Fish Oil for the Treatment of Cardiovascular Disease

Cardiology in Review. 18(5):258-263, SEP 2010

Arrhythmia and Sudden Death

Fish oil has been shown to have a direct electrophysiological effect on the myocardium. Initial experience with animal ischemia models demonstrated that the ventricular fibrillation threshold was increased in both animals fed or infused with omega-3 FA.23,24 This progressed to a demonstration, on a cellular and ion channel level, that omega-3 FA reduce both sodium currents and L-type calcium currents.2529 It is hypothesized that during ischemia, a reduction in the sodium ion current protects hyperexcitable tissue, and a reduction in the calcium ion current reduces arrhythmogenic depolarizing currents.30

Heart rate variability, a possible surrogate outcome for the risk of sudden death, was assessed in a randomized trial of myocardial infarction (MI) survivors with an ejection fraction of 40%. In the 49 patients that were randomized to either fish oil or olive oil, Holter monitor recordings showed an increase in heart rate variability in the fish oil group.31 In a larger cohort assessed in the Japan EPA Lipid Intervention Study (JELIS),32 however, no difference in heart rate variability could be attributed to fish oil.

Although there are no randomized data on fish oil consumption and protection from sudden death, observational studies have linked omega-3 FA with the prevention of sudden death. In a population-based, case-control study of sudden cardiac death victims, the mean red blood cell membrane omega-3 FA level of the lowest quartile, when compared with the mean level of the third quartile, was associated with a relative risk reduction of 70%.33 A similar finding was appreciated in a nested, prospective, case-control study of the Physician Health Study cohort of 22,000 healthy males. In the 119 patients that succumbed to sudden death, baseline omega-3 FA blood levels were significantly lower than in matched controls.34 Finally, in an analysis of data from the Nurses Health Study, a cohort study of 84,688 women, an inverse association was shown between fish consumption and CAD-related death. The investigators concluded that the reduction in CAD deaths was likely due to a reduction in sudden deaths, as there was no difference in the rate of MI when comparing high and low fish consumption.35

The randomized trials assessing the efficacy of fish oil supplementation on secondary prevention of CAD lend further evidence to the findings that fish oil may protect from sudden cardiac death.36 The Diet and Reinfarction Trial (DART),37 one of the first randomized trials of fish oil in CAD, has been interpreted as potential support for fish oil’s role in sudden death reduction because the primary outcome of all-cause mortality occurred within 2 months of the trial’s onset.38 After such a short time span, it was believed that atherosclerosis would not be altered and therefore another mechanism was reducing mortality. This was further supported by the fact that nonfatal MIs were not reduced. Although the actual modes of death other than CAD-related deaths were not documented, it has been postulated to be secondary to a reduction in sudden death.39 The Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-Prevenzione40 (GISSI-Prevenzione) trial, a larger randomized trial of fish oil in CAD, has also been interpreted as evidence for fish oil’s protection against sudden death. Sudden death, however, was not a primary end point. Rather, the reduction in fatal events was driven by a reduction in cardiovascular death, which included coronary death, cardiac death, and sudden death.

Three randomized trials assessing more than 600 patients with known malignant ventricular arrhythmia were carried out under the protection of implanted cardioverter defibrillator (ICD) therapy.4143 In all 3 of the trials, 75% of the patients had ischemic heart disease, survived ventricular tachycardia or ventricular fibrillation and were randomized to 1 to 3 g/d of fish oil. In the first trial of its kind, 402 patients with ICDs were randomized to either a fish oil or an olive oil supplement.41 Although statistical significance was not reached, after approximately 1 year the primary end-point of time to first ICD cardioversion for ventricular tachycardia or fibrillation or death from any cause was longer in the fish oil group. This finding was not replicated in a trial of 200 patients who were randomized to either fish oil or a placebo and followed for a median of approximately 2 years.42 In fact, time to first ICD cardioversion was not changed and the incidence of recurrent ventricular tachycardia and fibrillation was more common in the group assigned to fish oil. In the largest trial, 546 patients were randomized to supplemental fish oil or a placebo and were followed for a mean period of 1 year.43 The primary outcome of the rate of ICD cardioversion or all-cause mortality was not reduced. It was concluded in a recent meta-analysis of these trials that fish oil did not have a protective effect.44

The effect of fish oil on incident atrial fibrillation has not been studied in large randomized trials, and observational population-based trials show mixed results. The Danish Diet, Cancer and Health Study, and the Rotterdam Study followed 47,000 and 5100 middle-aged adults, respectively.45,46 Neither study found that the consumption of fish oil affected the incidence of atrial fibrillation. Similar findings were seen in the Women’s Health Initiative where there was no association between fish and omega-3 FA intake regarding incident atrial fibrillation.47 However, in a 12-year prospective, observational study of 4815 adults over the age of 65, daily fish consumption was associated with a 31% risk reduction in incident atrial fibrillation.48

Coronary Artery Disease

The DART study, published in 1989, was the first randomized trial to show the efficacy of fish oil on CAD.37 In the trial, 2033 post-MI patients were randomized to receive 3 types of diets: a diet that was either high in cereal fiber, polyunsaturated fat, or fish oil. The fish oil group consumed 200 to 400 g/wk of fatty fish (2 portions of fish per week) or 0.5 g/d of Maxepa fish oil supplement. At 2 years, the primary end point of all-cause mortality was reduced by 29% in the fish oil group, whereas no improvement was seen in the other dietary advice groups.

