The Prevention of Cardiac Arrhythmias and Sudden Death by N-3 Fatty Acids

By:
William E. Connor, M.D.
From:
The Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Medicine, L465, Oregon Health & Science University, Portland, Oregon 97239-3098

Sudden, unexpected death occurs in 300,000 Americans each year (1). Many of these deaths occur from latent coronary heart disease in individuals who have been previously well and who suddenly collapse. This catastrophical event occurs because of a cardiac arrhythmia, ventricular tachycardia or ventricular fibrillation. In these arrythmias, the pumping of blood by the heart virtually stops. The blood supply to the brain is interrupted, and the individual usually lapses into unconsciousness in a few minutes. Some of these people are resuscitated, but even then, after they are taken to a hospital, many still die. The prevention of sudden death in our population is a national imperative. The consumption of fish and fish oil, as will be explained below, may have an important role in preventing sudden, unexpected cardiac death.

After Dyerberg and Bang (2) reported that Greenland Eskimos had a much lower coronary mortality rate than Danes living in Greenland, the next step was to find out why the Eskimos had this particular advantage. These Danish scientists found that the diet of the Eskimos which was derived from seafood contained large quantities of the highly polyunsaturated n-3 fatty acids, eicosapentaenoic and docosahexaenoic acids (3). When consumed in the human diet, the concentrations of these fatty acids increased greatly in the blood and in the tissues of the body, including the heart.

Experimental Animal Studies

Among the first observers to document a mechanism for the beneficial effects of the n-3 fatty acids on the heart in the Greenland Eskimos were McLennan and associates from Australia who showed that feeding rats fish oil for several months prevented the ischemia-induced fatal ventricular arrhythmias (4,5). In their particular model, the coronary arteries were ligated, and then the rats developed an irreversible cardiac arrhythmia (ventricular fibrillation). The control diets that the rats were fed were composed of either saturated fat or monounsaturated fat, and the results were inevitable, ventricular fibrillation and death. When the rats were fed tuna fish oil containing the n-3 fatty acids, and the coronary arteries were then ligated, the usual irreversible ventricular arrhythmia was completely prevented. There then followed further observations by this same group in a primate, the marmoset. Others using the rat model have confirmed their observations (6).

Another early study suggesting the beneficial effects of n-3 fatty acids to prevent sudden cardiac death came from Iceland in (7). The author examined the levels of n-3 and n-6 fatty acid in the phospholipids from the hearts of rats fed diets containing cod liver oil, butter or corn oil. The individual phospholipids in the myocardial sarcolemma had vastly different fatty acid composition. Fatal ventricular fibrillation in rats and sudden cardiac death in humans were both accompanied by a high ratio of 20:4 n-6/22:6 n-3. The author, S.Gudbjarnason, stressed the balance between n-6 and n-3 fatty acids in cellular phospholipids as having an important role in sudden cardiac death, with high n-6 fatty acids promoting arrhythmias.

Peter McLennan who has done some of the outstanding work on the anti-arrhythmic actions of polyunsaturated fats has reviewed the experimental animal evidence about various polyunsaturated fats in cardiac arrhythmias (8). A comparison of the effects of fish oils and dietary vegetable oils indicates an enhanced anti-arrhythmia effect of fish oils over and above their content of various polyunsaturated fatty acids. A comparison of sheep fat and olive oil fat as control fats with sunflower seed oil and fish oil indicated an approximately fifty percent reduction in ventricular fibrillation by the omega-6 sunflower seed oil but about a ninety percent reduction after the omega-3 containing fish oil. The component fatty acid of fish oil which had the desirable effect in the myocardium to prevent ventricular fibrillation, was DHA. In the feeding of fish oil rich in EPA and DHA, only the DHA is incorporated in the myocardial phospholipids; very little EPA is incorporated and its level is not increased by fish oil feeding.

When pure EPA is fed there is only a slight elevation in myocardial DHA levels and only a very small increase in myocardial EPA. A myocardial membrane DHA composition of 18 percent or more is required for anti-arrhythmic effects during myocardial ischemia. The author does not mention that in vitro experiments with rat myocytes in culture indicate that EPA certainly prevents arrhythmias in these cells when so stimulated (9).

