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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.
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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