The Electrical Stabilizing Effect of n-3 Fatty Acids

1. The electrical stabilizing effect of n-3 fatty acidsThis electrical stabilizing action of the n-3 fatty acids can be demonstrated by a simple experiment. Fig. 10 shows a continuous tracing of the contraction of a single myocyte in a clump of myocytes on a microscope coverslip. Initially the myocyte is contracting regularly. Two platinum electrodes were placed across the cover slip with their tips dipped into the fluid perfusing the heart cells and connected to a voltage source. At stimulating electrical currents delivered at 15 volts it was possible to double or triple the spontaneous beating rate.

3. In considering clinical applications of the n-3 fish oil for prevention of fatal arrhythmias one should think broadly of the possibilities. We have shown that our experimental studies indicate that it probably does not matter what the underlying cause of the arrhythmia is. Cytosolic calcium overload as well as ischemia can cause serious arrhythmias. Other causes of arrhythmias may well also benefit from the administration of these n-3 fish oil fatty acids. Administration can be orally for prophylaxis or intravenously in arrhythmic emergencies.

4. Adverse effects of n-3 polyunsaturated fatty acidsThe n-3 fish oil fatty acids have been part of the human diet for hundreds of thousands of years. Aside from a rare person with an idiosyncratic sensitivity to them, they are generally safe. The FDA has approved the consumption of 3.5 g of fish oil daily and this is on the GRAS list (Generally Regarded As Safe). At these daily intakes a person might bruise more readily, than usual, especially if concomitantly taking aspirin, but this does not seem to cause clinically significant bleeding. There may be some transient GI discomfort or complaints of the fishy taste when taking fish oil supplements.

5. A recent publication has raised the possibility of potentially serious adverse effects in subjects with chronic and probably extensive cardiac disease. At present we can only speculate on the cause of the increased deaths Burr observed in subjects with “chronic angina”, whom he had advised to eat more oily fish. Perhaps this is related to the way the n-3 fatty acids inhibit the sodium current in partially depolarized heart cells, as discussed Our Hypothesis. By eliminating the function of partially depolarized cardiomyocytes, as shown in Fig. 7, they prevent their potential proarrhythmic effects.

6. Effects of n-3PUFAs on the brain and nervous system:Once we knew that the n-3 fatty acids of fish oil modulated the ionic currents in heart cells, we expected they would do the same in other excitable tissues, such as the brain and nervous systems. To find someone who was an expert on the nervous system we went to see a distinguished expert in the Department of Neuroscience at the Harvard Medical School.

8. The reason I present this experiment is that it illustrates a very important point. It shows that these fish oil fatty acids have the potential to markedly reduce the extent of brain damage that follows a stroke. It is the hyperactivity of the brain cells, which occurs in the ischemic brain tissue, which exhausts the supply of ATP within the neuronal cells, that results in the death of the neurons, just as we saw in our experiment with the heart following an acute myocardial infarction. Fatty acids have been shown to rapidly penetrate through the membranes of the blood brain barrier by nonionic diffusion. So one would only need to inject the n-3 fish oil fatty acids carried on serum albumin into the blood stream to reduce the brain damage following a stroke.

9. Prevention of epileptic seizure activity by n-3 fish oil fatty acids:So I flew to Holland where the University of Amsterdam has a large, active Epilepsy Institute. Professor Wadman was interested to test the effect of the fish oil fatty acids on the electrophysiology of CA1 hippocampal neurons, in which most epileptic seizures are initiated. It is the practice in patients with severe and relentless, continuous seizure activity to have a neurosurgeon remove the offending hippocampal neurons. This is done by entering the brain through the neo-cortex with a hollow needle and aspirating tissue sampling the tissue down through the hippocampal neurons.

10. Figure 12. Effect of DHA (16 M) on INa of CA1 neurons from an adult rat hippocampus.

11. Then I went to Leyden, where Dr. Voskul had a highly reliable rat model in which he could induce seizure activity electrically. We found that in this animal model that EPA, administered via a tail vein reduced the minimal electrical current to cause the first indication of increased hyperactivity, which was manifest by spontaneous twitching of the rat’s whiskers and also the electrictical activity to prevent a full epileptic seizure – see Figure 13. I never had the opportunity to test the possibility that the fish oil fatty acids would prevent seizure activity in patients with epilepsy, but at least we had found that they had potentially beneficial effects on the brain, as we had expected.