The Hock group in Philadelphia has also studied the effects of fish oil to reduce arrhythmia and sudden death in experimental animals (6). They first observed less ischemic damage after permanent coronary artery ligation in rats fed menhaden oil. There were significant increase in the n-3 fatty acid, DHA, in the myocardial phospholipids. They compared n-3 fatty acids with polyunsaturated fat fatty acids of the n-6 family, i.e. a comparison of dietary menhaden oil with corn oil, on the incidence of arrhythmias, ischemic damage and leukocyte infiltration into the perfused free wall of the left ventricle in an in vivo rat model of myocardial ischemia-reperfusion. Their results were interesting and challenging. They first observed much lower myocardial creatine kinase activity (an enzyme indicating muscle damage) after reperfusion in their particular model in rats fed menhaden oil. The incidence of ventricular fibrillation was significantly lower as compared with corn oil fed rats (only 14 percent vs. 91 percent, menhaden oil vs. corn oil). With the total arrhythmia score (ventricular tachycardia and ventricular fibrillation in rats subjected to 15 minutes of ischemia and then six hours of reperfusion), menhaden oil fed rats had a much lower score, 1.3 vs. 5.6 for corn oil fed rats. Sixteen of 21 menhaden oil-fed rats survived these experiments, but only nine of 22 rats survived after the corn oil background diet. The authors found greatly increased DHA in the myocardial phospholipids vs. the corn oil fed rats. The level of feeding was five percent by weight in the diet of corn and menhaden oils. The authors postulated that the greater n-3/n-6 ratio in myocardial phospholipid fatty acids might well be the discriminating factor producing the beneficial effects of menhaden oil vs. corn oil.

The next important studies were performed by Alexander Leaf and colleagues in Boston using a canine model of sudden cardiac death (10). When the left main coronary artery of the dog was ligated and an inflatable cuff placed around the left circumflex coronary artery, the dog was then placed on a treadmill. Sixty percent of the animals then became susceptible to ventricular arrhythmias. If the dogs were given intravenously an emulsion of fish oil fatty acids before the exercise ischemia test, fatal ventricular fibrillation was prevented in 10 of 13 dogs. When more purified fatty acids were used, EPA and DHA, there was a similar prevention of the arrhythmia.

Many studies of n-3 fatty acids have utilized cultured rat cardiomyocytes (9). In culture, these myocytes contract spontaneously and rhythmically. In such a preparation a number of substances will stimulate a rapid heart beat, the equivalent of ventricular fibrillation. In particular, a compound related to digitalis, ouabain, invariably induces the rapid rhythm. If n-3 PUFAs were added to the fluid profusing the isolated myocytes before the ouabain was administered, the expected arrhythmia was completely blocked. As in the McLennan experiments, saturated fatty acids and monounsaturated fatty acids did not prevent the arrhythmias from occurring in these rat myocytes.
The next set of experiments was designed to elucidate why the n-3 fatty acids from fish had their anti-arrhythmic effect. McLennan has carried forward his studies in the prevention of arrhythmias in rats by fish oil by defining the actual components of fish oil which may be effective in this preventative action (11). Low dietary intakes, 1.1 percent of total energy as docosacsanoelic acid, but not eicosapentaenoic acid, inhibited ischemia-induced cardiac arrhythmias. At higher intakes, DHA was more effective than EPA in retarding hypertension in the rats and also inhibiting the thromboxane A2 vasoconstrictor responses in the aorta of stroke-prone rats. In these results purified n-3 polyunsaturated fatty acids mimicked the cardiovascular actions of fish oil and indicated that docosahexaenoic acid was the principal component in bringing about cardiac protection. In these studies olive oil was the control fat. This demonstrated that a vegetable oil fatty acid such as the oleic acid of olive oil had no effect in preventing ventricular arrhythmias, an important point to consider by those who favor the use of olive oil in diets for coronary heart disease treatment.

