The Role of Fish Oil in Arrhythmia Prevention

July 29, 2015

Cardiology Class Act 7 min read

fishoilBy Steven Bolger

Peer Reviewed

Omega-3 fatty acids were first identified as a potential agent to prevent and treat cardiovascular disease through several epidemiologic studies of the Greenlandic Inuit in the 1970s suggesting that high consumption of fish oil was associated with a decreased risk of cardiovascular disease [1,2]. Fish oil contains two omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), that have been shown to be beneficial in treating hypertriglyceridemia and in the secondary prevention of cardiac events [3-5].

The GISSI-Prevenzione trial, published in 1999, was one of the first multicenter, randomized controlled trials to explore the effect of supplementation with omega-3 fatty acids on patients with recent myocardial infarctions [5]. The trial included 11,324 patients with recent myocardial infarctions. They were randomized to receive daily supplementation with either a capsule containing EPA and DHA in a 1-to-2 ratio or a placebo capsule for 3.5 years, with death from any cause, non-fatal myocardial infarction, and stroke as the composite primary endpoint. The trial demonstrated that supplementation with omega-3 fatty acids resulted in a significant reduction in the primary endpoint, with a relative risk reduction of 10% compared to placebo. The results of this trial suggested that a reduction in sudden cardiac death could be responsible for the decrease in mortality, sparking investigation of the potential anti-arrhythmic properties of omega-3 fatty acids.

Omega-3 fatty acids have been shown to increase the threshold of depolarization of cardiac muscle required for action potential generation in animal models, resulting in a decrease in arrhythmias. A 1994 study using a canine model showed that infusion of a fish oil emulsion resulted in a significantly decreased incidence of ventricular fibrillation compared to a control infusion in response to exercise-induced ischemia [6]. Further studies in rat cardiomyocytes revealed that the mechanism responsible for the reduction in arrhythmias is inhibition of voltage-dependent sodium and L-type calcium channels [7-9]. By shifting the cell membrane potential to a more negative value, omega-3 fatty acids increase the threshold required to generate an action potential, preventing the initiation of arrhythmias.

Several randomized controlled trials have failed to demonstrate that omega-3 fatty acid supplementation results in a reduction in ventricular arrhythmias in patients with implantable cardioverter-defibrillators. A 2005 trial of 200 patients with implantable cardioverter-defibrillators and recent episodes of sustained ventricular tachycardia or ventricular fibrillation showed no reduction in the risk of arrhythmias with fish oil supplementation [10]. The results of this trial furthermore suggested a possible pro-arrhythmic effect of omega-3 fatty acids. A 2006 trial similarly failed to show a reduction in ventricular tachycardia, ventricular fibrillation, or all-cause mortality in 546 patients with implantable cardioverter-defibrillators who received supplementation with omega-3 fatty acids [11].

A 2005 randomized controlled trial of 402 patients with implantable cardioverter-defibrillators, however, demonstrated a trend towards benefit in patients receiving supplementation with omega-3 fatty acids [12]. The primary endpoint selected for the trial was time to first episode of ventricular tachycardia, ventricular fibrillation, or death from any cause. Though the results did not show a significant reduction in the primary endpoint, patients who received omega-3 fatty acid supplementation showed a trend towards a prolonged time to the first episode of these arrhythmias or death from any cause, with a risk reduction of 28% and p-value of 0.057. Furthermore, the risk reduction was significant when probable episodes of ventricular tachycardia and ventricular fibrillation were included in the analysis, with a risk reduction of 31%.

With conflicting results from several trials, a systematic review was performed in 2008 of 12 randomized controlled trials to synthesize clinical data on the effects of fish oil on mortality and arrhythmia prevention [13]. The primary outcomes were defined as the arrhythmic end points of appropriate implantable cardioverter-defibrillator intervention and sudden cardiac death. The results of the meta-analysis showed that fish oil supplementation did not have a significant effect on arrhythmias and all-cause mortality. The review did demonstrate a significant reduction in deaths from cardiac causes consistent with previous studies, including the GISSI-Prevenzione trial.