13. Clinical evidence of cardiac benefits: While these studies on the basic mechanism by which the fish oil fatty acids may prevent fatal ventricular arrhythmias were in progress, a few clinical studies and many epidemiologic observations on the antiarrhytmic action of the n-3 fatty acids were made. A few selected examples are provided.The first clinical trial was published in 1989. It was a randomized controlled trial with a factorial design to see if in 2033 men dietary advice on fat, fish or fiber is beneficial in the secondary prevention of myocardial infarction (MI). No benefits accrued from the fat and fiber advice.

14. More recently another clinical trial was reported, “Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial”. This was a large, prospective, randomized, clinical trial of 11,324 patients who had a recent myocardial infarction. They were randomly assigned to four equal groups to test the effects of a daily dose of one capsule of 850 mg EPA +DHA, 300 mgs of vitamin E, n-3 PUFA plus vitamin E and a control group receiving neither. This was on top of optimal pharmacological treatment and lifestyle advice.

15. This study was reanalyzed and subsequently again published as the “Early protection against sudden cardiac death by n-3 polyunsaturated fatty acids after myocardial infarction: Time course analysis of the results of the GISSI-Prevenzione” in 2002. This reanalysis showed the reduction in risk of sudden cardiac death was nearly significant at 3 months accounting for 67% of the overall mortality benefit, became significant at 4 months, and was highly significant at 3.5 years, the end of the study, when it accounted for 59% of the n-3 PUFA advantage in mortality.

16. More recently the data in the Physicians’ Health Study has been examined to test whether n-3 fatty acid consumption would reduce the risk of sudden death in subjects without a history of preexisting cardiovascular disease. A prospective, nested, case-control analysis among apparently healthy men who were followed for 17 years in the Physicians’ Health Study was, retrospectively, conducted. 94 men were identified in whom sudden cardiac death occurred as the first manifestation of cardiovascular disease. 184 controls were matched with them for age and smoking status. The fatty acid composition of blood, which had been collected at baseline on all subjects, was determined.

17. These encouraging reports led us to hypothesize that these long-chain n-3 fatty may prevent ventricular arrhythmias in high-risk patients. To test this hypothesis four hundred two patients with implanted cardioverter-defibrillators (ICDs) who were at high risk for fatal ventricular arrhythmias were enrolled at 18 collaborating centers into our Fish oil Anti-arrhythmia Trial (FAAT).

18. Subjects were included who had an ICD implanted because of a history of cardiac arrest, sustained VT, or syncope with inducible VT/VF during electrophysiologic studies. The qualifying ICD must have been implanted within 12 months prior to entry into the study or the patient had at least one spontaneous ICD event for VT/VF in the preceding 12 months. Enrollees were randomized in a double-blinded, controlled fashion to either four 1.0 gelatin capsules of an ethyl ester concentrate of n-3 fatty acids (total daily dose of 2.6 g) or to four 1.0 g capsules of olive oil of identical appearance for 12 months.

19. At baseline, clinical data and blood samples were collected and subjects were told to eat no more than 2 fish meals in a month and to use olive oil rather than the common plant seed oils (corn oil, sunflower seed oil, etc.) for dressings for salads and other such uses. The recommendation to use olive oil is emphasized. 87% of enrollees indicate they had adhered to our advised diet for the duration of the trial. Substituting olive oil, which contains no n-6 fatty acids makes it like the Mediterranean diet, which reduces the n-6/n-3 ratio and favors the action of whatever amount of n-3 fatty acids are contained in the diet. This may account for the beneficial effects of fish oil fatty acids in this study but a lack of any benefit in another very recent study.

20. Subjects were asked to report at 3-month intervals to their respective medical centers to have their ICD reports collected and have blood samples drawn. The ICD reports were then submitted to a Core Electrophysiology Laboratory to have their ICD interpreted by two or more cardiac electrophysiologists blinded to the patients’ treatment. The blood samples were separated into plasma and packed cells, kept frozen at –70 to –80 oC and mailed to the Massachusetts General Hospital where the red cells were analyzed for their phospholipid content of fatty acids.

21. The Core EP Laboratory was responsible for endpoint confirmation. All reports showing arrhythmias and a random selection of negative reports were viewed by at least two electrophysiologist. Wherever disagreement occurred they were interpreted by a third. Each made his/her interpretation blinded to the supplement and the interpretation of the other electrophysiologists. The agreement between two of the interpretations was the accepted interpretation. “Confirmed events” were defined as spontaneous episodes of VT and/or VF causing ICD discharges for which intra-cardiac electrograms were available.

