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(Circulation. 1999;99:2452-2457.)
© 1999 American Heart Association, Inc.

Basic Science Reports

Prevention of Sudden Cardiac Death by Dietary Pure -3 Polyunsaturated Fatty Acids in Dogs

George E. Billman, PhD; Jing X. Kang, MD, PhD; Alexander Leaf, MD

From the Department of Physiology, The Ohio State University, Columbus, Ohio (G.E.B.) and Departments of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Mass (J.X.K., A.L.).

Correspondence to Alexander Leaf, MD, Massachusetts General Hospital, East, Building 149, 13th St, Charlestown, MA 02129. E-mail leaf.alexander1{at}mgh.harvard.edu

	Abstract

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Background—Rat diets high in fish oil have been shown to be protective against ischemia-induced fatal ventricular arrhythmias. Increasing evidence suggests that this may also apply to humans. To confirm the evidence in animals, we tested a concentrate of the free fish-oil fatty acids and found them to be antiarrhythmic. In this study, we tested the pure free fatty acids of the 2 major dietary -3 polyunsaturated fatty acids in fish oil: cis-5,8,11,14,17-eicosapentaenoic acid (C20:5-3) and cis-4,7,10,13,16,19-docosahexaenoic acid (C22:6-3), and the parent -3 fatty acid in some vegetable oils, cis-9,12,15--linolenic acid (C18:3-3), administered intravenously on albumin or a phospholipid emulsion.

Methods and Results—The tests were performed in a dog model of cardiac sudden death. Dogs were prepared with a large anterior wall myocardial infarction produced surgically and an inflatable cuff placed around the left circumflex coronary artery. With the dogs running on a treadmill 1 month after the surgery, occlusion of the left circumflex artery regularly produced ventricular fibrillation in the control tests done 1 week before and after the test, with the -3 fatty acids administered intravenously as their pure free fatty acid. With infusion of the eicosapentaenoic acid, 5 of 7 dogs were protected from fatal ventricular arrhythmias (P<0.02). With docosahexaenoic acid, 6 of 8 dogs were protected, and with -linolenic acid, 6 of 8 dogs were also protected (P<0.004 for each). The before and after control studies performed on the same animal all resulted in fatal ventricular arrhythmias, from which they were defibrillated.

Conclusions—These results indicate that purified -3 fatty acids can prevent ischemia-induced ventricular fibrillation in this dog model of sudden cardiac death.

Key Words: fatty acids • death, sudden • diet

	Introduction

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The -3 polyunsaturated fatty acids (PUFAs) prevent fatal cardiac ventricular ischemia-induced arrhythmias in animals^{1 2 3 4 5 6 7 8 9} and probably in humans.^{10 11 12 13 14 15} McLennan et al^{1 2 3} showed that rats fed a diet in which the major lipid constituent was saturated fatty acids suffered some 43% mortality from fatal ventricular fibrillation (VF) in response to the subsequent ligation of their coronary arteries. When the dietary fat was olive oil (monounsaturated fatty acids), there was no significant reduction in fatal VF. When sunflower seed oil was administered, there was a significant reduction of some 70% in fatal arrhythmic deaths, but when tuna fish oil was fed, the fatal arrhythmias were prevented whether the ligature remained on the coronary arteries or reflow occurred. They essentially confirmed the antiarrhythmic effects of the fish oil in a nonhuman primate (marmosets).³ Others have reported similar results in rats.^{4 5 6 7}

To find whether we could confirm these striking results, we studied a canine model of cardiac sudden death in which dogs are surgically prepared by ligation of their left anterior coronary artery, producing an anterior left ventricular infarction. A hydraulic cuff was placed around the left circumflex coronary artery (LCA) so that the vessel could be occluded later. The dogs are allowed a month to recover from the infarction and surgery, during which they are taught to run on a treadmill. The sympathetic stimulation resulting from the exercise plus the additional ischemia induced by occlusion of the LCA regularly produces reproducible sustained ventricular tachycardia or VF in some 60% of these dogs.^{16 17 18} Using this model, we have reported^{8 9} the effects of infusing an emulsion of a concentrated fish oil free -3 fatty acid intravenously just before the exercise-ischemia-stress test. In 10 of 13 dogs tested, the fish oil preparation prevented the fatal VF, compared with a control identical infusion of phospholipid emulsion of soybean oil (P<0.005), demonstrating that it was the fish oil that possessed the antiarrhythmic action, and not other possible confounding effects inherent in prolonged dietary studies. The present study was undertaken to determine which of the possible -3 fatty acid constituents of fish oil might be responsible for the antiarrhythmic actions of the -3 class of essential dietary PUFAs. We report that in this canine preparation, the 2 major dietary constituent -3 PUFAs, cis-5,8,11,14,17-eicosapentaenoic acid (C20:5-3, EPA) and cis-4,7,10,13,16,19-docosahexaenoic acid (C22:6-3, DHA) in fish oils, as well as the parent -3 PUFA present in some vegetable oils, cis-9,12,15--linolenic acid (C18:3-3, LNA) proved to be essentially equally antiarrhythmic when infused intravenously as the free fatty acid either as a phospholipid emulsion or carried on serum albumin.

