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Prevention of cardiac arrhythmia by dietary (n-3)
polyunsaturated fatty acids and their mechanism of
action
Nair S.S.D.; Leitch J.W.; Falconer J.; Garg M.L.
Australia
Journal of Nutrition (USA), 1997, 127/3
(383-393)
The role of marine fish oil (n-3) polyunsaturated fatty
acids in the prevention of fatal ventricular arrhythmia has
been established in experimental animals. Prevention of
arrhythmias arising at the onset of ischemia and reperfusion
is important because if untreated, they result in sudden
cardiac death. Animals supplemented with fish oils in their
diet developed little or no ventricular fibrillation after
ischemia was induced. Similar effects have also been observed
in cultured neonatal cardiomyocytes. Several mechanisms have
been proposed and studied to explain the antiarrhythmic
effects of fish oil polyunsaturated fatty acids, but to date,
no definite mechanism has been validated. The sequence of
action of these mechanisms and whether more than one mechanism
is involved is also not clear. Some of the mechanisms
suggested to explain the antiarrhythmic action of fish oils
include the incorporation and modification of cell membrane
structure by (n-3) polyunsaturated fatty acids, their direct
effect on calcium channels and cardiomyocytes and their role
in eicosanoid metabolism. Other mechanisms that are currently
being investigated include the role of (n-3) polyunsaturated
fatty acids in cell signalling mediated through
phosphoinositides and their effect on various enzymes and
receptors. This article reviews these mechanisms and the
antiarrhythmic studies using (n-3) polyunsaturated fatty
acids.
Fatty acids suppress voltage-gated Na+ currents in
HEK293t cells transfected with the alpha-subunit of the human
cardiac Na+ channel
Xiao Y.-F.; Wright S.N.; Ging Kuo Wang; Morgan J.P.; Leaf
A.
A. Leaf, 146 13th Street, Charlestown, MA 02129 United
States
Proceedings of the National Academy of Sciences of the United
States of America (United States), 1998, 95/5
(2680-2685)
Studies have shown that fish oils, containing n-3 fatty
acids, have protective effects against ischemia-induced, fatal
cardiac arrhythmias in animals and perhaps in humans. In this
study we used the whole-cell voltage- clamp technique to
assess the effects of dietary, free long-chain fatty acids on
the Na+ current (I(Na,alpha)) in human embryonic kidney
(HEK293t) cells transfected with the alpha-subunit of the
human cardiac Na+ channel (hH1(alpha)). Extracellular
application of 0.01 to 30 microM eicosapentaenoic acid (EPA,
C20:5n-3) significantly reduced I(Na,alpha) with an IC50 of
0.51 plus or minus 0.06 microM. The EPA-induced suppression of
I(Na,alpha) was concentration- and voltage- dependent. EPA at
5 microM significantly shifted the steady-state inactivation
relationship by -27.8 plus or minus 1.2 mV (n = 6, P <
0.0001) at the V(one-quarter) point. In addition, EPA blocked
I(Na,alpha) with a higher 'binding affinity' to hH1(alpha)
channels in the inactivated state than in the resting state.
The transition from the resting state to the inactivated state
was markedly accelerated in the presence of 5 microM EPA. The
time for 50% recovery from the inactivation state was
significantly slower in the presence of 5 microM EPA, from 2.1
plus or minus 0.8 ms for control to 34.8 plus or minus 2.1 ms
(n = 5, P < 0.001). The effects of EPA on I(Na,alpha) were
reversible. Furthermore, docosahexaenoic acid (C22:6n-3),
alpha- linolenic acid (C18:3n-3), conjugated linoleic acid
(C18:2n-7), and oleic acid (C18:1n-9) at 5 microM and
all-trans-retinoic acid at 10 microM had similar effects on
I(Na,alpha) as EPA. Even 5 microM of stearic acid (C18:0) or
palmitic acid (C16:0) also significantly inhibited
I(Na,alpha). In contrast, 5 *p EPA ethyl ester did not alter
I(Na,alpha) (8 plus or minus 4%, n = 8, P > 0.05). The
present data demonstrate that free fatty acids suppress
I(Na,alpha) with high 'binding affinity' to hH1(alpha)
channels in the inactivated state and prolong the duration of
recovery from inactivation.
n-3 Polyunsaturated fatty acids, heart rate
variability and ventricular arrhythmias in patients with
previous myocardial infarcts
Christensen J.H.; Gustenhoff P.; Korup E.; Aaroe J.; Toft E.;
Moller J.M.; Rasmussen K.; Dyerberg J.; Schmidt E.B.