Kang and Leaf have shown the protective effects of many free polyunsaturated fatty acids: EPA, DHA, alpha linolenic acid, arachidonic acid and linoleic acid were able to prevent certain induced arrhythmias. Oleic acid and stearic acid had no such effects (12).

Garg and co-workers have summarized the 28 studies on the prevention of cardiac arrhythmias by dietary n-3 polyunsaturated fatty acids and explored the mechanism of action (13). Twenty-one studies have been carried out in a variety of experimental animals including rats, marmoset monkeys, dogs and pigs. In addition, seven studies have been carried out in cultured rat cardiomyocytes. The investigators have surveyed two experimental models in animals. Ischemia was produced by coronary artery occlusion and then the resulting arrhythmias observed. In the second model ischemia was produced, and then the arrhythmia resulted when the heart was reperfused with blood to a previously ischemic region. Pre-feeding with fish oil prevented the usual arrhythmia and cardiac death. Acutely administered, the omega-3 EPA and DHA prevented the otherwise fatal arrhythmia.

Abeywardena and co-authors (14) examined the effect of long-term dietary supplementation of different fatty acids on arrhythmias in both rats and marmoset monkeys. Cardiac eicosanoids were reduced by fish oil feeding, which then resulted in less ventricular fibrillation. McLennan tied the association of the consumption of different dietary fatty acids and the vulnerability of the myocardiam to develop arrhythmias in adult marmoset monkeys (15). An increase in the threshold current required to produce ventricular fibrillation was observed in animals fed both sunflower seed oil and tuna fish oil compared to animals fed a saturated fat diet. In another study by this same group, hearts isolated from rats fed fish oil for 16 weeks were set up as a working heart model. Dietary fish oil prevented and reduced the severity of arrhythmias from the induction rats. Fish oil also raised the threshold for ventricular fibrillation. In the study by Charnock et al, dietary n-3 PUFA improved both the mechanical performance and the electrical stability of hearts in marmoset monkeys (16). The anti-arrhythmic effects of dietary n-3 fatty acid was independent of atherosclerosis induced vulnerability and was caused by the effect on the myocardial membrane alone. In the ischemia-reperfusion model, Hock et al fed rats menhaden oil containing both EPA and DHA for four weeks and found a reduction in ischemic damage to the heart and a lower incidence of fatal arrhythmias (6). In another study by McLennan et al tuna fish oil effectively reduced the vulnerability of the myocardium to both ischemic and reperfusion arrhythmias(17).

Of interest are the studies of Billman (1994) in dogs, which demonstrated that long chain n-3 PUFA prevented ischemia induced ventricular fibrillation when administered acutely (10). Dietary fish oil fatty acids were infused intravenously before inducing ischemia, and ventricular fibrillation was prevented in seven of eight animals. Since this infusion consisted of fish oil fatty acids one hour before the ischemia was induced, this indicated an acute effect of n-3 PUFA on the electrical properties of heart muscle cells. Long time dietary treatment was apparently not necessary to demonstrate these acute effects.

There was an important experimental study on the effects of n-3 polyunsaturated fatty acids on the cardiac sarcolemma Na+/H+ exchange (18). Note, the sarcolemma is the plasma membrane of a muscle fiber, in this instance the myocardium or heart muscle. Cardiac membranes highly enriched in sarcolemma vesicles were exposed to eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA). H+- dependent Na+ uptake was inhibited by 30-50 percent after treatment with physiological amounts of EPA and DHA. That was a specific effect of the n-3 PUFA because similar amounts of linoleic or linolenic acid had no significant effect on Na+/H+ exchange. The results provide insights into the cardio-protective actions of EPA and DHA in ischemia reperfusion experiments. Since it is already known that myocardial phospholipids will be enriched with EPA and DHA, especially DHA, after feeding animals diets high in these fatty acids from fish oil, these experiments have important relevance to answer the question of why EPA and DHA are cardio protective in humans.

