Effect of fish oil on arrhythmias and mortality: systematic reviewBMJ 2008; 337 doi: https://doi.org/10.1136/bmj.a2931 (Published 24 December 2008) Cite this as: BMJ 2008;337:a2931
All rapid responses
We read with interest the systematic review by Hernando León et al,
however, we wish to highlight an obvious omission which relates to the
potential for fish oils to be pro-arrhythmic in some sub groups of cardiac
patients. In the past, many anti-arrhythmic drug trials have shown
disappointing outcomes mainly due to their pro-arrhythmic side effects (1-
4). Animal experiments and cellular electrophysiological studies have
shown that fish oils have a diverse action on several cardiac ion
channels(5) not dissimilar to some broad spectrum anti-arrhythmic drugs
currently used in clinical practice. Some of these effects such as sodium
channel blockade and shortening of action potential duration could enhance
the risk of arrhythmias due to re-entrant mechanism.
In keeping with this, Raitt MH et al(6) showed that fish oils could
increase the incidence of ventricular tachycardia in a subset of patients
with implantable cardiovertor defibrillator whose qualifying arrhythmia
was VT. Similarly, fish oil supplementation increased risk of cardiac
death in patients with angina pectoris(7,8). These findings have been
substantiated by similar results in animal experiments where fish oils
increased risk of arrhythmias in a setting of acute regional ischaemia(9).
Such contradicting effects may be related to different mechanisms of the
prevailing arrhythmia in these population subgroups. Arrhythmias following
myocardial infarction and heart failure are induced by triggered
activity(10,11), while those in myocardial ischemia are caused by
Hence, it is conceivable that fish oils may have a combination of
anti & pro arrhythmic properties in different sub-sets of cardiac
patients and the beneficial effects in some patient sub-groups may be
negated by the pro-arrythmic effects on others in clinical trials using
unselected cohorts of cardiac patients.
This necessitates further research into the pro-arrhythmic properties
of fish oils which would help better patient selection and appropriate use
of fish oils (like any other anti-arrhythmic drug therapy) to obtain
optimal clinical benefits.
1.Boutitie F., Boissel J.P., Connolly S.J., Camm A.J., Cairns J.A.,
Julian D.G., et al. Amiodarone interaction with β-blockers: analysis
of the merged EMIAT (European Myocardial Infarct Amiodarone Trial) and
CAMIAT (Canadian Amiodarone Myocardial Infarction Trial) databases.
Circulation (1999) 99:2268–2275.
2.Danish Investigations of Arrhythmia and Mortality on Dofetilide
Study Group. Torp-Pederson C., Moller M., Bloch-Thomsen P.E., Kober L.,
Sandoe E., et al. Dofetilide in patients with congestive heart failure and
left ventricular dysfunction. Danish Investigations of Arrhythmia and
Mortality on Dofetilide Study Group. N Engl J Med (1999) 341:857–865.
3.The Cardiac Arrhythmia Suppression Trial (CAST) Investigators.
Preliminary report: effect of encainide and flecainide on mortality in a
randomized trial of arrhythmia suppression after myocardial infarction. N
Engl J Med (1989) 321:406–412.
4.Waldo A.L., Camm A.J., deRuyter H., Friedman P.L., MacNeil D.J.,
Pauls J.F., et al. Effect of d-sotalol on mortality in patients with left
ventricular dysfunction after recent and remote myocardial infarction. The
Lancet (1996) 348:7–12.
5.London B, Albert C, Anderson ME, Giles WR, Van Wagoner DR, Balk E,
Billman GE, Chung M, Lands W, Leaf A, McAnulty J, Martens JR, Costello RB,
Lathrop DA. 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.
6.Raitt M.H., Connor W.E., Morris C., Kron J., Halperin B., Chugh
S.S., 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.
7.Burr M.L., Gilbert J.F., Holliday R.M., Elwood P.C., Fehily A.M.,
Rogers S., et al. Effects of changes in fat, fish, and fibre intakes on
death and myocardial reinfarction: Diet And Reinfarction Trial (DART). The
Lancet (1989) 334:757–761.
8.Burr M.L., Ashfield-Watt P.A.L., Dunstan F.D.J. Lack of benefit of
dietary advice to men with angina: results of a controlled trial. Eur J
Clin Nutr (2003) 57(2):193–200.
9.Coronel R, Wilms-Schopman FJ, Den Ruijter HM, Belterman CN,
Schumacher CA, Opthof T, Hovenier R, Lemmens AG, Terpstra AH, Katan MB,
Zock P. Dietary n-3 fatty acids promote arrhythmias during acute regional
myocardial ischemia in isolated pig hearts. Cardiovasc Res. 2007 Jan
10.Janse M.J. Electrophysiological changes in heart failure and their
relationship to arrhythmogenesis. Cardiovasc Res (2004) 61:208–217.
11.Baartscheer A., Schumacher C.A., Belterman C.N.W., Coronel R.,
Fiolet J.W.T. SR calcium handling and calcium after-transients in a rabbit
model of heart failure. Cardiovasc Res (2003) 58:99–108.
12.Janse M.J., Wit A.L. Electrophysiological mechanisms of
ventricular arrhythmias resulting from myocardial ischemia and infarction.
Physiol Rev (1989) 69:1049–1169.
Competing interests: No competing interests
Before addressing the specifics of the commissioned editorial by
Brunner and Iso (1) and the paper by Leon et al, (2) neither of which
mention blood rheology, it is important to provide the reader with some
1. Since the recognition of the lack of heart disease in the Eskimos
and Inuits, despite their fat-rich diet, a significant body of information
records that fish oil enhances blood flow by increasing red cell
deformability and reducing blood viscosity.
