Prevention of sudden cardiac death by n−3 polyunsaturated fatty acids

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Abstract

This is a review of our present understanding of the mechanism by which the n−3 polyunsaturated fatty acids (PUFA) in fish oils prevent fatal ventricular arrhythmias in animals and cultured heart cells. A brief review of three clinical trials that suggest that these PUFAs prevent sudden cardiac death is also included in order to emphasize the potential importance of these fatty acids in human nutrition. The PUFAs act by stabilizing electrically every cardiac myocyte by modulating conductance of ion channels in the sarcolemma, particularly the fast, voltage-dependent sodium current and the L-type calcium currents, though other ion currents are also affected. Work in progress suggests that the primary site of action of the PUFAs may be on the phospholipid bilayer of the heart cells in the microdomains through which the ion channels penetrate the membrane bilayer in juxtaposition with the ion channels rather than directly on the channel protein itself. These PUFAs then allosterically alter the conformation and conductance of the channels. Both potential benefits and possible adverse effects of the PUFAs in man will be discussed. Knowing that the ion channels have been structurally conserved among all excitable tissues, we tested their effects on the electrophysiology of rat hippocampal CA1 neurons and found that the sodium and calcium ion channels in these neurons were also affected by PUFAs. An attempt to show the place of the PUFAs in human nutrition during the 2–4 million years of our evolution will conclude the review.

Introduction

An interest in free fatty acids in relation to cardiac arrhythmias was suspected at least 50 years ago. Then, reports stated that free fatty acids, rapidly released from ischemic myocardium, might be initiating fatal arrhythmias that contribute to sudden cardiac death from acute myocardial infarction (MI). However, ∼20 years later, there were suggestions that fish oil fatty acids might prevent fatal arrhythmias in humans (Gudbjarnason & Hallgrimsson, 1975). Murnaghan (1985) reported that while saturated fatty acids added to the perfusate of isolated rabbit hearts in vitro lowered the arrhythmia threshold, the addition of polyunsaturated α-linolenic acid (ALA) raised the threshold. However, in the same year, the definitive studies showing that polyunsaturated fatty acids (PUFA), particularly those in fish oil, prevented fatal ischemia-induced arrhythmias in rats were published (McLennan et al., 1985). McLennan also reported that ∼40% of rats that were fed diets, in which the major fatty acid component could be controlled, developed intractable ventricular fibrillation (VF) when their coronary arteries were ligated after ∼3 months on a diet in which saturated fatty acids were the major source of fat. The incidence of VF was unchanged with olive oil (monounsaturated) but was reduced ∼70% when the major source of dietary fat was from vegetable oils. With tuna fish oil, he reported, sustained arrhythmias were completely prevented with or without reflow to the ischemic myocardium (McLennan, 1993). Others have repeated these findings in rats Hock et al., 1990, Yang et al., 1993, Kinoshita et al., 1994, Anderson et al., 1996. McLennan et al. (1992) confirmed their findings in marmosets. These striking findings led us to pursue the possible mechanisms of the antiarrhythmic action of fish oil.

First, a brief description of PUFAs we will be discussing may be warranted. PUFAs are essential in our diet because we cannot synthesize them. They are also essential nutrients for optimal health of the cardiovascular, nervous, and undoubtedly other organ systems. Fig. 1 shows the major fatty acids of the two classes of PUFAs, the so-called n−6 (or ω−6) and the n−3 (ω−3). Both have a long acyl chain of 18–22 carbon atoms. The designation of n−6 is based on the fact that for that class, six carbon atoms from the methyl end of the fatty acids will be the first C=C double bond. Similarly, the first C=C double bond is encountered three carbons from the methyl end for the n−3 class. The parent fatty acid of the n−6 class is linoleic acid (LA) with 18 carbons and 2 double bonds, indicated in common usage as C18:2n−6. LA can be further elongated and desaturated in our bodies to yield arachidonic acid (C20:4n−6, AA), the source of the AA cascade. Although there is commonly shown a C22:5n−6 (docosapentaenoic acid), AA seems to be the physiological end of the n−6 class.

By analogy, the parent fatty acid of the n−3 class is linolenic acid, α-ALA (C18:3n−3). It is formed in the chloroplasts of green leaves, plankton, and algae by the desaturation of C18:2n−6 (LA). Vertebrates lack the desaturase to convert n−6 to n−3 PUFA, but krill eat the plankton, fish eat the krill, and bigger fish eat the smaller fish, which is how n−3 PUFA enters the human food chain. The 20 carbon n−3 analogue of AA is eicosapentaenoic acid (C20:5n−3, EPA), the first of the important fish oil fatty acids. The other physiologically active fish oil fatty acid is the elongation and desaturation product of EPA, namely docosahexaenoic acid (C22:6n−3, DHA), which is the major storage form of n−3 PUFAs in cell membrane phospholipids of heart cells and neurons. It is the longest and most unsaturated fatty acid normally present in our diet.

