The electrical stabilizing effect of n3 fatty acids This electrical stabilizing action of the n3 fat

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The electrical stabilizing effect of n-3 fatty
acidsThis 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.
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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.
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Adverse effects of n-3 polyunsaturated fatty
acidsThe 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.
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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.
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Effects of n-3PUFAs on the brain and nervous
systemOnce 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.
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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.
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Prevention of epileptic seizure activity by n-3
fish oil fatty acidsSo 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.
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Figure 12. Effect
of DHA (16 ?M) on INa of CA1 neurons
from an adult rat hippocampus.
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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 rats 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.
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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.
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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.
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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 GISSI-Prevenzione 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.
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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, case-control 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.
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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).
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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.
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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 n-6 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.
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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.
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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.
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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.
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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 EPADHA 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, Plt0.0001, where as at
baseline there were no differences in the means
3.4 ? 1.2 and 3.5 ? 1.2, respectively.
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In the primary analysis, according to
intent-to-treat 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 (P0.033).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.
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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.
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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.
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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.
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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.
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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 EPADHA 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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