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The electrical stabilizing effect of n-3
fatty acids
This electrical stabilizing action of the n-3
fatty acids can be demonstrated by a simple
experiment. Fig. 10 shows a continuous
tracing of the contraction of a single myocyte
in a clump of myocytes on a microscope
coverslip. Initially the myocyte is contracting
regularly. Two platinum electrodes were
placed across the cover slip with their tips
dipped into the fluid perfusing the heart cells
and connected to a voltage source. At
stimulating electrical currents delivered at 15
volts it was possible to double or triple the
spontaneous beating rate.
In considering clinical applications of the n-3
fish oil for prevention of fatal arrhythmias one
should think broadly of the possibilities. We
have shown that our experimental studies
indicate that it probably does not matter what
the underlying cause of the arrhythmia is.
Cytosolic calcium overload as well as
ischemia can cause serious arrhythmias.
Other causes of arrhythmias may well also
benefit from the administration of these n-3
fish oil fatty acids. Administration can be
orally for prophylaxis or intravenously in
arrhythmic emergencies.
Adverse effects of n-3 polyunsaturated
fatty acids
The n-3 fish oil fatty acids have been part of the
human diet for hundreds of thousands of years.
Aside from a rare person with an idiosyncratic
sensitivity to them, they are generally safe. The
FDA has approved the consumption of 3.5 g of
fish oil daily and this is on the GRAS list
(Generally Regarded As Safe). At these daily
intakes a person might bruise more readily, than
usual, especially if concomitantly taking aspirin,
but this does not seem to cause clinically
significant bleeding. There may be some transient
GI discomfort or complaints of the fishy taste
when taking fish oil supplements.
A recent publication has raised the possibility of
potentially serious adverse effects in subjects
with chronic and probably extensive cardiac
disease. At present we can only speculate on
the cause of the increased deaths Burr observed
in subjects with “chronic angina”, whom he had
advised to eat more oily fish. Perhaps this is
related to the way the n-3 fatty acids inhibit the
sodium current in partially depolarized heart
cells, as discussed Our Hypothesis. By
eliminating the function of partially depolarized
cardiomyocytes, as shown in Fig. 7, they
prevent their potential proarrhythmic effects.
Effects of n-3PUFAs on the brain and
nervous system:
Once we knew that the n-3 fatty acids of fish
oil modulated the ionic currents in heart
cells, we expected they would do the same in
other excitable tissues, such as the brain
and nervous systems. To find someone who
was an expert on the nervous system we
went to see a distinguished expert in the
Department of Neuroscience at the Harvard
Medical School.
The reason I present this experiment is that it
illustrates a very important point. It shows that
these fish oil fatty acids have the potential to
markedly reduce the extent of brain damage that
follows a stroke. It is the hyperactivity of the brain
cells, which occurs in the ischemic brain tissue,
which exhausts the supply of ATP within the
neuronal cells, that results in the death of the
neurons, just as we saw in our experiment with the
heart following an acute myocardial infarction. Fatty
acids have been shown to rapidly penetrate through
the membranes of the blood brain barrier by
nonionic diffusion. So one would only need to inject
the n-3 fish oil fatty acids carried on serum albumin
into the blood stream to reduce the brain damage
following a stroke.
Prevention of epileptic seizure activity by
n-3 fish oil fatty acids:
So I flew to Holland where the University of
Amsterdam has a large, active Epilepsy Institute.
Professor Wadman was interested to test the
effect of the fish oil fatty acids on the
electrophysiology of CA1 hippocampal neurons,
in which most epileptic seizures are initiated.
It is the practice in patients with severe and
relentless, continuous seizure activity to have a
neurosurgeon remove the offending hippocampal
neurons. This is done by entering the brain
through the neo-cortex with a hollow needle and
aspirating tissue sampling the tissue down
through the hippocampal neurons.
Figure 12.
Effect of DHA
(16 M) on INa of
CA1 neurons
from an adult rat
hippocampus.
Then I went to Leyden, where Dr. Voskul had a
highly reliable rat model in which he could induce
seizure activity electrically. We found that in this
animal model that EPA, administered via a tail
vein reduced the minimal electrical current to
cause the first indication of increased
hyperactivity, which was manifest by
spontaneous twitching of the rat’s whiskers and
also the electrictical activity to prevent a full
epileptic seizure – see Figure 13. I never had the
opportunity to test the possibility that the fish oil
fatty acids would prevent seizure activity in
patients with epilepsy, but at least we had found
that they had potentially beneficial effects on the
brain, as we had expected.
Clinical evidence of cardiac benefits:
While these studies on the basic mechanism by
which the fish oil fatty acids may prevent fatal
ventricular arrhythmias were in progress, a few
clinical studies and many epidemiologic
observations on the antiarrhytmic action of the
n-3 fatty acids were made. A few selected
examples are provided.