J.H. Christensen, Medicinsk Endokrinologisk Afdeling, Aalborg
Sygehus, DK-9100 Aalborg Denmark
Ugeskrift for Laeger (Denmark), 1997, 159/37
(5525-5529)
There is evidence for an antiarrhythmic effect of n-3
polyunsaturated fatty acids (n-3 PUFA) in animals. The aim of
the present study was to investigate the effect of dietary n-3
PUFA on ventricular arrhythmias and heart rate variability
(HRV) in patients with a previous myocardial infarction.
Fifty-five patients were randomized to receive either 5.2 g of
n-3 PUFA daily for 12 weeks or placebo in a double blind,
placebo-controlled study. Prior to randomization a 24-hour
Holter recording was obtained, and this was repeated at the
end of the study. The major end-points were the number of
ventricular extrasystoles (VE)/24 hours and the 24-hour HRV. A
non-significant decrease in VE/24 hours was found in both the
n-3 PUFA group and among controls after dietary
supplementation, whereas HRV significantly increased after n-3
PUFA compared to both baseline values (p = 0,04) and to
controls (p = 0,01). The present study therefore supports the
hypothesis that n-3 PUFA may have an antiarrhythmic effect in
humans.
Randomized, double-blind, placebo-controlled trial
of fish oil and mustard oil in patients with suspected acute
myocardial infarction: The Indian experiment of infarct
survival - 4
Singh R.B.; Niaz M.A.; Sharma J.P.; Kumar R.; Rastogi V.;
Moshiri M.
Prof. R.B. Singh, Preventive Cardiology, Heart Research
Laboratory, Medical Hospital and Research Centre,
Moradabad-10, UP 244001 India
Cardiovascular Drugs and Therapy (USA), 1997, 11/3
(485-491)
In a randomized, placebo-controlled trial, the effects of
treatment with fish oil (eicosapentaenoic acid, 1.08 g/day)
and mustard oil (alpha-linolenic acid, 2.9 g/day) mere
compared for 1 year in the management of 122 patients (fish
oil, group A), 120 patients (mustard oil, group B), and 118
patients (placebo, group C) with suspected acute myocardial
infarction (AMI). Treatments were administered about (mean) 18
hours after the symptoms of AMI in all three groups. The
extent of cardiac disease, rise in cardiac enzymes, and lipid
peroxides were comparable among the groups at entry into the
study. After 1 year total cardiac events were significantly
less in the fish oil and mustard oil groups compared with the
placebo group (24.5% and 28% vs. 34.7%, p < 0.01). Nonfatal
infarctions were also significantly less in the fish oil and
mustard oil groups compared with the placebo group (13.0% and
15.0% vs. 25.4%, p < 0.05). Total cardiac deaths showed no
significant reduction in the mustard oil group; however, the
fish oil group had significantly less cardiac deaths compared
with the placebo group (11.4% vs. 22.0%, p < 0.05). Apart
from the decrease in the cardiac event rate, the fish oil and
mustard oil groups also showed a significant reduction in
total cardiac arrhythmias, left ventricular enlargement, and
angina pectoris compared with the placebo group. Reductions in
blood lipoproteins in the two intervention groups were modest
and do not appear to be the cause of the benefit in the two
groups. Diene conjugates showed a significant reduction in the
fish oil and mustard oil groups, indicating that a part of the
benefit may be caused by the reduction in oxidative stress.
The findings of this study suggest that fish oil and mustard
oil, possibly due to the presence of n-3 fatty acids, may
provide rapid protective effects in patients with AMI.