	Methods

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Fifty-two mongrel dogs (15.4 to 20.9 kg) were used in this study. The surgical preparation of the dogs has been described in previous publications.^{16 17 18} Briefly, the dogs were anesthetized and instrumented to measure LCA blood flow and ventricular electrograms. A hydraulic occluder was placed around the LCA, and the left anterior coronary artery was ligated, producing an anterior-wall myocardial infarction. Fourteen dogs died suddenly within the first 72 hours after the coronary artery ligation. Two additional animals could not be classified (see below) because of the rupture of the hydraulic occluder and were therefore eliminated from the study.

The principles governing the care and treatment of animals as expressed by the American Physiological Society were followed at all times during this study. In addition, the procedures used in this study were approved by the Ohio State University Institutional Animal Care and Use Committee.

Experimental Protocol
The studies began 3 to 4 weeks after the production of the myocardial infarction. The animals were walked on a motor-driven treadmill and adapted to the laboratory during this period. Their susceptibility to VF was tested, as previously described.^{16 17 18} Briefly, the animals ran on a motor-driven treadmill while workload was increased every 3 minutes for 18 minutes or until a criterion heart rate of 210 bpm (70% of maximum) was attained. During the last minute of exercise, the LCA was occluded, the treadmill was stopped, and the occlusion was maintained for an additional minute. The dogs were defibrillated promptly, but only after the animal was unconscious (10 to 20 seconds after VF began). Twenty-two animals (susceptible) developed VF during the exercise plus ischemia test, but the remaining 14 (resistant) did not. The resistant animals were excluded from the study. Five animals were not successfully resuscitated. Thus, studies were completed on 17 animals identified as susceptible to VF, and 6 of the dogs were studied twice, with a different fatty acid used on each occasion.

One week later, the exercise-plus-ischemia test was repeated after the following treatments: an intravenous infusion of 1 the following purified -3 fatty acids: EPA (n=7, 20:5-3; 98.4% free EPA, 1.1% free DHA; Pronova-Biocare, A/S), DHA (n=8, 22:6-3; 90.8% free DHA, 0.9% EPA; Pronova-Biocare, A/S), or LNA (n=8, >99% LNA; Nu-Check-Prep, Inc). In all experiments, the 1.0 mL or 0.86 g of LNA was prepared in 100 mL normal saline with 10 g purified delipidated BSA (Sigma Chemical Co), and the pH was adjusted with sodium hydroxide to 7.6 to 8.0. Four of the 7 experiments with EPA and 5 of the 8 experiments with DHA were similarly administered (0.86 g carried on albumin). In the remaining 3 experiments with EPA or with DHA, 5 mL of the pure fatty acid was administered as egg lecithin emulsions, as previously reported.^{8 9} The mixtures were briefly sonicated to yield an opalescent and stable suspension. The preparation was infused slowly over 90 minutes just before the exercise-plus-ischemia test.

Finally, 1 week after the completion of each -3 fatty acid study, a second control exercise-plus-ischemia test was repeated after an infusion of either a lipid emulsion prepared from soybean oil (n=7, Intralipid, Clinetic Nutrition Co) or saline (n=10).