The first clinical trial was published in 1989.
It was a randomized controlled trial with a
factorial design to see if in 2033 men dietary
advice on fat, fish or fiber is beneficial in the
secondary prevention of myocardial infarction
(MI). No benefits accrued from the fat and fiber
advice.
More recently another clinical trial was
reported, “Dietary supplementation with n-3
polyunsaturated fatty acids and vitamin E
after myocardial infarction: results of the
GISSI-Prevenzione trial”. This was a large,
prospective, randomized, clinical trial of
11,324 patients who had a recent myocardial
infarction. They were randomly assigned to
four equal groups to test the effects of a daily
dose of one capsule of 850 mg EPA +DHA,
300 mgs of vitamin E, n-3 PUFA plus vitamin E
and a control group receiving neither. This
was on top of optimal pharmacological
treatment and lifestyle advice.
This study was reanalyzed and subsequently
again published as the “Early protection against
sudden cardiac death by n-3 polyunsaturated
fatty acids after myocardial infarction: Time
course analysis of the results of the GISSIPrevenzione” in 2002. This reanalysis showed
the reduction in risk of sudden cardiac death
was nearly significant at 3 months accounting
for 67% of the overall mortality benefit, became
significant at 4 months, and was highly
significant at 3.5 years, the end of the study,
when it accounted for 59% of the n-3 PUFA
advantage in mortality.
More recently the data in the Physicians’ Health
Study has been examined to test whether n-3 fatty
acid consumption would reduce the risk of sudden
death in subjects without a history of preexisting
cardiovascular disease. A prospective, nested, casecontrol analysis among apparently healthy men who
were followed for 17 years in the Physicians’ Health
Study was, retrospectively, conducted. 94 men were
identified in whom sudden cardiac death occurred
as the first manifestation of cardiovascular disease.
184 controls were matched with them for age and
smoking status. The fatty acid composition of
blood, which had been collected at baseline on all
subjects, was determined.
These encouraging reports led us to
hypothesize that these long-chain n-3
fatty may prevent ventricular arrhythmias
in high-risk patients. To test this
hypothesis four hundred two patients
with implanted cardioverter-defibrillators
(ICDs) who were at high risk for fatal
ventricular arrhythmias were enrolled at
18 collaborating centers into our Fish oil
Anti-arrhythmia Trial (FAAT).
Subjects were included who had an ICD
implanted because of a history of cardiac arrest,
sustained VT, or syncope with inducible VT/VF
during electrophysiologic studies. The
qualifying ICD must have been implanted within
12 months prior to entry into the study or the
patient had at least one spontaneous ICD event
for VT/VF in the preceding 12 months. Enrollees
were randomized in a double-blinded, controlled
fashion to either four 1.0 gelatin capsules of an
ethyl ester concentrate of n-3 fatty acids (total
daily dose of 2.6 g) or to four 1.0 g capsules of
olive oil of identical appearance for 12 months.
At baseline, clinical data and blood samples were
collected and subjects were told to eat no more than
2 fish meals in a month and to use olive oil rather
than the common plant seed oils (corn oil,
sunflower seed oil, etc.) for dressings for salads and
other such uses. The recommendation to use olive
oil is emphasized. 87% of enrollees indicate they
had adhered to our advised diet for the duration of
the trial. Substituting olive oil, which contains no n6 fatty acids makes it like the Mediterranean diet,
which reduces the n-6/n-3 ratio and favors the
action of whatever amount of n-3 fatty acids are
contained in the diet. This may account for the
beneficial effects of fish oil fatty acids in this study
but a lack of any benefit in another very recent
study.
Subjects were asked to report at 3-month
intervals to their respective medical centers
to have their ICD reports collected and have
blood samples drawn. The ICD reports were
then submitted to a Core Electrophysiology
Laboratory to have their ICD interpreted by
two or more cardiac electrophysiologists
blinded to the patients’ treatment. The blood
samples were separated into plasma and
packed cells, kept frozen at –70 to –80 oC and
mailed to the Massachusetts General
Hospital where the red cells were analyzed
for their phospholipid content of fatty acids.
The Core EP Laboratory was responsible for
endpoint confirmation. All reports showing
arrhythmias and a random selection of negative
reports were viewed by at least two
electrophysiologist. Wherever disagreement
occurred they were interpreted by a third. Each
made his/her interpretation blinded to the
supplement and the interpretation of the other
electrophysiologists. The agreement between
two of the interpretations was the accepted
interpretation. “Confirmed events” were defined
as spontaneous episodes of VT and/or VF
causing ICD discharges for which intra-cardiac
electrograms were available.
