The Role of Omega-3 Polyunsaturated Fatty Acids in Cardiovascular Health
Sara Jean Barrett, ND, is a naturopathic physician, board-certified by the North American Board of Naturopathic Examiners (NABNE). She runs her own practice, Alternative Solutions for Health, in Bloomington, Minnesota.
Corresponding author: Sara Jean Barrett, ND
Over the past 3 decades, the potential benefit of omega-3 polyunsaturated fatty acids (?-3 PUFAs) on cardiovascular health has been widely researched. This boom in research began with a study in Greenland that discovered low rates of cardiovascular disease (CVD) in the indigenous population eating a diet rich in ?-3 PUFAs.1 Historically, humans consumed roughly equal amounts of omega-6 polyunsaturated fatty acid (?-6 PUFA) and ?-3 PUFA.2 Due to decreased fish consumption and increased consumption of foods high in ?-6 PUFAs, the current Western diet ratio of ?-6 to ?-3 PUFAs is 20-30:1.2 ?-6 linoleic acid and ?-3 ?-linolenic acid share a common enzyme and compete for metabolic conversion into physiologically active metabolites. Excess ?-6 PUFA can reduce tissue levels of ?-3 PUFA.3
Essential Fatty Acids
Essential fatty acids (EFAs) are PUFAs that must be supplied through the diet because the body is unable to produce them. Dietary EFAs are subclassified into ?-6 and ?-3 PUFAs. Dietary sources of ?-3 PUFA include fish oils rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) together with plants rich in ?-linolenic acid. PUFAs are converted into bioactive eicosanoids (eg, leukotrienes, prostaglandins, and thromboxanes) as seen in Figure 1. Eicosanoids derived from arachidonic acid are generally proinflammatory whereas those derived from ?-3 PUFAs tend to be anti-inflammatory.4
Mechanism of Action
Individual PUFAs have a wide range of effects on biochemical and physiologic functions. Like other PUFAs, EPA and DHA are incorporated in the cell membrane and modulate cellular function. As mentioned previously, ?-3 PUFAs modulate the eicosanoid system toward vasodilation and reduction in proatherogenic cytokines and growth factors.5 In addition, ?-3 PUFAs improve endothelial function,6 decrease platelet aggregation,7,8,9 decrease thrombin formation,10 reduce serum triglycerides,11-13 and reduce blood pressure.14 O?Keefe et al found that supplementation with EPA and DHA significantly decreased heart rate (HR) at rest, improved postexercise HR recovery, and increased HR variability.15 ?-3 PUFAs may also play a role in plaque stabilization; low serum EPA is associated with incidence and vulnerability of coronary plaques.16,17
The ?-3 index measures the concentration of EPA and DHA as a percentage of total PUFAs in the membrane of red blood cells (RBCs). As opposed to measurements in serum the half-life of EPA and DHA is 4 to 6 times longer in RBCs.18 This index is also highly reflective of PUFA composition of the myocardium.19 The ?-3 index correlates with long-term PUFA intake.20 Siscovick et al found that small increases in ?-3 PUFA levels in RBCs were associated with reduction in the risk of primary cardiac arrest.21 In a case-controlled study conducted by Block et al, participants with the lowest ?-3 PUFA content in RBCs had a three-fold increase in the odds of developing acute coronary syndrome (ACS) compared to those with the highest ?-3 PUFA content.22 This biomarker remained significant even after controlling for other ACS risk factors and appears to provide an independent assessment of ACS risk.22 Harris et al concluded that the ?-3 indices associated with the lowest risk for death from coronary heart disease (CHD) are around 8%, whereas the indices associated with the highest risk are <4%.23 The goal of 8% might be further refined with continued research. Since the values are largely determined by diet, the ?-3 index could prove to be a modifiable risk factor for CVD.
Primary and Secondary Prevention
The first evidence of cardiovascular benefit from dietary ?-3 PUFAs came from studies of Greenland?s indigenous population in the 1970s.1 Since then numerous studies have been conducted, attempting to elucidate the effects of ?-3 PUFA on CVD.
