trials. Atherosclerosis 2012; 221:536–543. This meta-analysis of 16 randomized controlled trials showed that EPA–DHA supplementation significantly increased FMD, a marker of endothelial function. 41. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness. A systematic review and meta-analysis. J Am Coll Cardiol 2010; 55:1318–1327. 42. Pase MP, Grima NA, Sarris J. Do long-chain n-3 fatty acids reduce arterial stiffness? A meta-analysis of randomised controlled trials. Br J Nutr 2011; 106:974–980. 43. Gao L-g, Cao J, Mao Q-x, et al. Influence of omega-3 polyunsaturated fatty acid-supplementation on platelet aggregation in humans: a meta-analysis of randomized trials. Atherosclerosis 2013; 226:328–334.
Volume 25 Number 1 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
