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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
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
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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
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The
-3 polyunsaturated fatty acids (PUFAs) prevent
fatal cardiac ventricular ischemia-induced
arrhythmias in animals1 2 3 4 5 6 7 8 9 and probably in
humans.10 11 12 13 14 15 McLennan et al1 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 reported8 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.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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)(Rn-Rn-1,
s)-1/2.20
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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).
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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.
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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.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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 acids8 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 ICaL prevents the excessive
cytosolic Ca2+
fluctuations35 38 responsible for many "triggered
arrhythmias" initiated by delayed afterpotentials. The
suppression of INa 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
(INa), 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.
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Acknowledgments |
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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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R. N. Lemaitre, I. B. King, T. E. Raghunathan, R. M. Pearce, S. Weinmann, R. H. Knopp, M. K. Copass, L. A. Cobb, and D. S. Siscovick Cell Membrane Trans-Fatty Acids and the Risk of Primary Cardiac Arrest Circulation, February 12, 2002; 105(6): 697 - 701. [Abstract] [Full Text] [PDF]
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