The Nurse?s Health Study followed 84 688 female nurses and found that women with higher consumption of fish and ?-3 PUFAs have a lower risk of CVD (P < .001), particularly deaths from CVD.24
The Japan Public Health Center?s (JPHC) study followed 41575 participants who were free of a prior diagnosis of CVD for 11 years. The risk of CVD was approximately 40% lower among persons eating fish 8 ?/week than among those eating fish once weekly.25 This finding implies that high intake of fish can further reduce risk of initial CVD events.
The first randomized, controlled trial of dietary fish intake in secondary cardiovascular prevention was the Diet and Reinfarction Trial (DART), which followed 2033 men diagnosed with a myocardial infarction (MI). The intervention group consumed an average of 200 to 400 g of fatty fish weekly, estimated to provide 500 to 800 mg of ?-3 PUFA daily. The study found a reduction of 29% after 2 years in mortality from all causes and a 16% reduction in risk of ischemic events. This trial suggested that ingestion of modest amounts of fatty fish reduced mortality in men after an MI.26
The largest study to date of ?-3 PUFAs and cardiovascular disease was the Gruppo Italiano per lo Studio della Sopravvivenza nell?Infarto Miocardio (GISSI)-Prevenzione. This randomized, large-scale, double-blind, placebo-controlled trial compared post-MI participants taking 300 mg of vitamin E, 850 mg of EPA/DHA in roughly equal amounts, or both vitamin E and ?-3 PUFA, with control participants receiving usual care only for 3.5 years. The results showed that compared to control participants, those taking ?-3 PUFAs showed relative risk reductions of 20% for all deaths, 30% for cardiovascular deaths, and 45% for sudden deaths.27
Based on the overwhelming evidence indicating an inverse relationship between ?-3 PUFA intake and CVD risk, clinicians should use ?-3 PUFAs in all individuals who have had a first MI.28,29
The reduction in sudden cardiac death (SCD) seen in primary and secondary prevention studies is likely due to the antiarrhythmic effect of ?-3 PUFAs.30-33 At high levels of ?-3 PUFA, an ?-3 index of over 11%, the incidence of SCD is very low.34 Calo et al conducted the first trial investigating the efficacy of perioperative treatments with ?-3 PUFAs in preventing atrial fibrillation (AF) in individuals undergoing coronary artery bypass graft (CABG) surgery. The results of this randomized, controlled study showed a significant reduction in the incidence of postoperative AF events (P = .013) and a reduction in length of hospital stay. Postoperative ?-3 PUFA therapy included approximately 850 mg of EPA and DHA in an average EPA/DHA ratio of 1:2.35 Heidt et al reported similar results with a perioperative infusion of ?-3 PUFA, reducing the incidence of AF after CABG (P < .05) and leading to a shorter stay in the ICU and hospital.36 A meta-analysis conducted by He et al found that ?-3 PUFA therapy was associated with a 34% decreased odds of AF after open heart surgery when compared with controls.37
A benefit from ?-3 PUFA may even exist for cardiac transplant recipients. Supplementation with 3.4 g/day of EPA+DHA reduced heart rate and prolonged QRS interval duration in heart transplant patients.38 Treatment with ?-3 PUFA may also reduce long-term, continuous blood pressure after heart transplantation (3.4 g/d).39 Andreassen et al found that postoperative, daily administration of 4 g of ?-3 PUFA to heart transplant participants was effective as a hypertension prophylaxis, and the researchers hypothesized that preservation of microvascular endothelial function could be a contributing factor.40
Factors Influencing Outcomes
Studies have not shown consistency in the effect of ?-3 PUFA on CVD risk. Ethnicity, statin use, and mercury contamination are factors that can account for some of this variation. According to Patel et al, some of the effects of ?-3 PUFA are limited to cultures with a high intake of ?-3 PUFA. Ethnicity also moderates the uptake of ?-3 PUFAs from the diet, suggesting dietary intake and dosing requirements for supplements may vary according to ethnicity.41
Contrary to previous research,1,26,27,42 recent meta-analyses examining efficacy of ?-3 PUFA supplements do not confirm a protective effect on CVD.43,44 An explanation for this discrepancy could be the fact that concomitant statin use is much more prevalent in populations of recent studies, unlike populations in previous studies for whom the supplements showed a protective effect. Statin drugs may inhibit ?-3 PUFA via several mechanisms, including increasing arachidonic acid and altering mitochondrial function.45 Eussen et al found that statin treatment modified the effects of ?-3 PUFAs on the incidence of major cardiovascular events.46