All data were recorded on a Gould model 2800S 8-channel chart recorder and a Teac model MR-30 cassette FM tape recorder. The following data were obtained: LCA blood flow and a ventricular electrogram from which heart rate was determined with a Gould biotachometer. Coronary blood flow was measured with a University of Iowa model 545C pulsed Doppler flowmeter and was used to verify complete LCA occlusion. Hemodynamic data were averaged for periods of 5 seconds during the last minute of each exercise level, immediately before coronary occlusion, and at the 60-second time point (or immediately before VF) during the occlusion. Fatty acid concentrations in the nonesterified, triglyceride, and phospholipid fractions of plasma were determined by conventional methods, as reported from this laboratory.¹⁹

The data were analyzed by a 2-factor (drugxocclusion) ANOVA for repeated measures. When the F ratio was found to exceed a critical value (P<0.05), Scheffé's test was used to compare the means. The effects of the infused -3 fatty acids on susceptibility to VF were determined by Fisher's exact test. All data are reported as the mean±SEM. Cardiac arrhythmias were analyzed at a paper speed of 25 mm/s. PR interval and QTc were analyzed at 100 m/s before and at the end of the infusion of the -3 fatty acid emulsion. QT interval (QTc) was corrected for heart rate by the Bazett formula, ie, QTc=(QT, ms)(R_n-R_n-1, s)^-1/2.²⁰

	Results

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As in previous studies,^{8 9 16 17 18} ventricular flutter (which degenerates into VF) was reproducibly induced with each presentation of the control (ie, either saline or soybean oil infusion) exercise plus ischemia tests. The average time to ventricular flutter onset was 59.6±4.2 seconds (range, 42.0 to 104 seconds) for the first control occlusion and 55.2±4.4 seconds (range, 24.0 to 101 seconds) for the second control occlusion. The 2 control exercise plus ischemia tests also elicited similar changes in heart rate (first occlusion: control, 207.1±8.6 and occlusion, 225.6±9.5 bpm; second occlusion: control, 203.8±11.6 and occlusion, 234.8±10.1 bpm).

Representative recordings obtained from the same animals before and after pretreatment with the -3 fatty acid emulsion are displayed in the Figure. In contrast to the control occlusion, EPA, DHA, or LNA significantly reduced the incidence of ventricular flutter-fibrillation, protecting 5 of 7 (P=0.0105), 6 of 8 (P=0.0035), and 6 of 8 (P=0.0035) animals, respectively. In contrast, the control lipid emulsion of triglycerides of soybean oil containing some 7% to 8% esterified LNA (Intralipid, n=7) failed to protect any animal from malignant arrhythmias (Figure, panel D).

View larger version (28K): [in this window] [in a new window]   Figure 1. Representative experiments demonstrating preventive effect of pure -3 long-chain PUFAs on fatal ischemia-induced ventricular flutter or VF. A, B, and C show control exercise-ischemia test and response 1 week later to same protocol after administration of EPA, DHA, or LNA, respectively, just before stress. D is control with soybean oil, which was performed 1 week after tests with -3 fatty acids on each dog. Note that in all controls, exercise-ischemia test resulted in ventricular flutter, which long experience has shown rapidly degenerates into VF. Defibrillation permitted following test of -3 fatty acids a week later, followed after a further week by final control for that dog experiment. Black tracings are periods during which recording paper rate was slowed to condense tracing. Black tracings after release of occlusion have a similar explanation and are not due to nonsustained arrhythmias; period of occlusion is too short to cause reflow phenomena. Horizontal bar to right of each control is time marker and represents 1.0 second for each set of tracings.

The effects of the purified -3 fatty acids on resting hemodynamic parameters are displayed in Table 1. Importantly, and in contrast to our previous studies with infusions of phospholipid emulsions of fish oil free fatty acids, pure EPA, DHA, or LNA did not significantly alter the resting, preexercise heart rate, PR interval, or QTc interval.

View this table: [in this window] [in a new window]   Table 1. Effect of -3 Fatty Acids on Resting Hemodynamic Parameters

Finally, plasma -3 fatty acid levels were determined before and after the infusion of the emulsions or albumin solutions. Blood was obtained from 3 dogs before and after intravenous infusion of 1 mL of pure LNA carried on 10 g of delipidated albumin. Because of transportation and laboratory difficulties, however, we were unfortunately able to obtain results on only 1 animal that lacked the prior cardiac infarction. These infusions elicited a significant increase in the nonesterified fatty acid fraction of each of the fatty acids infused, with only a small but significant increase (P<0.05) in the triglyceride fraction and none detectable in the phospholipid fraction (Table 2). This is consistent with our evidence that only the PUFAs in the free, nonesterified form are antiarrhythmic.²¹ Once incorporated into the phospholipids in cardiac cell membranes, they have no antiarrhythmic effects until once again liberated by phospholipases. It is important to remember that these reported values of nonesterified fatty acid do not represent the concentration of free monomeric fatty acids in plasma water, because >99.9% will be carried bound to albumin and proteins.

