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Hernando León, Marcelo C Shibata, Soori Sivakumaran, Marlene Dorgan, Trish Chatterley, and Ross T Tsuyuki
Effect of fish oil on arrhythmias and mortality: systematic review
BMJ 2008; 337: a2931 [Abstract] [Full text]
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[Read Rapid Response] Fish oil, blood viscosity,arrythmias and mortality.
Leslie O Simpson   (20 January 2009)
[Read Rapid Response] Pro-arrhythmic effects of fish oils
Palaniappan Saravanan, Neil C Davidson   (24 January 2009)

Fish oil, blood viscosity,arrythmias and mortality. 20 January 2009
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Leslie O Simpson,
retired experimental pathologist
Dunedin, New Zealand 9077

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Re: Fish oil, blood viscosity,arrythmias and mortality.

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 basic information.

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 breath !

References.

1. Brunner E, Iso H. Fishoil and secondary prevention of cardiovascular disease. The mechanism and size of any effect are uncertain. BMJ 2009;338: 118-9.

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 -7.

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. Athersclerosis 1983;46:321-31.

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. Atherosclerosis 1985;55:267-81.

7. Kamada T, Yamashita T, Baba Y, et al. Dietary sardine oil increases erythrocyte membrane fluidity in diabetic patients. Diabetes 1986;35:604- 11.

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 Metab 1989;33:359-67.

Competing interests: None declared
Pro-arrhythmic effects of fish oils 24 January 2009
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Palaniappan Saravanan,
Specialist Registrar & Research Fellow
University Hospital of South Manchester, Manchester, M23 9LT, UK,
Neil C Davidson

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Re: Pro-arrhythmic effects of fish oils

We read with interest the systematic review by Hernando Leσn 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 reentry(12).

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.

References:

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. 2007, 4;116(10):e320-35

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 15;73(2):386-94.

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: None declared