The Lyon Diet Heart Study, performed shortly after the DART study, was a prospective trial of 607 survivors of MI who were randomized to either a Mediterranean diet or a regular Western diet.49 At a mean follow-up of 27 months, the primary end point of death from cardiovascular causes and nonfatal deaths had a 73% relative risk reduction—a positive effect that continued at follow up assessment at a mean of 46 months.50 FA analysis of plasma lipids showed that in the patients randomized to a Mediterranean diet, there was a higher concentration of alpha-linolenic acid as well as EPA. Fish, however, was consumed in similar amounts by both the Western and Mediterranean diet groups. The higher blood level of EPA in the Mediterranean diet arm was attributed to its synthesis from alpha-linolenic acid, which was 60-times higher than the plasma concentration of EPA. In addition, the risk reduction that occurred in this trial could not be attributed to one particular diet intervention because as the consumption of fruits and vegetables increased, the consumption of monounsaturated fat increased, while saturated fat and cholesterol were decreased.

The GISSI-Prevenzione trial40 showed similar findings. In this open-label trial, 11,324 post-MI patients were followed for 3.5 years after randomization to either 1 g/d of omega-3 FA, vitamin E, both, or none. In the 2836 patients assigned to only omega-3 FA, the primary end point of death, nonfatal MI or stroke, was reduced by 10%. This decreased risk occurred despite a minimal triglyceride-lowering effect because of the relatively low dose of omega-3 FA. Of note, the GISSI-Prevenzione trial was done prior to the pervasive use of lipid-lowering agents. Only about 40% of patients were on any form of lipid-lowering therapy.

Heart Failure

The GISSI-Heart Failure trial was the first blinded, randomized trial to assess the efficacy of fish oil supplements in patients with heart failure.51 The trial enrolled 7046 subjects with heart failure; 60% with New York Heart Association class II symptoms and 40% with a history of MI. The majority of patients were on a standard heart failure regimen, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, and spironolactone, but only 22% were on a statin. At an average of 3.9 years, the coprimary end points of death and death or hospital admission for cardiovascular reasons were reduced by approximately 9% with fish oil supplementation. Sudden cardiac death, a secondary end-point, showed a statistically nonsignificant relative risk reduction of 7% with fish oil. There was also a reduction in 2 other arrhythmia-related secondary end-points: first hospitalization for ventricular arrhythmia and presumed arrhythmic death.

31. Christensen JH, Gustenhoff P, Korup E, et al. Effect of fish oil on heart rate variability in survivors of myocardial infarction: a double blind randomized controlled trial. BMJ. 1996;312:677–678.[PMC free article] [PubMed]

32. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid (EPA) on major coronary events in hypercholesterolemic patients (JELIS): a randomized open-label blinded endpoint analysis. Lancet. 2007;369:1090–1098. [PubMed]

33. 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.[PubMed]

34. 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. [PubMed]

35. Hu F, Bronner L, Willet WC, et al. Fish and omega-3 fatty acid intake and risk of coronary heart disease in women. JAMA. 2002;287:1815–1821. [PubMed]

36. Majmudar MD, Tompkins C, Bachmann JM, et al. Effects of lipid-altering therapies on ventricular arrhythmias and sudden cardiac death. Cardiol Rev. 2009;17:60–69. [PubMed]

37. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fiber intakes on death and myocardial reinfarction: Diet and Reinfarction Trial (DART) Lancet. 1989;334:757–761. [PubMed]

38. Burr M. Secondary prevention of CHD in UK men: the Diet and Reinfarction Trial and its sequel. Proc Nutr Soc. 2007;66:9–15. [PubMed]

39. Burr M. Reflections on the Diet and Reinfarction Trial (DART) Eur Heart J. 2001;3(suppl D):D75–D78.

40. GISSI-Prevenzione Investigators. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet. 1999;354:447–455. [PubMed]

41. Raitt MH, Connor 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;293:2884–2891. [PubMed]

42. Leaf A, Albert CM, Josephson M, et al. Prevention of fatal arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake. Circulation. 2005;112:2762–2768. [PubMed]

43. Brouwer IA, Zock PL, Camm AJ, et al. Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators: the Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) randomized trial. JAMA. 2006;295:2613–2619. [PubMed]

44. 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 Heart J. 2009;30:820–826.[PMC free article] [PubMed]

45. Frost L, Vestergaard P. n-3 fatty acids consumed from fish and risk of atrial fibrillation or flutter: the Danish Diet, Cancer, and Health Study. Am J Clin Nutr. 2005;81:50–54. [PubMed]

46. Brouwer IA, Heeringa J, Geleijnse JM, et al. Intake of very long chain n-3 fatty acids from fish and incidence of atrial fibrillation: the Rotterdam Study. Am Heart J. 2006;151:857–862. [PubMed]

47. Berry JD, Prineas RJ, van Horn L, et al. Dietary fish intake and incident atrial fibrillation (from the Women’s Health Initiative) Am J Cardiol. 2010;105:844–848. [PMC free article] [PubMed]

48. Mozaffarian D, Psaty B, Rimm EB, et al. Fish intake and risk of incident atrial fibrillation. Circulation. 2004;110:368–373. [PMC free article] [PubMed]

49. De Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet. 1994;343:1454–1459. [PubMed]

50. De Lorgeril M, Salen P, Martin JL, et al. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation. 1999;99:779–785. [PubMed]

51. Tavazzi L, Maggioni AP, Marchioli R, et al. GISSI-HF Investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomized, double-blind, placebo-controlled trial. Lancet. 2008;372:1223–1230. [PubMed]