However, a large study is necessary to confirm this
suggestion.
omega3 fatty acids in the prevention-management of
cardiovascular disease
Simopoulos A.P.
A.P. Simopoulos, Center Genetics, Nutrition and Hlth, 2001 S
Street N.W., Washington, DC 20009 USA
Canadian Journal of Physiology and Pharmacology (Canada),
1997, 75/3 (234-239)
Epidemiologic studies show that populations who eat fish
versus those who do not have a reduced death rate from
cardiovascular disease. Experimental studies have shown that
omega-3 fatty acids affect the function of cells involved in
atherothrombosis in numerous ways, including the modification
of eicosanoid products in the cyclooxygenase and lipoxygenase
pathways, the reduced synthesis of cytokines and
platelet-derived growth factor, and alterations of leukocyte
and endothelial cell properties. Intervention studies in
patients with restenosis, myocardial infarction, and cardiac
arrhythmias with omega-3 fatty acid supplementation have been
addressed in several clinical studies. The ingestion of
omega-3 fatty acids following one episode of myocardial
infarction appears to decrease the rate of cardiac death.
These effects of omega-3 fatty acids appear to be due to their
antiarrhythmic properties. In fact, fish oil has been shown to
reduce ventricular arrhythmias and to be more beneficial than
currently used pharmacologic agents. The dose, duration, and
mechanisms involved in the prevention and management of
cardiovascular disease following omega-3 fatty acid ingestion
or supplementation need to be investigated by double blind
controlled clinical trials.
Omega-3 fatty acids and prevention of
cardiovascular disease
Grynberg A.; Oudot F.; McLennan P.L.; Athias P.
A. Grynberg, INRA, Faculte de Pharmacie, 4, Avenue de
l'Observatoire, F-75270 Paris Cedex 06 France
Cahiers de Nutrition et de Dietetique (France), 1997, 32/2
(107-114)
Most of the cardio-vascular disease (CVD) risk factors may
be controlled by nutrition. Polyunsaturated fatty acids (PUFA)
of the omega3 series are known for their beneficial effect on
risk, but could also influence the CVD severity through their
action on the heart, very sensitive to diet-induced
alterations of membrane composition. Introducing omega3 PUFA
in the diet results in an inversion of the AA/DHA ratio,
mainly due to an increase in DHA content. In several
experimental models, such structural changes were reported to
affect cardiac functions. Arrhythmia which occurs during
ischemia and reperfusion, is largely reduced when the membrane
contains 20% DHA. Moreover, the membrane omega3 PUFA appear to
increase energy utilization efficiency. This may be related to
the positive effect of fish oil on the decrease of heart rate
in rat in vivo, and on the recovery of mitochondrial function
in the post-ischemic heart. At a more cellular level, the
omega3 PUFAs (particularly DHA) can influence the activity of
phospholipase A2, which contributes to membrane homeostasis,
the prostaglandin production or the function of adrenergic
receptors, a key system in the regulation of cardiac activity.
Quite similar effects were reported in pathological conditions
since the presence of omega3 PUFAs in the membranes enhances
the cellular recovery after hypoxia and blocks the stimulation
of prostacycline synthesis induced by post-hypoxic
reoxygenation. However, much research remains to be done, in
order to understand the interactions between diet-induced
membrane alterations and cardiac physiology, pathology, and
pharmacology.
Vitamin E analogues reduce the incidence of
ventricular fibrillations and scavenge free radicals
Walker M.K.; Vergely C.; Lecour S.; Abadie C.; Maupoil V.;
Rochette L.
L. Rochette, Laboratoire de Physiopathologie, Faculte de
Medecine, 7 Boulevard Jeanne d'Arc, 21033 Dijon Cedex
France
Fundamental and Clinical Pharmacology (France), 1998, 12/2
(164-172)
The aim of our study was to analyse the protective effects
of different alpha-tocopherol analogues 1) against
fibrillations induced by an ischemia-reperfusion sequence, and
2) to further investigate in vitro the radical scavenging
properties of these analogues by two sensitive methods.
