PRECLINICAL STUDY: EDITORIAL COMMENT
Fish Oil and Prevention of Atrial Fibrillation*
Dariush Mozaffarian, MD, DrPH, FACC*
Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, and Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
* Reprint requests and correspondence: Dr. Dariush Mozaffarian, 665 Huntington Avenue, Building 2-319, Boston, Massachusetts 02115. (Email: dmozaffa{at}hsph.harvard.edu).
A substantial body of evidence, including findings from experiments, observational studies, and clinical trials, indicates that consumption of fish or fish oil reduces the incidence of fatal ventricular arrhythmias, manifested as coronary death or sudden death (1). It is of growing interest whether fish or fish oil consumption might influence atrial arrhythmias, particularly atrial fibrillation (AF), which is the most common cardiac arrhythmia and afflicts more than 2.2 million Americans (2). The incidence of AF increases dramatically with age—lifetime risk after age 40 is 1 in 4—and results in fatigue, reduced exercise tolerance, and increased risk and severity of stroke (2). Once AF has developed, anticoagulation reduces stroke risk (although with attendant bleeding risks), but other treatment options are limited. Thus, prevention of AF should be the paramount goal.
In this issue of the Journal, Sarrazin et al. (3) have evaluated the effect of fish oil in a canine model of vagally induced AF. Adult dogs were fed regular chow or chow plus fish oil (1.2 g/day, containing 480 mg/day of eicosapentaenoic acid + docosahexaenoic acid) for 14 days. Atrial fibrillation was induced by both extra stimulus (premature atrial complex [PAC]) and burst-pacing techniques. In the fish-oil-fed dogs, the risk of sustained AF was  70% to 80% lower for PAC-induced AF and 42% lower for burst-pacing-induced AF (p < 0.05 for each comparison).
Myocardial biopsies revealed a 100% rise in atrial n-3 fatty acid levels and 50% reductions in atrial connexin levels with fish oil consumption. In a substudy, control dogs with inducible AF were re-evaluated after intravenous infusion of fish oil (1.4 g); induction of sustained AF by PACs was less frequent than before the infusion.
Several strengths are evident. An experimental design generally minimizes confounding from other known or unknown risk factors. The dogs were otherwise healthy and fed reasonable doses of fish oil, providing a relatively unperturbed biologic model. Controlled vagal stimulation, electrophysiological induction of AF, and anesthesia limited the pathways influencing the risk of AF, allowing evaluation of a relatively direct (rather than indirect) effect of fish oil on the heart (e.g., it is unlikely that findings could be explained by effects of fish oil on autonomic tone, vascular resistance, or endothelial function). Myocardial biopsies provided direct confirmation of the effects of fish oil on atrial n-3 fatty acid content and connexin levels.
Limitations are also present. The fish oil treatments were neither randomized nor blinded, raising the possibility of bias due to differences in the experimental groups or in the investigators’ induction or ascertainment of AF. The intravenous substudy lacked an appropriate control group, as dogs with inducible AF in the first attempt were simply re-examined after an intravenous infusion (the less common occurrence of AF during the second attempt might have been seen in any group of dogs in whom AF was inducible in a first attempt, reflecting a type of regression toward the mean). More meticulous consideration of such issues in epidemiologic design would have enhanced the study. Also, of course, the generalizability of these findings to spontaneously occurring AF in humans is unclear.
Atrial fibrillation represents a final clinical manifestation of multiple and likely relatively distinct pathoetiologic influences, from adrenergic and vagal activity in athletes and younger adults to reduced myocardial compliance and ventricular dysfunction in older adults. This heterogeneity suggests that risk factors and effective treatments will likely vary depending on the specific characteristics and predominant pathoetiologies of AF in the population (e.g., comparing younger vs. older adults, spontaneous vs. postoperative AF, or primary prevention vs. restoration of sinus rhythm vs. prevention of recurrence). These issues must be carefully considered when weighing the generalizability and implications of different investigations, and this heterogeneity may account for the conflicting results of prior (and likely future) studies of fish or fish oil and AF.
In a prospective observational study among older adults, consumption of tuna or other broiled or baked fish was associated with a 35% lower incidence of AF (p = 0.001), after adjustment for other risk factors (4). In contrast, 2 subsequent observational studies did not find inverse associations between fish consumption and AF incidence (5,6). Conversely, in an open-label randomized trial among 160 patients undergoing cardiac surgery, perioperative fish oil treatment (2 g/day) reduced the occurrence of postoperative AF from 33.3% to 15.2% (p = 0.01) (7). The clinical heterogeneity of AF suggests that the major mechanisms for AF prevention by fish oil may vary in different populations. In the postoperative setting, mechanisms that produce relatively acute benefits may predominate, such as possible effects of fish oil on postischemic recovery (8), left ventricular filling (9), vagal activity (10), or atrial electrophysiology (e.g., due to effects on myocardial ion channels [11] or connexins [3,12]). For the AF seen with aging, mechanisms that produce longer-term benefits may be more important, such as effects of fish oil on blood pressure (13), systemic vascular resistance (14,15) and reactivity (16,17), and endothelial activation (18), which might mitigate long-term ventricular (and atrial) remodeling and augment myocardial compliance.