2. There is a significant
literature concerning the role of poorly deformable red cells and
increased blood viscosity in the pathophysiology of both cardiovascular
and cerebrovascular disorders.
3. So it is of some relevance that in 1985, Kromhout et al (3) reported
that a small daily intake of oily fish resulted in a 50% reduction in
coronary heart disease in a 20 year fillow-up study. It is noteworthy
that the beneficial effects of fish oil are not restricted to cardiac
events. In 2003, Noaghiul and Hibbeln (4)reported that, "...greater
seafood consumption predicted lower lifetime prevalence rates of bipolar 1
disorder, bipolar 2 disorder and bipolar spectrum disorder."
In the introduction to their paper,Leon et al (2) discussed various
aspects of studies involving omega-3 fatty acids without mention of their
effects on blood flow. But in 1983(5)and in 1985(6) studies of the
effects of omega-3 supplements in healthy subjects were published by
investigators in Japan and England. Both studies showed that the effects
of the omega-3 supplements were to increase red cell deformability
(possibly by improving erythrocyte lipid fluidity) and to reduce blood
viscosity. Many others have published similar findings. Having shown by
a spin-label technique that in diabetic red cells, the erythrocyte lipids
were hyperviscous, Kamada et al (7) reported that after diabetics had
taken 2700mg of sardine oil for 8 weeks, the erythrocyte membrane lipid
fluidity was not different from those of non-diabetics. Although there is
published information which shows that blood pressure is related directly
to blood viscosity, this has failed to gain clinical recognition, so the
findings of Bach et al (8) are relevant. They found that after a daily
intake of 2.52g of omega-3 fatty acids for 5 weeks, plasma viscosity,
erythrocyte rigidity and systolic blood pressure were reduced
significantly. All of these findings may be interpreted as showing that
any functional improvements associated with omega-3 supplements were a
consequence of improved blood flow.
But blood flow was not mentioned in the article by Leon et al (2) and
there was speculation about changes in ion and sodium channels in
arrhythmias. The paper was based upon 12 papers which had been distilled
from 6713 papers, but none of those analysed included observations on
blood rheology. Given that arrhythmias are a heterogeneous group of
events which influence cardiac rhythm, is it reasonable to expect that 12
papers would find useful information about the effects of fish oil on
unselected arrhythmias ? An analysis of arrhythmias seems to show that in
most cases blood flow is not a factor, but there are some which appear to
be influenced by blood flow. As both the sinoatrial node and the
atrioventricular node are supplied by the right coronary artery, it is
possible that changes in the flow rate in that artery could influence
cardiac rhythm. Ectopic rhythm may result from ischemia or hypoxia, both
of which imply impaired blood flow. Both ventricular extrasystole and
ventricular tachycardia may be precipitated by events which stiffen red
cells, namely exercise, tobacco, alcohol and epinephrine. It seems
reasonable to conclude that because of the diversity of arrhythmias, there
would be little likelihood of finding a relationship between arrhythmias
and the effects of fish oil, particularly when the effects of the fish oil
were not considered.
An important aspect of the editorial (1) was that it began with a
comment about the NICE recommendation that patients should eat oil fish
AFTER a myocardial infarction. Surely,in terms of published information,
it would have been more rational to suggest that those at risk should be
taking oily fish as a preventive measure. But on the basis of other NICE
guidelines it is clear that NICE does not recognise blood rheology as an
important factor in the pathophysiology of many disorders. Leon et al
raised the question, "Are the benefits of fish oils greater than the now
much better medical and surgical treatments for secondary prevention ?"
On the basis of the effects in Eskimos and Inuits, fish oil used as a
preventive measure would be much cheaper and possibly more effective.
What is most intriguing is that without reference to the 1980s reports
concerning the actions of omega-3, the authors concluded that valuable new
evidence will emerge from the German OMEGA study. I wait with bated
1. Brunner E, Iso H. Fishoil and secondary prevention of cardiovascular
disease. The mechanism and size of any effect are uncertain. BMJ
2. Leon H, Shibata MC, Sivakumaran S, et al. Effect of fish oil on
arrhythmias and mortality: systematic review. BMJ 2009;338:2931.
3. Kromhout D, Bosschieter EH, Coulander C, et al. The inverse relation
between fish consumption and 20 year mortality from coronary heart
disease. N Engl J Med 1985;312: 1205-9.
4. Noaghiul S, Hibbeln JR. Cross-national comparisons of seafood
consumption and rates of bipolar disorder. Am J Psychiatry 2003;160: 2222
5. Terano T, Hirai A, Hamazaki T, et al. Effect of oral administration
of highly purified eicosapentaenoic acid on platelet function, blood
viscosity and red cell deformability in healthy human subjects.
6. Cartwright IJ, Pockley AG, Galloway JH, et al. The effects of dietary
omega-3 polyunsaturated fatty acids on erythrocyte membrane phospholipids,
erythrocyte deformability and blood viscosity in healthy volunteers.
7. Kamada T, Yamashita T, Baba Y, et al. Dietary sardine oil increases
erythrocyte membrane fluidity in diabetic patients. Diabetes 1986;35:604-
8. Bach R, Schmidt U, Jung F, et al. Effects of fish oil capsules in two
doseages on blood pressure, platelet functions, haemorheological and
clinical chemical parameters in apparently healthy subjects. Ann Nutr
Competing interests: No competing interests