Concerning 1: isolated rat hearts underwent 10 min of coronary
ligation followed by reperfusion and the alpha-tocopherol
analogues were infused 15 min before occlusion. Functional
parameters including heart rate and fibrillations were
recorded. Concerning 2: the beta-phycoerythrin assay was
utilised to determine the oxygen radical absorbing capacity:
(ORAC) of these vitamin E analogues against peroxyl radicals.
Electron paramagnetic resonance (EPR) was used to measure
their scavenger abilities on hydroxyl radical and superoxide
anion production. Concerning 1: ventricular fibrillation times
were reduced for all analogues treated hearts at
concentrations of 1 microM and 5 microM, with Trolox being the
most efficacious. Concerning 2: in our experimental conditions
of intense production of free radicals, scavenging IC50 values
for hydroxyl radical were 1.15, 2.17 and 4.04 mM for Trolox,
MDL 74270 and MDL 74366 respectively. Superoxide anion IC50
values were 1.0 and 6.75 mM for Trolox and MDL 74270. Our
results show that water-soluble analogues of vitamin E are
effective in the prevention of coronary ligation induced
reperfusion arrhythmia under our experimental conditions.
Moreover, our data demonstrate that these vitamin E analogues
are effective scavengers for a variety of radicals. Our
studies support the view that compounds that can either
inhibit the formation or scavenge free radicals can protect
the heart against arrhythmia associated with
ischemia-reperfusion.
Antioxidant activity of U-83836E, a second
generation lazaroid, during myocardial Ischemia/Reperfusion
injury
Campo G.M.; Squadrito F.; Campo S.; Altavilla D.; Avenoso A.;
Ferlito M.; Squadrito G.; Caputi A.P.
G.M. Campo, Institute of Pharmacology, School of Medicine,
University of Messina, Piazza XX Settembre no 4, 98122 Messina
Italy
Free Radical Research (United Kingdom), 1997, 27/6
(577-590)
The 21-aminosteroid compounds are potent lipid per
oxidation inhibitors belonging to a new class of antioxidants
given the collective name of 'lazaroids'. They protect cells
from oxidative damage induced by oxygen-based free radicals in
a variety of in vitro and in vivo test systems. U-83836E is
one of the second-generation lazaroids that are based on a non
steroidal structure characterized by a ring portion of
alpha-tocopherol bonded with various amine groups. We
investigated the ability of U-83836E to reduce myocardial
damage in rats undergoing left coronary artery occlusion for
60 min followed by 6 hours of reperfusion. This
ischemia/reperfusion model produced wide heart necrosis,
membrane lipid peroxidation, ventricular arrhythmias, tissue
neutrophil infiltration and a marked decrease in endogenous
antioxidants. Intravenous administration of U-83836E, (7.5, 15
and 30 mg/kg) at onset of reperfusion, reduced myocardial
necrosis, expressed as a percentage of either the area at risk
or the total left ventricle (p < 0.001), improved
haemodynamic conditions by decreasing ventricular arrhythmias
(p < 0.005), limited membrane lipid peroxidation (evaluated
by assessing conjugated dienes, p < 0.001; and
4-hydroxy-nonenal, p < 0.001) restored the endogenous
antioxidants vitamin E (p < 0.001), and superoxide
dismutase (pt < 0.001). Furthermore, the lazaroid inhibited
the derimental hydroxyl radical formation (p < 0.001),
evaluated indirectly by a trapping agent and reduced heart
neutrophil infiltration, measured by testing cardiac tissue
elastase (p < 0.001) that is released from the stimulated
granulocytes at the site of injury. These data suggest that
this compound could be a new useful tool to study the
mechanisms of oxidative damage during myocardial
infarction.
Trace elements and cardioprotection: Increasing
endogenous glutathione peroxidase activity by oral selenium
supplementation in rats limits reperfusion-induced
arrhythmias
Tanguy S.; Boucher F.; Besse S.; Ducros V.; Favier A.; De
Leiris J.