View this table: [in this window] [in a new window]   Table 2. Changes in Fatty Acid Composition of Six Dietary PUFAs in Plasma Lipid Fractions With Infusion of the Pure PUFAs

	Discussion

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There is growing, but still inadequate, evidence that long-chain -3 fatty acids may be antiarrhythmic in humans.^{10 11 12 13 14 15} For this reason, we turned to animal and laboratory studies to determine (1) whether we could confirm the evidence from animal studies that fish or fish oil could prevent ischemia-induced fatal VF, then (2) which specific fatty acids were antiarrhythmic and (3) a plausible physiological or biochemical mechanism to explain the antiarrhythmic cardiac effects of these fatty acids. We have done this to provide a rational and compelling basis for essential clinical trials.

In this study, we show that the 3 most common dietary PUFAs of the -3 class are all potent antiarrhythmic agents when infused intravenously just before the exercise-plus-ischemia stress in this reproducible dog model of cardiac sudden death. When infused as the free fatty acids carried physiologically largely on albumin, the free fatty acids are delivered in seconds directly to the cardiac phospholipid membranes, where they are in place to exert their antiarrhythmic potential. When they are ingested in the diet, however, the situation is different and circuitous. They are ingested largely as triglycerides and absorbed as free fatty acids and monoglycerides but are rapidly and efficiently resynthesized in gut wall and liver back to triglycerides. They appear in the circulation largely in chylomicrons and LDLs, from which they are liberated in the periphery and liver by lipoprotein and hepatic lipases and then picked up on the fatty acid binding sites of serum albumin. They are carried on the albumin to membrane phospholipids of heart, brain, and other tissues, into which they very rapidly partition. There they are preferentially incorporated into membrane phospholipids and stored triglycerides. In these storage forms, they are not antiarrhythmic.²¹ But with ischemia, severe exertion, or major sympathetic adrenergic discharge, phospholipases and lipases quickly liberate the stored fatty acids, especially the -3 PUFAs,^{22 23} and these PUFAs, in their free form, can prevent the arrhythmias.²⁴ Infusing the PUFAs intravenously simply bypasses this more circuitous route of delivery. If ingested on a regular basis, they will be present in the stored forms to be available when needed. The problem confronting us on the modern Western diet is that the -3 PUFAs have been gradually disappearing from our diets,²⁵ and if they are not available in the stored lipids, no protection can be afforded and mortality is very high.²⁶

This distinction in the routes of delivery requires a further consideration. Although LNA, as we report, was equally effective as pure EPA or DHA, when administered intravenously, does not necessarily mean that it will also be equally antiarrhythmic when ingested. If the amount of stored -3 PUFAs determines the availability of their free form in times of stress, then we must consider the ability of dietary LNA versus the fish-oil EPA and DHA to increase the stored forms of -3 PUFAs in the heart and other tissues, including adipocytes. DHA is clearly the normal, preferred storage form of -3 fatty acids in heart and brain, where it can account for a large percentage of the fatty acids incorporated into the sn-2 position of membrane phospholipids. LNA, however, is largely metabolized and results in lesser net storage of -3 PUFAs.^{27 28} LNA has other beneficial effects, so that the antiarrhythmic effects of dietary LNA compared with EPA plus DHA will need to be resolved by clinical trials. For taste, odor, and greater resistance to auto-oxidation than EPA and DHA, LNA has important, desirable characteristics compared with the fish-oil fatty acids, EPA and DHA.

What makes the -3 PUFAs favored antiarrhythmic agents? McLennan³ reported that in his rat studies, when the major dietary fat was sunflower seed oil (77% linoleic acid, <1% LNA) there was some 70% reduction in fatal VF when coronary arteries were ligated compared with diets high in saturated or monounsaturated fats. We have confirmed that the -6 as well as the -3 PUFAs are antiarrhythmic.²⁴ The problem is that arachidonic acid (C20:4-6) in the presence of active cyclooxygenase is oxygenated to thromboxane A₂ and prostaglandins, all of which (except prostacyclin) are arrhythmogenic to varying degrees, whereas the metabolites of EPA are not.²⁹ For this reason, we have recommended the -3 PUFAs for clinical usage.