Sarrazin et al. (3) have added an important new piece to this puzzle. In addition to demonstrating clear anti-AF effects of fish oil in a controlled experiment, the effects of fish oil consumption on connexin levels and the relations of these differences with inducibility of AF are particularly intriguing. In vitro, n-3 fatty acids affect connexins, improving the functional distribution of cell interface connexins in cultured rat astrocytes (19) and suppressing hypoxia-reperfusion-induced phosphorylation of connexin 43 in cultured human endothelial cells (12). The present findings confirm in vivo that fish oil consumption affects connexins and suggest a novel potential mechanism for the antiarrhythmic effects of n-3 fatty acids that should stimulate further research in this field. The positive results of the observational study (4) and open-label trial (7), together with the present findings from Sarrazin et al. (3), paint a tantalizing picture that a simple, low-risk, and low-cost dietary intervention could reduce the incidence of AF, the most common complication of cardiac surgery and the most common cardiac arrhythmia in the general population.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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1. Mozaffarian D, Rimm EB. Fish intake, contaminants, and human health: evaluating the risks and the benefits JAMA 2006;296:1885-1899.[Abstract/Free Full Text]2. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee Circulation 2007;115:e69-e171.[Free Full Text] 3. Sarrazin J-F, Comeau G, Daleau P, et al. Reduced incidence of vagally induced atrial fibrillation and expression levels of connexins by n-3 polyunsaturated fatty acids in dogs J Am Coll Cardiol 2007;50:1505-1512.[Abstract/Free Full Text] 4. Mozaffarian D, Psaty BM, Rimm EB, et al. Fish intake and risk of incident atrial fibrillation Circulation 2004;110:368-373.[Abstract/Free Full Text] 5. 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.[Abstract/Free Full Text] 6. 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 fibrillationThe Rotterdam study. Am Heart J 2006;151:857-862.[CrossRef][Web of Science][Medline] 7. 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;45:1723-1728.[Abstract/Free Full Text] 8. Pepe S, McLennan PL. Cardiac membrane fatty acid composition modulates myocardial oxygen consumption and postischemic recovery of contractile function Circulation 2002;105:2303-2308.[Abstract/Free Full Text] 9. McLennan PL, Barnden LR, Bridle TM, Abeywardena MY, Charnock JS. Dietary fat modulation of left ventricular ejection fraction in the marmoset due to enhanced filling Cardiovasc Res 1992;26:871-877.[Abstract/Free Full Text] 10. O’Keefe Jr. JH, 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;97:1127-1130.[CrossRef][Web of Science][Medline] 11. Leaf A, Kang JX, Xiao YF, Billman GE. Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of prevention of arrhythmias by n-3 fish oils Circulation 2003;107:2646-2652.[Free Full Text] 12. Zhang YW, Morita I, Yao XS, Murota S. Pretreatment with eicosapentaenoic acid prevented hypoxia/reoxygenation-induced abnormality in endothelial gap junctional intercellular communication through inhibiting the tyrosine kinase activity Prostaglandins Leukot Essent Fatty Acids 1999;61:33-40.[CrossRef][Web of Science][Medline] 13. Geleijnse JM, Giltay EJ, Grobbee DE, Donders AR, Kok FJ. Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials J Hypertens 2002;20:1493-1499.[CrossRef][Web of Science][Medline] 14. Demaison L, Blet J, Sergiel JP, Gregoire S, Argaud D. Effect of dietary polyunsaturated fatty acids on contractile function of hearts isolated from sedentary and trained rats Reprod Nutr Dev 2000;40:113-125.[CrossRef][Web of Science][Medline] 15. Mozaffarian D, Gottdiener JS, Siscovick DS. Intake of tuna or other broiled or baked fish versus fried fish and cardiac structure, function, and hemodynamics Am J Cardiol 2006;97:216-222.[CrossRef][Web of Science][Medline] 16. Chin JP, Gust AP, Nestel PJ, Dart AM. Marine oils dose-dependently inhibit vasoconstriction of forearm resistance vessels in humans Hypertension 1993;21:22-28.[Abstract/Free Full Text] 17. Kenny D, Warltier DC, Pleuss JA, Hoffmann RG, Goodfriend TL, Egan BM. Effect of omega-3 fatty acids on the vascular response to angiotensin in normotensive men Am J Cardiol 1992;70:1347-1352.[CrossRef][Web of Science][Medline] 18. De Caterina R, Liao JK, Libby P. Fatty acid modulation of endothelial activation Am J Clin Nutr 2000;71:213S-223S.[Abstract/Free Full Text] 19. Champeil-Potokar G, Chaumontet C, Guesnet P, Lavialle M, Denis I. Docosahexaenoic acid (22:6n-3) enrichment of membrane phospholipids increases gap junction coupling capacity in cultured astrocytes Eur J Neurosci 2006;24:3084-3090.[CrossRef][Web of Science][Medline]
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