Prof. J. De Leiris, Grp. Physiopathol. Cell. Cardiaque, CNRS
ESA 5077, Universite Joseph Fourier, BP 53X38041 Grenoble
Cedex France
Journal of Trace Elements in Medicine and Biology (Germany),
1998, 12/1 (28-38)
Oxyradicals have been implicated as a possible cause of
reperfusion- arrhythmias (RA). However, the use of diverse
exogenous oxyradical scavengers designed to reduce RA has
given contradictory results. The aim of the present study was
to determine whether enhancing the activity of the main
endogenous enzyme involved in peroxide elimination in cardiac
cells, namely glutathione peroxidase, may limit RA in isolated
heart preparations by increasing their antioxidant status. For
this purpose, a group of 15 male Wistar rats received a
selenium enriched diet for ten weeks (1.5 mg Se/kg diet).
Control animals (n=15) received a standard diet containing
0.05 mg Se/kg diet. The incidence of early ventricular
arrhythmias was investigated during the reperfusion period
following 10 min regional ischemia induced ex-vivo by left
coronary artery ligation. Our results show that
selenium-supplementation significantly increased the global
selenium status of the animals. In the isolated heart
preparations, the selenium supplementation induced a
significant reduction of the severity of RA as assessed by the
arrhythmia score and the limitation of the incidence of both
ventricular tachycardia (control: 91% vs, selenium: 36%,
p<0.05) and irreversible ventricular fibrillation (control:
45% vs selenium: 0%, p<0.05). These effects were associated
with a significant increase in cardiac mitochondrial and
cytosolic glutathione peroxidase activities in both the left
and the right ventricles. These results illustrate the
potential protective effect of selenium against ischemia-
reperfusion injury and suggest that peroxides might play a key
role in the genesis of some aspects of the reperfusion
syndrome.
Randomized, double-blind placebo-controlled trial
of coenzyme Q10 in patients with acute myocardial
infarction
Singh R.B.; Wander G.S.; Rastogi A.; Shukla P.K.; Mittal A.;
Sharma J.P.; Mehrotra S.K.; Kapoor R.; Chopra R.K.
Dr. R.B. Singh, Heart Research Lab, MHRC, Civil Lines,
Moradabad-10 (UP) 244001 India
Cardiovascular Drugs and Therapy (United States), 1998, 12/4
(347-353)
The effects of oral treatment with coenzyme Q10 (120 mg/d)
were compared for 28 days in 73 (intervention group A) and 71
(placebo group B) patients with acute myocardial infarction
(AMI). After treatment, angina pectoris (9.5 vs. 28.1), total
arrhythmias (9.5% vs. 25.3%), and poor left ventricular
function (8.2% vs. 22.5%) were significantly (P < 0.05)
reduced in the coenzyme and group than placebo group. Total
cardiac events, including cardiac deaths and nonfatal
infarction, were also significantly reduced in the coenzyme
Q10 group compared with the placebo group (15.0% vs. 30.9%, P
< 0.02). The extent of cardiac disease, elevation in
cardiac enzymes, and oxidative stress at entry to the study
were comparable between the two groups. Lipid peroxides, diene
conjugates, and malondialdehyde, which are indicators of
oxidative stress, showed a greater reduction in the treatment
group than in the placebo group. The antioxidants vitamin A,
E, and C and beta-carotene, which were lower initially after
AMI, increased more in the coenzyme Q10 group than in the
placebo group. These findings suggest that coenzyme Q10 can
provide rapid protective effects in patients with AMI if
administered within 3 days of the onset of symptoms. More
studies in a larger number of patients and long-term follow-up
are needed to confirm our results.
Effect of coenzyme Q10 therapy in patients with
congestive heart failure: A long-term multicenter randomized
study
Morisco C.; Trimarco B.; Condorelli M.