In this study, all the free fatty acids were infused carried on albumin, their main physiological plasma transporter, not just as emulsions of phospholipid vesicles or aggregates as in our earlier dog studies.^{8 9} Each albumin molecule has been shown by NMR spectroscopy to contain binding sites for free fatty acids.³⁰ There are an estimated 8 to 10 fatty acid molecules that may bind per molecule of albumin.³¹ This would mean that the 10 g of albumin solution we infused could "carry" some 1.5 mmol of the 2.6 mmol of DHA represented in the 0.86 g pure DHA administered. The remaining unbound 1.1 mmol in the limited 100-mL volume of infusate would exceed the critical micellar concentration and form lamellar aggregates.³² But once in the circulation, these aggregates would rapidly give up their free fatty acid load to surrounding cells or commingle and bind to the endogenous circulating plasma albumin of the dog, which in the postabsorptive state carries only some 0.5 to 1.5 mmol fatty acids per molecule of albumin. Thus, the hemolysis observed with phospholipid emulsions loaded with free fatty acids^{8 9} was largely avoided with the albumin infusions. However, the resulting plasma volume expansion can constrain the quantities of albumin that can be safely administered. In a 20-kg dog, the 10 g of albumin would expand the intravascular volume acutely by some 20%. In an animal or human with a compromised cardiovascular system, this might induce acute congestive heart failure.

As seen in Table 1, several of the functional cardiovascular effects we reported as prominent features in the earlier dog experiments, which were performed by infusing generally 5.0 mL of the free fatty acid concentrate of the fish-oil PUFAs in a phospholipid emulsion,^{8 9} ie, the slower resting pulse rate and the prolonged PR and shortened QTc intervals, did not occur with the lower 1.0 mL of the pure PUFAs carried on albumin. Whether this is a dose effect, some other factor in the fish oil concentrates, or the hemolysis resulting from the lytic effect of the free fatty acid emulsion we do not know, but the albumin carrier seems to be a safer method of administering the free fatty acids intravenously, should that ever be necessary in an emergency.

We now have learned a great deal about the mechanism by which these PUFAs exert their antiarrhythmic effects.^{24 33 34 35 36 37 38 39 40} Simply by partitioning into the membrane phospholipids of every myocyte in the heart without covalently binding to any membrane constituent,²⁴ they affect the electrophysiology of each myocyte to make it resistant to arrhythmias.^{33 38} They accomplish this by modulating the conduction of several membrane ion channels.^{34 35 36} At present, we think that the suppression of the L-type Ca²⁺ and voltage-dependent Na⁺ currents are most important, and both begin to show inhibition at very low ambient concentrations of PUFAs (10 to 20 nmol/L).^{34 35 36} Inhibition of I_CaL prevents the excessive cytosolic Ca²⁺ fluctuations^{35 38} responsible for many "triggered arrhythmias" initiated by delayed afterpotentials. The suppression of I_Na markedly prolongs the inactivated state of the Na⁺ channel, with shift of the steady-state inactivation to more negative potentials.^{34 36} This latter action is important, we think, to protect the heart from ischemia-induced arrhythmias. In ischemic zones of myocardium, partially depolarized cells are potential arrhythmogenic risks. Their resting membrane potentials are closer to the threshold for the gating of the sodium current (I_Na), so that any further small depolarizing stimulus, if it occurs during a vulnerable time in the electrical cycle of the heart, may set off an arrhythmia. But because of the strong voltage-dependence of the shift of the steady-state inactivation to more negative potentials, these ischemic myocytes are quickly eliminated from further activation,^{36 40} while myocytes in the nonischemic myocardium continue their normal function.

In conclusion, the 3 major dietary -3 fatty acids are demonstrated to be potent antiarrhythmic agents for the prevention of ischemia-induced fatal ventricular arrhythmias in this dog model of cardiac sudden death (Table 3 summarizes all our dog studies). It is apparent that a basic control of cardiac function by common dietary fatty acids exists that has been largely overlooked. The -3 PUFAs have been part of the human diet for some 2 to 4 million years²⁵ and are safe.¹⁹ With some 250 000 sudden cardiac deaths annually, largely due to VF, in the United States alone²⁶ there may be a potential large public health benefit from the practical application of this recent understanding.

View this table: [in this window] [in a new window]   Table 3. Prevention of Ischemia-Induced Fatal Ventricular Arrhythmias by -3 Polyunsaturated Fatty Acids in a Dog Model of Sudden Cardiac Death

	Acknowledgments

 
This study was supported in part by a grant from the American Heart Association, Ohio Affiliate, and the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, grant DK-38165. We thank Pronova Biocare, Lysaker, Norway, for their gift of the pure fish oil preparations and the Flax Council of Canada for the pure -linolenic acid used in this study.

Received October 19, 1998; revision received December 31, 1998; accepted January 15, 1999.

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