Fish Oil For Atrial Fibrillation Prevention

In addition to trials investigating ventricular arrhythmias in patients with implantable cardioverter-defibrillators, there have been several observational studies exploring the effect of fish oil on the incidence of atrial fibrillation, which have yielded conflicting results. The Danish Diet, Cancer, and Health Study, a prospective cohort study, found that consumption of omega-3 fatty acids from fish was not associated with a reduction in the risk of atrial fibrillation or flutter [14]. The cohort for this study included 47,949 individuals living in Denmark with a mean age of 56 years. The Rotterdam Study found that consumption of EPA and DHA was similarly not associated with a reduction in the risk of developing atrial fibrillation [15]. The cohort for this study included 5184 patients with a mean age of 67.4 years who lived in the Netherlands. A 12-year prospective, observational study by Mozaffarian and colleagues of 4815 patients over the age of 65, however, found that consumption of fish was associated with a 31% reduction in the risk of atrial fibrillation [16].

The mixed results between these studies may reflect differences in the baseline characteristics of the cohorts of the three studies. The Mozaffarian study placed an age restriction on the cohort of the study, resulting in a mean age of 72.8 years, compared to 56 years for the Danish Diet, Cancer, and Health Study and 67.4 years for the Rotterdam Study. The risk of atrial fibrillation increases with age; thus, the reduction in risk of atrial fibrillation in response to omega-3 fatty acid supplementation may only be appreciable in elderly populations at highest risk [17-18]. The assessment of dietary intake of omega-3 fatty acids also differed between the studies depending on the method of information collection. The Rotterdam study, for example, obtained information via a questionnaire and follow-up interview with a dietician, while the Mozaffarian study employed only a questionnaire.

The 2012 OPERA trial was the first randomized controlled trial to assess the effect of omega-3 fatty acid supplementation on atrial fibrillation [19]. The OPERA trial randomized 1516 patients with a mean age of 64 years who were scheduled for cardiac surgery to receive either a daily fish oil capsule or placebo for 3-5 days before the surgery and for 10 postoperative days or until discharge, whichever came first. The results of the trial showed that perioperative supplementation with fish oil did not reduce the risk of postoperative atrial fibrillation compared to the placebo.

Overall, the results of studies exploring the potential anti-arrhythmic effects of omega-3 fatty acids in reducing the risk of atrial fibrillation have been conflicting. A 2010 meta-analysis of 10 randomized controlled trials examining the role of omega-3 fatty acids in preventing atrial fibrillation found no evidence of significant effects of omega-3 fatty acids on atrial fibrillation prevention [20].

In conclusion, although omega-3 fatty acid supplementation has been shown to provide several potential cardiovascular benefits, trials have failed to consistently show that omega-3 fatty acids have significant anti-arrhythmic effects. The reasons for the inconsistent results are unknown, and perhaps may be related to patient selection, type of fish oil preparation, fish oil dose, or other factors. Meta-analyses of randomized controlled trials have not shown a reduction in either ventricular arrhythmias or atrial fibrillation. Additional studies are necessary to further characterize the role of fish oil in preventing arrhythmias.

Steven Bolger is a 3rd year medical student at NYU School of Medicine

Peer reviewed by Robert Donnino, MD, Cardiology Editor, Clinical Correlations,  NYU Langone Medical Center

 Image courtesy of Wikimedia Commons

References

  1. Bang HO, Dyerberg J, Hjøorne N. The composition of food consumed by Greenland Eskimos. Acta Med Scand. 1976;200(1-2):69-73. http://onlinelibrary.wiley.com/doi/10.1111/j.0954-6820.1976.tb08198.x/pdf

 

  1. Dyerberg J, Bang HO, Stoffersen E, Moncada S, Vane JR. Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis? Lancet. 1978;2(8081):117-119. http://www.sciencedirect.com/science/article/pii/S0140673678915052#

 

  1. Balk EM, Lichtenstein AH, Chung M, Kupelnick B, Chew P, Lau J. Effects of omega-3 fatty acids on serum markers of cardiovascular disease risk: a systematic review. Atherosclerosis. 2006;189(1):19-30. http://www.sciencedirect.com/science/article/pii/S0021915006000694