The mechanisms of the antiarrhythmic effects of n-3 fatty acids as suggested by the experimental animal studies were as follows (13):

1. The effect of n-3 PUFA on sodium and calcium channels
2. The effects on the inositol-lipid cycle and self-signaling
3. Direct effect of free fatty acids on the myocardium
4. Modification of the fatty acid composition of membrane phospholipids
5. The effect on the eicosanoid system
6. The effect on the myocardial enzymes and receptors

“It has been aptly said that n-3 PUFA modifies so many different factors, it is impossible to attribute all of their beneficial effects to a single action” (Leaf 1994).

In summary, n-3 fatty acids from fish (EPA and DHA) have been shown to inhibit and prevent cardiac arrhythmias in a variety of experimental animals and in isolated myocytes in culture. All experiments were strongly positive. Thus, the stage was set for studies in humans.

Part II: Human Studies of N-3 Fatty Acids and Sudden Death

The epidemiological observations about the prevention of heart deaths by a diet rich in the n-3 polyunsaturated fatty acids from seafood led to further observations in humans. These consisted of prospective studies and actual clinical trials. Clearly, in the animal and cell culture studies, attention was properly directed to the possible prevention of sudden death.

An early case controlled study occurred in the Physicians Health Study (19). Healthy men were followed up to 17 years and the incidence of sudden deaths was monitored in the study. There was also analysis of the composition of blood to determine the levels of EPA and DHA at baseline. The levels of EPA plus DHA in the blood predicted the outcome. The highest EPA plus DHA concentrations in the blood led to a 72 percent and 81percent risk reductions in the incidence of sudden death. The data stress the importance of fish and fish oil consumption in the prevention of coronary heart disease.

In the Cardiovascular Health Study, Siskovick and colleagues investigated the association of the plasma phospholipid concentrations of EPA, DHA and alpha linolenic acid as biomarkers of n-3 PUFA intake with the risk of fatal ischemic heart disease and non-fatal myocardial infarction in older adults (20). A higher plasma phospholipid concentration of EPA plus DHA was associated with a 50 percent or greater lower risk of fatal ischemic heart disease, after adjustment for all other risk factors, (p=0.01). As in other studies, EPA plus DHA was not associated with less non-fatal myocardial infarction. The data were consistent with a possible anti-arrhythmic effect of these fatty acids.
In a second observation from the Cardiovascular Health Study of Seattle, Washington, the usual fish consumption was later determined in 3,910 adults in a population-based prospective cohort study (21). The consumption of tuna and other broiled or baked fish correlated well with the plasma phospholipid long chain n-3 fatty acids, whereas consumption of fried fish or fish sandwiches did not. The participants were followed for 9.5 years. Those consuming tuna and other broiled or baked fish had a lower risk of total ischemic heart disease deaths (p=0.001) and arrhythmic deaths (p=0.001) but not for non-fatal myocardial infarctions. There was a 49 percent lower risk of IHD deaths and a 48 percent lower risk of arrhythmic deaths among persons consuming tuna/other fish three or more times per week compared to those consuming less than once per month. There was no benefit from the consumption of fried fish or fish sandwiches, which probably had a lower content of n-3 PUFA.

The Physicians' Health Study and the Nurses' Health Study have long been sources of important information about nutrition and the occurrence of chronic disease, especially coronary heart disease. In 2002 came two reports about the effects of long-chain n-3 fatty acid or omega-3 fatty acid intake and the risk of sudden death and coronary heart disease. These are both prospective, controlled studies in apparently healthy individuals who were followed for many years. In the Physicians' Health Study healthy men were followed for up to 17 years (22). The fatty acid composition of previously collected baseline blood was analyzed for 94 men in whom sudden death occurred as the first manifestation of cardiovascular disease and for 184 controls matched for age and smoking status. Again, as in many other prospective studies, baseline blood levels of long-chain n-3 fatty acids were inversely related to the risk of sudden death (p=0.007). The risk of sudden death was significantly lower among the men with levels in the third and the fourth quartiles of blood levels of long-chain n-3 fatty acids. This report stressed a reduced risk of sudden death in men who had higher blood levels of n-3 fatty acids (EPA and DHA) found in fish.