Clinica Medica, Facolta di Medicina e Chirurgia, Universita
degli Studi 'Federico II', Via S. Pansini 5, I-80131 Napoli
Italy
Clin. Invest. Suppl. (Germany), 1993, 71/8 (S 134-S
136)
The improved cardiac function in patients with congestive
heart failure treated with coenzyme Q10 supports the
hypothesis that this condition is characterized by
mitochondrial dysfunction and energy starvation, so that it
may be ameliorated by coenzyme Q10 supplementation. However,
the main clinical problems in patients with congestive heart
failure are the frequent need of hospitalization and the high
incidence of life-threatening arrhythmias, pulmonary edema,
and other serious complications. Thus, we studied the
influence of coenzyme Q10 long-term treatment on these events
in patients with chronic congestive heart failure (New York
Heart Association functional class III and IV) receiving
conventional treatment for heart failure. They were randomly
assigned to receive either placebo (n = 322, mean age 67
years, range 30-88 years) or coenzyme Q10 (n = 319, mean age
67 years, range 26-89 years) at the dosage of 2 mg/kg per day
in a 1-year double-blind trial. The number of patients who
required hospitalization for worsening heart failure was
smaller in the coenzyme Q10 treated group (n = 73) than in the
control group (n = 118, P < 0.001). Similarly, the episodes
of pulmonary edema or cardiac asthma were reduced in the
control group (20 versus 51 and 97 versus 198, respectively;
both P < 0.001) as compared to the placebo group. Our
results demonstrate that the addition of coenzyme Q10 to
conventional therapy significantly reduces hospitalization for
worsening of heart failure and the incidence of serious
complications in patients with chronic congestive heart
failure.
Serum concentration of lipoprotein(a) decreases on
treatment with hydrosoluble coenzyme Q10 in patients with
coronary artery disease: discovery of a new role.
Singh RB, Niaz MA
Centre of Nutrition, Medical Hospital and Research Centre,
Moradabad, India.
Int J Cardiol 1999 Jan;68(1):23-9
OBJECTIVE: To examine the effect of coenzyme Q10
supplementation on serum lipoprotein(a) in patients with acute
coronary disease.
STUDY DESIGN: Randomized double blind placebo controlled
trial.
SUBJECTS AND METHODS: Subjects with clinical diagnosis of
acute myocardial infarction, unstable angina, angina pectoris
(based on WHO criteria) with moderately raised lipoprotein(a)
were randomized to either coenzyme Q10 as Q-Gel (60 mg twice
daily) (coenzyme Q10 group, n=25) or placebo (placebo group,
n=22) for a period of 28 days.
RESULTS: Serum lipoprotein(a) showed significant reduction
in the coenzyme Q10 group compared with the placebo group
(31.0% vs 8.2% P<0.001) with a net reduction of 22.6%
attributed to coenzyme Q10. HDL cholesterol showed a
significant increase in the intervention group without
affecting total cholesterol, LDL cholesterol, and blood
glucose showed a significant reduction in the coenzyme Q10
group. Coenzyme Q10 supplementation was also associated with
significant reductions in thiobarbituric acid reactive
substances, malon/dialdehyde and diene conjugates, indicating
an overall decrease in oxidative stress.
CONCLUSION: Supplementation with hydrosoluble coenzyme Q10
(Q-Gel) decreases lipoprotein(a) concentration in patients
with acute coronary disease.
Coenzyme Q10 administration increases brain
mitochondrial concentrations and exerts neuroprotective
effects.
Matthews RT, Yang L, Browne S, Baik M, Beal MF
Neurochemistry Laboratory, Neurology Service, Massachusetts
General Hospital and Harvard Medical School, Boston, MA 02114,
USA.
Proc Natl Acad Sci U S A 1998 Jul
21;95(15):8892-7
Coenzyme Q10 is an essential cofactor of the electron
transport chain as well as a potent free radical scavenger in
lipid and mitochondrial membranes. Feeding with coenzyme Q10
increased cerebral cortex concentrations in 12- and
24-month-old rats. In 12-month-old rats administration of
coenzyme Q10 resulted in significant increases in cerebral
cortex mitochondrial concentrations of coenzyme Q10. Oral
administration of coenzyme Q10 markedly attenuated striatal
lesions produced by systemic administration of
3-nitropropionic acid and significantly increased life span in
a transgenic mouse model of familial amyotrophic lateral
sclerosis. These results show that oral administration of
coenzyme Q10 increases both brain and brain mitochondrial
concentrations. They provide further evidence that coenzyme
Q10 can exert neuroprotective effects that might be useful in
the treatment of neurodegenerative diseases.
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