All randomized patients were included in the
intention to treat analysis. The primary analysis,
based upon confirmed events, was an intention to
treat analysis of the survival free of appropriate ICD
events for VT/VF and /or death from any cause.
Secondary analyses were performed including
“probable events” as defined. The intention-to-treat
analysis included all confirmed ICD events during
the 12 month period after the first dose of the study
drug was taken, irrespective of the duration of
treatment. Two “on treatment” analyses were done
The first included all ICD reports that occurred no
later than two months after the treatment was
stopped. The “second on treatment” analysis was
limited to those who were compliant for the duration
of the trial.
One hundred forty two subjects (35% of enrollees)
discontinued their prescribed supplements before
completing their year in the trial. Time to
discontinuation did not differ significantly
between the two arms. In our intent-to-treat
analysis, all these individuals who discontinued
their supplements are included. Among patients
who had blood levels analyzed at their last visit
the 110 randomized to fish oil had a significantly
higher content of EPA+DHA as percent of the total
fatty acids in the phospholipids of red blood cells
compared with the 119 receiving olive oil (mean
level  SEM = 7.6  0.3 vs. 3.5  0.1, P<0.0001,
where as at baseline there were no differences in
the means 3.4  1.2 and 3.5  1.2, respectively.
In the primary analysis, according to intent-totreat there was a trend toward a longer time to
the first ICD event for VT/VF confirmed by
electrograms or death from any cause among
patients randomized to fish oil compared with
those randomized to olive oil, but the difference
was not significant (P= 0.057). When “probable
events” were added to the endpoint, the
reduction in risk became significant; (P=0.033).
In the “on treatment” analysis of “confirmed”
events, which included all who had taken any
prescribed oil supplement during the 12 months
there were no significant differences between
the two arms of the trial.
Our results are consistent with the beneficial
antiarrhythmic effects of n-3 fatty acids reported
in animal and laboratory studies and earlier
clinical trials. Therefore, these data suggest that
these n-3 fatty acids may provide an alternative
to antiarrhythmic drugs for reducing VT/VF in
patients. The 38% reduction in the combined
end points that included probable VT/VF is
smaller, but comparable to the 44% reduction
observed with Sotalol, a type III antiarrhythmic
drug. However, unlike pharmaceutical
antiarrhythmic drugs, the n-3 fatty acids have
not been demonstrated to have proarrhythmic
properties and are not toxic.
With some 300,000 to 400,000 deaths annually from
fatal ventricular arrhythmias in the USA alone and
millions more worldwide these deaths constitute a
significant public health failure. What others and we
have found for the effects of fish oil fatty acids to
prevent fatal cardiac arrhythmias seems to have the
potential for considerable public health benefits.
Despite the hundreds of millions of dollar, which the
pharmaceutical industry has spent trying to develop
an antiarrhythmic drug, none has yet been produced
which is both safe and effective. The fish oil fatty
acids, by contrast, have been part of the human diet
for hundreds of thousands of years and they are
safe. They also are as effective as the best of the
pharmaceutical antiarrhythmic drugs.
Do fish oil fatty acids prevent
atherosclerosis?
Why do clinical trials fail to demonstrate an
antiatheroclerotic action, whereas they
show potent antiarrhythmic effects?
It has been shown that the polyunsaturated
fatty acids cause many biochemical,
biophysical and physiologic effects in
animals and humans, which would be
expected to prevent atherosclerosis. They
do not, however, show antiatherosclerotic
effects in short term studies in humans.
Inuits and Japanese, who have a lifelong
intake of fish and fish oils, have a low
incidence of atherosclerotic changes in their
arteries. This has been shown repeatedly.
By contrast in short term studies of the
administration of fish oil fatty acids prevention
of the atherosclerotic process is not observed.
This shows in the Burr clinical trial of 1989 and
the GISSI Prevenzione of 2001, both of which
showed a reduction in fatal ventricular
arrhythmias (SCD) but with no reduction in
new myocardial infarctions with fish oils.
We may conclude that the evidence has been
strengthened that fish oil fatty acids can prevent
sudden cardiac death in humans. The evidence
today supports the recommendations of the
American Heart Association that everyone should
be having at least 2 meals weekly of fatty fish to
maintain a healthy heart. For those that have
coronary heart disease, had an MI, or have a family
history among close relatives including ventricular
arrhythmias, they should, in addition, be taking a
fish oil supplement of at least 1.0 g of EPA+DHA
regularly daily. We can go a step further to add that
to obtain maximal benefit from the amount of n-3
fish oil fatty acid ingested, it is necessary
simultaneously to reduce the n-6 plant seed oils in
the diet.
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