 

  1. Harris WS. n-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr. 1997;65(5 Suppl):1645S-1654S. http://ajcn.nutrition.org/content/65/5/1645S.long

 

  1. 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(9177):447-455. http://www.sciencedirect.com/science/article/pii/S0140673699070725

 

  1. Billman GE, Hallaq H, Leaf A. Prevention of ischemia-induced ventricular fibrillation by omega 3 fatty acids. Proc Natl Acad Sci U S A. 1994;91(10):4427-4430. http://www.pnas.org/content/91/10/4427.long

 

  1. Kang JX, Xiao YF, Leaf A. Free, long-chain, polyunsaturated fatty acids reduce membrane electrical excitability in neonatal rat cardiac myocytes. Proc Natl Acad Sci U S A. 1995;92(9):3997-4001. http://www.pnas.org/content/92/9/3997.long

 

  1. Xiao YF, Kang JX, Morgan JP, Leaf A. Blocking effects of polyunsaturated fatty acids on Na+ channels of neonatal rat ventricular myocytes. Proc Natl Acad Sci U S A. 1995;92(24):11000-11004. http://www.pnas.org/content/92/24/11000.long

 

  1. Xiao YF, Gomez AM, Morgan JP, Lederer WJ, Leaf A. Suppression of voltage-gated L-type Ca2+ currents by polyunsaturated fatty acids in adult and neonatal rat ventricular myocytes. Proc Natl Acad Sci U S A. 1997;94(8):4182-4187. http://www.pnas.org/content/94/8/4182.long

 

  1. 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(23):2884-2891. http://jama.jamanetwork.com/article.aspx?articleid=201082

 

  1. Brouwer IA, Zock PL, Camm AJ, et al; SOFA Study Group. 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(22):2613-2619. http://jama.jamanetwork.com/article.aspx?articleid=202999

 

  1. 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(18):2762-2768. http://circ.ahajournals.org/content/112/18/2762.long

 

  1. León H, Shibata MC, Sivakumaran S, Dorgan M, Chatterley T, Tsuyuki RT. Effect of fish oil on arrhythmias and mortality: systematic review. BMJ. 2008;337:a2931. http://www.bmj.com/content/337/bmj.a2931.long

 

  1. 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(1):50-54. http://ajcn.nutrition.org/content/81/1/50.long

 

  1. Brouwer IA, Heeringa J, Geleijnse JM, Zock PL, Witteman JC. Intake of very long-chain n-3 fatty acids from fish and incidence of atrial fibrillation. The Rotterdam Study. Am Heart J. 2006;151(4):857-862. http://www.sciencedirect.com/science/article/pii/S000287030500757X

 

  1. Mozaffarian D, Psaty BM, Rimm EB, et al. Fish intake and risk of incident atrial fibrillation. Circulation. 2004;110(4):368-373. http://circ.ahajournals.org/content/110/4/368.long

 

  1. Psaty BM, Manolio TA, Kuller LH, et al. Incidence of and risk factors for atrial fibrillation in older adults. Circulation. 1997;96(7):2455-2461. http://circ.ahajournals.org/content/96/7/2455.long

 

  1. Furberg CD, Psaty BM, Manolio TA, Gardin JM, Smith VE, Rautaharju PM. Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study). Am J Cardiol. 1994;74(3):236-241. http://www.sciencedirect.com/science/article/pii/0002914994903638

 

  1. Mozaffarian D, Marchioli R, Macchia A, et al; OPERA Investigators. Fish oil and postoperative atrial fibrillation: the Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) randomized trial. JAMA. 2012;308(19):2001-2011. http://jama.jamanetwork.com/article.aspx?articleid=1389226

 

  1. Liu T, Korantzopoulos P, Shehata M, Li G, Wang X, Kaul S. Prevention of atrial fibrillation with omega-3 fatty acids: a meta-analysis of randomised clinical trials. Heart. 2011;97(13):1034-1040. http://heart.bmj.com/content/97/13/1034.l