In the Nurses' Health Study, data was taken from 84,688 female nurses, age 34-39, and free from coronary heart disease (CHD) when enrolled at baseline in 1980 (23). At 16 years of follow-up there were 1,513 cases of cardiovascular disease. After adjustment for other risk factors, the multivariate relative risks of CHD were 0.79 for fish consumption 1-3 times per month, 0.71 for fish consumed once per week. 0.69 for fish eaten 2-4 times per week and 0.66 for fish consumption five or more times per week (p=0.001), all compared to no fish consumption. Similar findings occurred across quintiles of omega-3 fatty acid intakes. The higher the intake of omega-3 fatty acids from fish, the lower the risk of CHD and especially for CHD Deaths.

Clinical trials and further associations to prove this hypothesis then occurred. The first clinical trial was carried out in Wales by Burr and colleagues (24). They conducted a randomized controlled trial in 2,033 men who had survived a myocardial infarction. The trial was based on dietary advice on fat, fish and fiber, to find out which one would be protective in preventing further episodes of heart disease. Only benefits from fish or fish oil consumption resulted, however. At the end of two years there was a 29 percent decrease in the mortality of the men who had received advice to eat fish or take fish oil, compared to the men who had not received fish advice. The 29 percent reduction in deaths from heart disease in those who ate fish or took fish oil was considered a reduction in deaths from cardiac arrhythmias, since the total number of cardiac episodes was not decreased. Men who developed heart disease survived because they did not have the serious and fatal arrhythmic disturbances.

In 1997 there came a report from India by Singh and co-workers (25). In this study 360 patients with suspected myocardial infarction were randomized to placebo, fish oil
(2 g of EPA plus DHA per day), or mustard seed oil. The number of episodes of sudden deaths was 11.2% in the fish oil group, versus 22.0% in the placebo group. This study also suggested an effect of fish oil fatty acids on the prevention of sudden death.

The most important clinical trial was the GISSI-PREVENZIONE trial, a very large randomized clinical trial of 11, 334 patients who had had a myocardial infarction (26). There were four intervention groups: one group received EPA plus DHA as a fish oil capsule (850 mg), another group received vitamin E, a third group received fish oil plus vitamin E and a fourth group received only placebo. The vitamin E supplement had no effect. The fish oil supplement reduced the deaths from heart disease by 10-15 percent, depending upon the analysis, the relative risk of death was reduced by 14-20 percent and the risk of cardiovascular deaths by 17-30 percent. There was a 45 percent reduction in sudden deaths. This 1999 study was re-analyzed in 2002 (27). It was shown that the risk of sudden death was significantly prevented by only three months of treatment with fish oil and there was a 67 percent reduction in the overall deaths. This benefit continued for 3½ years to the end of the study. It is important to recognize that the benefit from fish oil occurred early. Instead of dying from sudden death after the onset of a myocardial infarction, fish oil treated men survived in greater numbers.

A recent meta-analysis of randomized trials of n-3 polyunsaturated fatty acids in coronary heart disease identified eleven trials between 1966 and 1999. These included 7,951 patients in the intervention and 7,855 in the controlled groups (28). The risk ratio of myocardial infarction of patients who were consuming an n-3 polyunsaturated enriched diet compared to controlled diets was 0.8 or a p value of 0.01. The risk of fatal myocardial infarction in this meta-analysis was 0.7, p less than 0.001. In five trials, sudden death was associated with the risk ratio of 0.7, p less than 0.01. Overall mortality was less as well. The conclusion of the authors from this meta-analysis indicated that dietary and non-dietary intakes of n-3 PUFA reduced overall mortality from myocardium infarction and sudden death in patients with coronary heart disease.

The clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and the mechanism of prevention of arrhythmia by n-3 fish oils is now well established (1). Both the clinical and animal studies showing the anti-arrhythmic effects of n-3 PUFA convey exactly the same message: namely that fish oil fatty acids are a powerful but simple modality to prevent the 300,000 episodes of sudden death occurring in the United States annually. The mechanism of the anti-arrhythmic actions is to modulate ion channels, so as to stabilize the cardiac myocytes electrically. Fatty acids act to inhibit the fast, voltage dependant sodium current and the L-type calcium currents. It was suggested also that the electrical activity in brain neurons is similarly modulated by the n-3 fatty acids quieting action on all excitable tissues, including the neurons of the central nervous system.