In our diets today, the n−6 fatty acids are abundantly available from plant seed oils. The common cooking and table oils such as corn, sunflower seed, and safflower oils contain >70% n−6 fatty acids, namely LA. The n−3 fatty acids today come largely from marine sources, although some plants and plant oils contain ALA (e.g., soybean oil ∼8%, canola oil ∼11%, and flax seed oil ∼50%). There is a small conversion of ALA to EPA and much less continues to DHA. Furthermore, storage of ALA in cell membranes is virtually nil, as it seems largely to be metabolized for energy.

Section snippets

Clinical evidence for an antiarrhythmic effect of n−3 polyunsaturated fatty acids

It is not the purpose of this review to include the clinical effects of the n−3 fish oil fatty acids but to adhere to their pharmacological and electrophysiological actions on the heart. Nevertheless, it will be of interest to readers, who may not have followed this field, to know that there is accumulating evidence supporting the view that these PUFAs are antiarrhythmic in humans. This may justify their reading the remainder of this review. This will be a highly selected and limited inclusion

Prevention of ischemia-induced sudden cardiac death by n−3 polyunsaturated fatty acids in dogs

Initially, we wanted to see if we could confirm the findings of McLennan and Charnock. To do this, we studied a highly reliable canine model of sudden cardiac death (Billman et al., 1989). Ligating the left main coronary artery and leaving a hydraulic inflatable cuff around the left circumflex artery produced a surgically induced MI. The dogs were allowed about a month to recover from the surgery and the MI during which they were trained to run on a treadmill. The dogs were then screened for

Effects of polyunsaturated fatty acids on the contractility of cultured neonatal rat cardiomyocytes

Having confirmed the earlier work on the antiarrhythmic action of n−3 PUFA in the whole animal, we started to determine the mechanism by which the n−3 PUFAs produced their antiarrhythmic effects. To have a simple, available model to study in which we could visualize the production of arrhythmias and the possible prevention of the arrhythmias by the PUFA, we studied cultured neonatal rat cardiomyocytes (Kang & Leaf, 1994). Hearts are quickly removed from 1- or 2-day-old rat pups after

Electrophysiological effects of polyunsaturated fatty acids

The antiarrhythmic actions of the PUFAs result from their effects on the electrophysiology of cardiomyocytes (Kang et al., 1995). As seen in Fig. 5, they cause slight hyperpolarization of the resting or diastolic membrane potential and the threshold voltage for the gating of the Na+ channel becomes more positive. This results in an increased depolarizing stimulus of ∼40–50% required to induce an action potential. In addition, the refractory period, phase 4 of the cardiac cycle, is prolonged by

Possible sites of primary action of the polyunsaturated fatty acids

Thus, the modulatory actions of the PUFAs on the conductance of ion channels account for the electrical stabilization of heart cells, which result in prevention of arrhythmias. How these conduction changes are brought about at present remains unanswered. One approach to this question would be to identify the primary site of action of the PUFAs in the sarcolemma. There would seem to be at least 3 possibilities: (i) the PUFAs might interact or bind directly to the ion channel protein, affecting

Adverse effects of n−3 polyunsaturated fatty acids—real and hypothetical

The n−3 fish oil fatty acids have been a part of the human diet for 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 GRASS 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 result in clinically significant bleeding (Leaf et

Effects of n−3 fatty acids on the brain

Once we knew that the fish oil fatty acids regulated the electrical activity of the heart, we thought they must have similar effects on other excitable tissues (i.e., neurons and muscles) since they all share the same electrical communication system and much homology has been preserved among the ion channels of excitable tissues. Therefore, with our colleagues in the Netherlands, we studied the effects of the n−3 PUFAs on the sodium and calcium currents in CA1 neurons freshly isolated from the

As an aspect of human nutrition during human evolution

Finally, let us try to put the n−3 fatty acids into the larger picture of human nutrition. This was an attempt to utilize the methods of evolutionary medicine to find the place of the n−3 PUFAs in human nutrition (Leaf & Weber, 1987). Admittedly, the method in this case is very crude, but our best estimates suggest that these fatty acids were once present in human diet in amounts nearly as large as were the other or n−6 class of PUFAs. This was during the 2–4 million years of human existence,

Conclusions

It is apparent that there exists a basic control of cardiac and other excitable tissues by common dietary fatty acids, which has been largely overlooked. With ∼250,000 or more sudden cardiac deaths annually, largely from VF in the USA alone and millions more worldwide, there may be a potential large public health benefit from this recent understanding. The knowledge that these fatty acids have direct physical effects on the fundamental property of the nervous system, namely its electrical

Acknowledgements

Studies from the authors' laboratories have been supported in part by research grants DK38165 from NIDDK and by HL62284 from the HLBI of the National Institutes of Health of the U.S. Public Health Services.

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