Finally, another explanation for conflicting results in studies on ?-3 PUFA and CVD is the mercury content of fish. Mercury promotes lipid peroxidation, and exposure increases the risk of cardiovascular disease.47,48 Mercury exposure may also reduce the protective effects of fish on cardiovascular health.49,50 The lack of association between increased fish intake and a reduction in CVD that some studies have seen may be due to mercury consumption.47
In 1997, the Food and Drug Administration (FDA) ruled that intake of up to 3 g/day of marine ?-3 PUFA is generally recognized as safe (GRAS).51 The National Center for Complementary and Alternative Medicine (NCCAM) warns that fish liver oils are not the same as fish oil and contain vitamins A and D, both of which can be potentially toxic in large doses.52
Some species of fish can contain harmful environmental contaminants. Methyl mercury, for example, is bio-concentrated in the aquatic food chain. High mercury contents of dietary ?-3 PUFA derived from fish may diminish the cardioprotective effects of fish consumption.49,50,53 Local advisories may be useful for guidance on the safety of fish caught from lakes, rivers, and coastal areas. Organochlorines may also contaminate marine products and marine-oil concentrates. A study of 45 fish oils available from retail outlets around the world found that they varied widely in their concentrations of organochlorine contaminants.54 To reduce the levels of organochlorine contaminants in fish oil, deodorization via distillation is recommended.55
Hemostasis is often a concern regarding ?-3 PUFA supplementation. The prolongation of bleeding time with ?-3 PUFA supplementation is usually modest, and no reports of serious bleeding have appeared.56,57 Some evidence suggests that ?-3 PUFAs do not reduce the risk of ventricular tachycardia/fibrillation for individuals with implantable, cardioverter defibrillators and may actually be proarrhythmic in this population.58
The majority of epidemiologic and controlled interventional studies have demonstrated that marine- and plant-derived ?-3 PUFAs have beneficial effects on CVD. The ?-3 index may prove to be a valuable tool for assessing an individual?s need for increased ?-3 PUFA through diet or supplementation.
A vast majority of patients are on statin drugs, and while these drugs may attenuate the benefits from ?-3 PUFA, it seems that coadministration of a statin drug with ?-3 PUFA may be indicated in cases where the drug is necessary.59,60 Coadministration of ?-3 PUFA with a statin improves lipid profiles in individuals with hypertriglyceridemia to a greater extent than statin treatment alone.61,62
Research in ?-3 PUFA is continually expanding. In the future, two large-scale trials might contribute to a further understanding of the role of ?-3 PUFA in primary prevention: (1) A Study of Cardiovascular Events in Diabetes (ASCEND) and (2) the VITamin D and OmegA-3 TriaL (VITAL). ASCEND will directly compare aspirin and ?-3 PUFA in primary prevention of CVD in diabetic individuals who were without CVD at the time of inclusion, with follow-up scheduled until 2017. VITAL has recruited 20 000 participants without a history of CVD or cancer, studying daily supplementation with vitamin D and/or 1 g of ?-3 PUFA to assess the preventive effects of the supplements.
Table 1 summarizes the official recommendations on ?-3 PUFAs for CVD prevention by major official organizations, such as the American Heart Association (AHA), American College of Cardiology (ACC), World Health Organization (WHO), Joint British Societies, and the European Society of Cardiology (ESC).
- Bang HO, Dyerberg J. Lipid metabolism and ischemic heart disease in Greenland Eskimos. In: Draper HH, ed. Advanced Nutrition Research. New York, NY: Plenum Press; 1980:1-32.
- Simopoulos AP. Evolutionary aspects of omega-3 fatty acids in the food supply. Prostaglandins Leukot Essent Fatty Acids. 1999;60(5-6):421-429.
- Lands WE. Biochemistry and physiology of n-3 fatty acids. FASEB J. 1992;6(8):2530-2536.
- Simopoulous AP. Essential fatty acids in health and chronic disease. Am J Clin Nutr. 1999;70(3)(suppl):560S-569S.
- De Caterina R, Cybulsky MI, Clinton SK, Gimbrone MA Jr, Libby P. The omega-3 fatty acid docosahexaenoate reduces cytokine-induced expression of proatherogenic and proinflammatory proteins in human endothelial cells. Arterioscler Thromb.1994;14(11):1829-1836.