An accompanying editorial in Circulation emphasized the protective effects of fish fatty acids on myocardial vulnerability and sudden death (29). This diet- heart hypothesis is expressed in the following way:

(1) The dietary intake of n-3 PUFA increases cell membrane and free fatty acid content of n-3 PUFA.
(2) Higher n-3 PUFA levels favorably alter cardiac ion channel function.
(3) The altered ion channel function alters the cardiac action potential.
(4) The alteration in the action potential reduces myocardial vulnerability to ventricular fibrillation, which can result in sudden death.

The editorial calls for increased attention by clinicians, researchers and policy makers to this diet - heart hypothesis and to the translation of this considerable body of experimental evidence into clinical practice.

Table 1 summarizes possible beneficial effects of fish oil to prevent heart disease (30).
Strong and consistent evidence supports the strongest action of fish oil in the prevention of sudden death heart attacks. Fish oil also is antithrombotic or anti-blood clotting; it reduces the plasma triglyceride concentration; it is anti-inflammatory, inflammation being a prominent part of the fatty clogging of the arteries known as atherosclerosis; it decreases the concentration of cytokines and inhibits the movement of white blood cells into the atherosclerotic plaques. Finally, fish oil improves cardiac output with less oxygen consumption by the myocardium for a given amount of work. All of these effects have been demonstrated in humans as well as animals who have been given fish or fish oil as part of the total dietary picture.

TABLE 1: Potential Mechanisms by Which Omega-3 Fatty Acids May Reduce Risk for Cardiovascular Disease.

1. Reduce susceptibility of the heart to ventricular arrhythmia 2. Anti thrombogenic 3. Hypotriglyceridemic (both fasting and postprandial) 4. Retard growth of atherosclerotic plaque 5. Reduce platelet-derived growth factor 6. Antiinflammatory 7. Promote nitric oxide-induced endothelial relaxation 8. Mildly hypotensive 9. Enhance the efficiency of cardiac contractions.

 

TABLE 2: The Sources of EPA and DHA Which Act to Prevent Arrhythmias of the Heart

1. EPA and DHA perfuse the heart after a meal of fish or after taking fish oil 2. EPA and DHA released into the blood from fat stores (adipose tissue) 3. EPA and DHA derived from the breakdown of fat and phospholipids present in the heart itself 4. EPA and DHA in lipoproteins of the blood from the liver

The Relevance of the Prevention of Sudden Death by Omega-3 Fatty Acids in Various Population Groups:

The effects of omega-3 fatty acids from fish and fish oil and the prevention of sudden cardiac death have been studied in a number of different populations of men and women. The clinical traials have been conducted exclusively in men who have recovered from myocardial infarction at the time of entry into the study. The men were otherwise healthy individuals and had normal cardiac function, having recovered completely from acute myocardial infarction. These post myocardial infarction patients were recruited in the clinical trial because they would be expected to have a much higher rate of a second coronary episode, arrhythmic or otherwise, than the general population. The numbers that would have to be studied, if patients were drawn from the general population, would preclude the carrying out of such a trial.

On the other hand, cohort studies and associative studies have been carried out in healthy individuals. The best studies have been in healthy men, The Health Professionals Study, and in healthy women, the Nurses Health Study (22,23). Thousands of individuals were recruited for both of these studies and were followed for long periods of time to relate the intake of omega-3 fatty acids from fish with the occurrence of sudden death or other coronary episodes. The odds ratio of an episode of sudden death was usually 50 percent or less in those individuals consuming fish. Fish meals one to two times per week were sufficient to prevent sudden death.

In other studies, particularly those of Siscovick and colleagues (20), previously healthy individuals developed near fatal or fatal arrhythmias. The individuals who ate fish on a regular basis had a much better survival than those who did not eat fish. Again, the mortality was 50 percent less in the fish-eating group who had a high level of EPA and DHA in their red blood cell fatty acids.