22. All randomized patients were included in the intention to treat analysis. The primary analysis, based upon confirmed events, was an intention to treat analysis of the survival free of appropriate ICD events for VT/VF and /or death from any cause. Secondary analyses were performed including “probable events” as defined. The intention-to-treat analysis included all confirmed ICD events during the 12 month period after the first dose of the study drug was taken, irrespective of the duration of treatment. Two “on treatment” analyses were done The first included all ICD reports that occurred no later than two months after the treatment was stopped. The “second on treatment” analysis was limited to those who were compliant for the duration of the trial.

23. One hundred forty two subjects (35% of enrollees) discontinued their prescribed supplements before completing their year in the trial. Time to discontinuation did not differ significantly between the two arms. In our intent-to-treat analysis, all these individuals who discontinued their supplements are included. Among patients who had blood levels analyzed at their last visit the 110 randomized to fish oil had a significantly higher content of EPA+DHA as percent of the total fatty acids in the phospholipids of red blood cells compared with the 119 receiving olive oil (mean level  SEM = 7.6  0.3 vs. 3.5  0.1, P<0.0001, where as at baseline there were no differences in the means 3.4  1.2 and 3.5  1.2, respectively.

24. In the primary analysis, according to intent-to-treat there was a trend toward a longer time to the first ICD event for VT/VF confirmed by electrograms or death from any cause among patients randomized to fish oil compared with those randomized to olive oil, but the difference was not significant (P= 0.057). When “probable events” were added to the endpoint, the reduction in risk became significant; (P=0.033).In the “on treatment” analysis of “confirmed” events, which included all who had taken any prescribed oil supplement during the 12 months there were no significant differences between the two arms of the trial.

25. Our results are consistent with the beneficial antiarrhythmic effects of n-3 fatty acids reported in animal and laboratory studies and earlier clinical trials. Therefore, these data suggest that these n-3 fatty acids may provide an alternative to antiarrhythmic drugs for reducing VT/VF in patients. The 38% reduction in the combined end points that included probable VT/VF is smaller, but comparable to the 44% reduction observed with Sotalol, a type III antiarrhythmic drug. However, unlike pharmaceutical antiarrhythmic drugs, the n-3 fatty acids have not been demonstrated to have proarrhythmic properties and are not toxic.

26. With some 300,000 to 400,000 deaths annually from fatal ventricular arrhythmias in the USA alone and millions more worldwide these deaths constitute a significant public health failure. What others and we have found for the effects of fish oil fatty acids to prevent fatal cardiac arrhythmias seems to have the potential for considerable public health benefits. Despite the hundreds of millions of dollar, which the pharmaceutical industry has spent trying to develop an antiarrhythmic drug, none has yet been produced which is both safe and effective. The fish oil fatty acids, by contrast, have been part of the human diet for hundreds of thousands of years and they are safe. They also are as effective as the best of the pharmaceutical antiarrhythmic drugs.

27. Do fish oil fatty acids prevent atherosclerosis?Why do clinical trials fail to demonstrate an antiatheroclerotic action, whereas they show potent antiarrhythmic effects? It has been shown that the polyunsaturated fatty acids cause many biochemical, biophysical and physiologic effects in animals and humans, which would be expected to prevent atherosclerosis. They do not, however, show antiatherosclerotic effects in short term studies in humans.

28. Inuits and Japanese, who have a lifelong intake of fish and fish oils, have a low incidence of atherosclerotic changes in their arteries. This has been shown repeatedly. By contrast in short term studies of the administration of fish oil fatty acids prevention of the atherosclerotic process is not observed. This shows in the Burr clinical trial of 1989 and the GISSI Prevenzione of 2001, both of which showed a reduction in fatal ventricular arrhythmias (SCD) but with no reduction in new myocardial infarctions with fish oils.

29. We may conclude that the evidence has been strengthened that fish oil fatty acids can prevent sudden cardiac death in humans. The evidence today supports the recommendations of the American Heart Association that everyone should be having at least 2 meals weekly of fatty fish to maintain a healthy heart. For those that have coronary heart disease, had an MI, or have a family history among close relatives including ventricular arrhythmias, they should, in addition, be taking a fish oil supplement of at least 1.0 g of EPA+DHA regularly daily. We can go a step further to add that to obtain maximal benefit from the amount of n-3 fish oil fatty acid ingested, it is necessary simultaneously to reduce the n-6 plant seed oils in the diet.

30. REFERENCES