- Moertl D, Hammer A, Steiner S, Hutuleac R, Vonbank K, Berger R. Dose-dependent effects of omega-3-polyunsaturated fatty acids on systolic left ventricular function, endothelial function, and markers of inflammation in chronic heart failure of nonischemic origin: a double-blind, placebo-controlled, 3-arm study. Am Heart J. 2011;161(5):915.e1-9.
- von Schacky C, Fischer S, Weber PC. Long-term effects of dietary marine omega-3 fatty acids upon plasma and cellular lipids, platelet function, and eicosanoid formation in humans. J Clin Invest. 1985;76(4):1626-1631.
- von Schacky C. Prophylaxis of atherosclerosis with marine omega-3 fatty acids: a comprehensive strategy. Ann Intern Med. 1987;107(6):890-899.
- Phang M, Lincz L, Seldon M, Garg ML. Acute supplementation with eicosapentaenoic acid reduces platelet microparticle activity in healthy subjects. J Nutr Biochem. 2012;23(9):1128-1133.
- Gajos G, Zalewski J, Rostoff P, Nessler J, Piwowarska W, Unda A. Reduced thrombin formation and altered fibrin clot properties induced by polyunsaturated omega-3 fatty acids on top of dual antiplatelet therapy in patients undergoing percutaneous coronary intervention (OMEGA-PCI clot). Arterioscler Thromb Vasc Biol. 2001;31(7):1696-1702
- Wei MY, Jacobson TA. Effects of eiocosapentaenoic acid versus docosahexaenoic acid on serum lipids: a systematic review and meta analysis. Curr Atheroscler Rep. 2011;13(6):474-483.
- Bernstein AM, Ding EL, Willett WC, Rimm EB. A meta-analysis shows that docosahexaenoic acid from algal oil reduces serum triglycerides and increases HDL-cholesterol and LDL-cholesterol in persons without coronary heart disease. J Nutr. 2012;142(1):99-104.
- Dayspring TD. Understanding hypertriglyceridemia in women: clinical impact and management with prescription omega-3-acid ethyl esters. Int J Womens Health. March 2011;3:87-97.
- Morgan DR, Dixon LJ, Hanratty CG, et al. Effects of dietary omega-3 fatty acid supplementation on endothelium-dependent vasodilation in patients with chronic heart failure. Am J Cardiol. 2006;97(4):547-551.
- O?Keefe JH Jr, Abuissa H, Sastre A, Steinhaus DM, Harris WS. Effects of omega-3 fatty acids on resting heart rate, heart rate recovery after exercise, and heart rate variability in men with healed myocardial infarctions and depressed ejection fractions. Am J Cardiol. 2006;97(8):1127-1130.
- Amano T, Matsubara T, Uetani T, et al. Impact of omega-3 polyunsaturated fatty acids on coronary plaque instability: an integrated backscatter intravascular ultrasound study. Atherosclerosis. 2011;218(1):110-116.
- Kashiyama T, Ueda Y, Nemoto T, et al. Relationship between coronary plaque vulnerability and serum n-3/n-6 polyunsaturated fatty acid ratio. Circ J. 2011;75(10):2432-2438.
- Cao J, Schwichtenberg KA, Hanson NQ, Tsai MY. Incorporation and clearance of omega-3 fatty acids in erythrocyte membranes and plasma phospholipids. Clin Chem. 2006;52(12):2265-2272.
- Harris WS, Sands SA, Windsor SL, et al. Omega-3 fatty acids in cardiac biopsies from heart transplantation patients: correlation with erythrocytes and response to supplementation. Circulation. 2004;110(12):1645-1649.
- Sun Q, Ma J, Campos H, Hankinson SE, Hu FB. Comparison between plasma and erythrocyte fatty acid content as biomarkers of fatty acid intake in US women. J Clin Nutr. 2007;86(1):74-81.
- 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(17):1363-1367.
- Block RC, Harris WS, Reid KJ, Sands SA, Spertus JA. EPA and DHA in blood cell membranes from acute coronary syndrome patients and controls. Atherosclerosis. 2008;197(2):821-828.
- Harris WS, von Schacky C. The omega-3 index: a new risk factor for death from coronary heart disease? Prev Med. 2004;39(1):212-220.