The basic mechanism of the prevention of sudden death would be expected to be similar whether the individual had had a previous myocardial infarction and was now healthy or whether the individual had never had any cardiac episode. The data from one study could be transferred to a similar finding in other studies. Thus, the conclusion is logical that omega-3 fatty acids from fish and fish oil prevent sudden death in healthy individuals including those who have recovered from a past episode of myocardial infarction. The data, drawn from the clinical trials are equally supportive of a similar action of EPA and DHA to prevent sudden death in both groups of individuals, previously healthy individuals and those now healthy but who have recovered from previous heart disease.

Since almost 50 percent of the deaths in the population of the United States occur from coronary heart disease, it is evident that thousands of presumably healthy individuals will ultimately experience an episode of coronary heart disease, either as angina pectoris, myocardial infarction, heart failure or an arrhythmic episode resulting in sudden death. The clinical trial data in individuals who have recovered from myocardial infarction is applicable to the presumably healthy population who have occult atherosclerotic disease, which will lead to a cardiac episode in half of them. The presumption that the clinical trial data should be applicable to the general population is certainly valid because of the widespread penetration of atherosclerotic disease in the United States.

However, if the heart is severely diseased, perhaps fish oil and n-3 fatty acids might not have a beneficial effect. Such a study was reported at the annual meeting of the American Heart Association, November 2003. A group from Oregon Health & Science University reported a two-year double-blind study of fish oil vs. olive oil in 200 patients with implanted defibrillators. The endpoints were episodes of ventricular arrhythmias, such as ventricular fibrillation or ventricular tachycardia. The results after two years showed no difference between olive oil and fish oil. This occurred despite the achievement of very high concentrations of EPA plus DHA in the plasma and erythrocytes. There were fewer deaths in the fish oil treated groups, but the study was not powered to show this kind of difference. The investigators were surprised by this result, but believe it simply indicates a different mechanism for arrhythmias in hearts that are already diseased and badly scarred. A completely different situation is present when a healthy heart suddenly develops ventricular fibrillation as a result of sudden atherosclerotic occlusion of a major coronary artery. The investigators do not believe that the results of this study indicate a generalized failure of fish oil to prevent arrhythmias, but just a specific failure in a particular group of patients.

Two recent reviews emphasize the importance of n-3 fatty acids from fish in the prevention of sudden death and coronary disease, and, in particular, the mechanisms of their anti-arrhythmic effects. Lee and Lip from England emphasize that n-3 fatty acids seem to stabilize electrically, resulting in reduced susceptibility to ventricular arrhythmias, thereby decreasing the risk of sudden death (31). N-3 fatty acids should be regarded as a part of comprehensive secondary prevention strategy after myocardial infarction.

The second review by De Caterina and colleagues states that n-3 fatty acids may be effective and safe antiarrhythmic agents (32). Having been a part of the human diet for two to four million years of evolution, the safety of n-3 fatty acids from fish is assured. Their use is indicated in all patients who have already sustained a heart attack and probably to prevent a fatal arrhythmia at the time of the first heart attack. However, there is only presumptive data for primary prevention of coronary death by ventricular arrhythmias.

Summary:

The numerous animal and myocyte tissue culture studies all document an anti-arrhythmic effect of the n-3 or omega-3 fatty acids from fish, reducing the risk of sudden death. The mechanism of this preventive action rests upon the ability of fish oil to stabilize favorably the sodium and calcium channels of the heart. With few exceptions, the clinical trials and the correlative studies in humans provide further evidence of the prevention of sudden death by n-3 fatty acids from fish oil.

I conclude, based on the publicly available scientific evidence, that omega-3 fatty acids may reduce the risk of sudden death heart attacks. I also conclude from that evidence that omega-3 fatty acids may reduce the risk of cardiac arrhythmias.

In conclusion, there is near consensus, if not total agreement, among all scientists who have published research in the peer-reviewed literature that there is significant scientific agreement in support of the following health claims:

• Omega-3 Fatty Acids may prevent cardiac arrhythmias.
• Omega-3 Fatty Acids may prevent sudden death heart attacks.

Respectfully submitted,
William E. Connor, M.D.

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