- Hu FB, Bronner L, Willett WC, et al. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women. JAMA. 2002;287(14):1815-1821.
- Iso H, Kobayashi M, Ishihara J, et al; JPHC Study Group. Intake of fish and n3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center-based (JPHC) study cohort 1. Circulation. 2006;113(2):195-202.
- Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet and Reinfarction Trial (DART). Lancet. 1989;2(8666):757-761.
- No authors listed. 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(9177):447-455.
- De Caterina R, Madonna R, Zucchi R, La Rovere MT. Antiarrhythmic effects of omega-3 fatty acids: from epidemiology to bedside. Am Heart J. 2003;146(3):420-430.
- Wang C, Harris WS, Chung M, et al. n-3 fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr. 2006;84(1):5-17.
- Mozaffarian D, Prineas RJ, Stein PK, Siscovick DS. Dietary fish and n-3 fatty acid intake and cardiac electrocardiographic parameters in humans. J Am Coll Cardiol. 2006;48(3):478-484.
- Marchioli R, Barzi F, Bomba E, et al; GISSI-Prevenzione Investigators. 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 Miocardio (GISSI)-Prevenzione. Circulation. 2002;105(16):1897-1903.
- Reiffel JA, McDonald A. Antiarrhythmic effects of omega-3 fatty acids. Am J Cardiol. 2006;98(4A):50i-60i.
- Leaf A, Albert CM, Josephson M, et al; Fatty Acid Antiarrhythmia Trial Investigators. Prevention of fatal arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake. Circulation. 2005;112(18):2762-2768.
- von Schacky C. Omega-3 fatty acids: antiarrhythmic, proarrhythmic or both? Curr Opin Clin Nutr Metab Care. 2008;11(2):94-99.
- Calo L, Bianconi L, Colivicchi F, et al. N-3 fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial. J Am Coll Cardiol. 2005;45(10):1723-1728.
- Heidt MC, Vician M, Stracke SK, et al. Beneficial effects of intravenously administered n-3 fatty acids for the prevention of atrial fibrillation after coronary bypass surgery: a prospective randomized study. Thorac Cardiovasc Surg. 2009;57(5):276-280.
- He Z, Yang L, Tian J, Yang K, Wu J, Yao Y. Efficacy and safety of omega-3 fatty acids for the prevention of atrial fibrillation: a meta-analysis. Can J Cardiol. 2013;29(2):196-203.
- Harris WS, Gonzales M, Laney N, Sastre A, Borkon AM. Effects of omega-3 fatty acids on heart rate in cardiac transplant recipients. Am J Cardiol. 2006;98(10):1393-1395.
- Holm T, Andreassen AK, Aukrust P, et al. Omega-3 fatty acids improve blood pressure control and preserve renal function in hypertensive heart transplant patients. Eur Heart J. 2002;22(5):428-43
- Andreassen A, Hartmann A, Offstad J, Geiran O, Kvernebo K, Simonsen S. Hypertension prophylaxis with omega-3 fatty acids in heart transplant recipients. J Am Coll Cardiol. 1997;29(6):1324-1331.
- Patel JV, Tracey I, Hughes EA, Lip GY. Omega-3 polyunsaturated acids and cardiovascular disease: notable ethnic differences or unfulfilled promise? J Thromb Haemost. 2010;8(10):2095-2104.
- Kromhout D, Bosschieter EB, de Lezenne Coulander C. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med. 1985;312(19):1205-1209.
- Kwak SM, Myung SK, Lee YJ, Seo HG; Korean Meta-analysis Study Group. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med. 2012;172(9):686-694.
- Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA. 2012;308(10):1024-1033.
- de Lorgeril M, Salen P, Defaye P, Rabaeus M. Recent findings on the health effects of omega-3 fatty acids and statins, and their interactions: do statins inhibit omega-3? BMC Med. January 2013;11:5.
- Eussen SR, Geleijnse JM, Giltay EJ, Rompelberg CJ, Klungel OH, Kromhout D. Effects of n-3 fatty acids on major cardiovascular events in statin users and non-users with a history of myocardial infarction. Eur Heart J. 2012;33(13):1582-1588.
- Salonen JT, Seppanen K, Nyyssonen K, et al. Intake of mercury from fish, lipid peroxidation, and the risk of myocardial infarction and coronary, cardiovascular, and any death in eastern Finnish men. Circulation. 1995;91(3):645-655.
- Houston MC. Role of mercury toxicity in hypertension, cardiovascular disease, and stroke. J Clin Hypertens (Greenwich). 2011;13(8):621-627.
- Virtanen JK, Voutilainen S, Rissanen TH, et al. Mercury, fish oils, and risk of acute coronary events and cardiovascular disease, coronary heart disease, and all-cause mortality in men in eastern Finland. Arterioscler Thromb Vasc Biol. 2005;25(1):228-233.
- Virtanen JK, Laukkanen JA, Mursu J, Voutilainen S, Tuomainen TP. Serum long-chain n-3 polyunsaturated fatty acids, mercury, and risk of sudden cardiac death in men: a prospective population-based study. PLoS One. 2012;7(7):e41046.
- Food and Drug Administration; US Department of Health and Human Services. Substances affirmed as generally recognized as safe: menhaden oil. CFR Part 184. http://www.gpo.gov/fdsys/pkg/FR-1997-06-05/pdf/97-14683.pdf. Published June 5, 1997. Accessed April 11, 2013.
- US Department of Health and Human Services. Omega-3 supplements: an introduction. National Center for Complementary and Alternative Medicine Web site. http://nccam.nih.gov/health/omega3/introduction.htm. Published July 2009. Updated November 2012. Accessed April 11, 2013
- Guallar E, Sanz-Gallardo MI, van?t Veer P, et al; Heavy Metals and Myocardial Infarction Study Group. Mercury, fish oils, and the risk of myocardial infarction. N Engl J Med. 2002;347(22):1747-1754.
- Jacobs MN, Santillo D, Johnston PA, Wyatt CL, French MC. Organochlorine residues in fish oil dietary supplements: comparison with industrial grade oils. Chemosphere. 1998;37(9-12):1709-1721.
- Hilbert G, Lillemark L, Balchen S, Hojskov CS. Reduction of organochlorine contaminants from fish oil during refining. Chemosphere. 1998;37(7):1241-1252.
- Knapp HR. Dietary fatty acids in human thrombosis and hemostasis. Am J Clin Nutr. 1997;65(5)(suppl):1687S-1698S.
- Bays HE. Safety considerations with omega-3 fatty acid therapy. Am J Cardiol. 2007;99(6A):35C-43C.
- Raitt MH, Conner WE, Morris C, et al. Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial. JAMA. 2005;293(23):2884-2891.
- Durrington PN, Bhatnagar D, Mackness MI, et al. An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertryglyceridaemia. Heart. 2001;85(5):544-548.
- Nambi V, Ballantyne CM. Combination therapy with statins and omega-3 fatty acids. Am J Cardiol. 2006;98(4A):34i-38i.
- Nordoy A, Bonaa KH, Nilsen H, Berge RK, Hansen JB, Ingebretsen OC. Effects of simvastatin and omega-3 fatty acids in plasma lipoproteins and lipid peroxidation in patients with combined hyperlipidemia. J Intern Med. 1998;243(2):163-170.
- Lee JH, O?Keefe JH, Lavie CJ, Marchioli R, Harris WS. Omega-3 fatty acids for cardioprotection. Mayo Clin Proc. 2008;83(3):324-332.
- Kris-Etherton PM, Harris WS, Appel LJ; American Heart Association Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002;106(21):2747-2757.
- Guidelines for secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update. American College of Cardiology Web site. http://cardiocompass.cardiosource.org/cc2/openCont1?smID=929. Accessed April 2, 2013.
- World Health Organization. Diet, Nutrition and the Prevention of Chronic Diseases: Report of a Joint WHO/FAO Expert Consultation. Geneva, Switzerland: World Health Organization; 2003.
- British Cardiac Society; British Hypertension Society; Diabetes UK; HEART UK; Primary Care Cardiovascular Society; The Stroke Association. JBS 2: Joint British Societies? guidelines on prevention of cardiovascular disease in clinical practice. Heart. December 2005;91(suppl 5):v1-v52.
- Reiner Z, Catapano AL, De Backer G, et al; The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J. 2011;32(14):1769?1818.