Membrane Effects of the n-3 Fish Oil Fatty Acids, which Prevent Fatal Ventricular Arrhythmias

Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Journal of Membrane Biology (Impact Factor: 2.46). 08/2005; 206(2):129-39. DOI: 10.1007/s00232-005-0789-9
Source: PubMed


Fish oil fatty acids are known to exert beneficial effects on the heart and vascular systems. We have studied the membrane effects on ion channel conductance by the n-3 fish oil fatty acids that account for these beneficial effects. We have confirmed that these fatty acids prevent fatal cardiac arrhythmias in a reliable dog model of sudden cardiac death. This finding was followed by experiments indicating that the n-3 fatty acids electrically stabilize heart cells and do so largely through modulation of the fast voltage-dependent Na(+) currents and the L-type Ca(2+) channels in a manner, which makes the heart cells resistant to arrhythmias. Others and we have demonstrated that these membrane effects on the heart can prevent fatal cardiac arrhythmias in humans.

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    • "The molecular and cellular interaction has been delineated extensively in several reviews (Leaf A et al. 2005b; Dhein S et al. 2005; McLennan PL & Abeywardena MY 2005; Lombardi F 2007; Den Ruijter HM et al. 2007; Siddiqui RA et al. 2008). In the following some important aspects potentially explaining heterogeneous clinical effects of Ω-3 on cardiac rhythm are summarized: There are three major ways in which Ω-3 may interfere with cellular and membrane function, thereby potentially moderating cardiac rhythm (see also Figure 1): a) Direct interactions of Ω-3 with membrane bound proteins like the fast sodium channel, the voltage-gated L-type Ca 2+ channel, specific potassium channels, and the Na + /Ca ++ -exchanger (Hallaq H et al. 1990 & 1992; Honore E et al. 1994; Xiao YF et al. 1995 & 1997; Kang JX & Leaf A 1996, Leifert WR et al. 1999; Leaf A 2003; Den Ruijter HM et al. 2007; Wang RX et al. 2010). "
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    ABSTRACT: The effects of supplementation of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on prevalence and severity of depression were evaluated in patients after a myocardial infarction. A cross-sectional evaluation (posttest-only design) within the prospective, randomized, controlled, multicenter OMEGA trial was performed in patients after myocardial infarction at 12 months' follow-up (N = 2,081; age, mean = 64 years; men, 76.7%; women, 21.8%) from April 2005 to June 2007. Patients received supplementation with ethyl esters 90 (460-mg EPA and 380-mg DHA) or placebo for 12 months. Depression was assessed with the Beck Depression Inventory-II (BDI-II); a BDI-II cutoff score of ≥ 14 was used as diagnosis of depression. When the total population was evaluated, no effects of EPA/DHA supplementation on depressive symptoms according to BDI-II score (mean [SD]) could be demonstrated: EPA/DHA (n = 1,046), 7.1 (6.9); placebo (n = 1,035), 7.1 (7.0); P = .7. The post hoc analyses of depressed patients with and without antidepressants revealed a tendency toward an antidepressant effect in patients with EPA/DHA supplementation as monotherapy: EPA/DHA (n = 125), 19.4 (5.8); placebo (n = 113), 19.9 (5.1); P = .07. However, in depressed patients with EPA/DHA supplementation as adjunctive to conventional antidepressants, a clinically relevant antidepressant effect was demonstrated: EPA/DHA (n = 33), 20.9 (7.1); placebo (n = 29), 24.9 (8.5); P < .05. EPA/DHA supplementation in the total sample of patients after myocardial infarction had no effect on depressive symptoms. The clinically relevant antidepressant effect in the subgroup of depressed patients with EPA/DHA supplementation as adjunctive to conventional antidepressants that was revealed in the post hoc analysis might provide a basis for a controlled, prospective trial of omega-3 augmentation of antidepressants in patients after myocardial infarction. identifier: NCT00251134.
    The Journal of Clinical Psychiatry 11/2013; 74(11):e1037-e1045. DOI:10.4088/JCP.13m08453 · 5.50 Impact Factor
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    • "Saturated fatty acids have no double bonds between their carbon atoms allowing the molecule to become " saturated " with the maximal number of possible hydrogen atoms attaching. Unsaturated forms of fatty acids possess biophysical, structural, and dynamic properties essential for normal cellular function (Leaf et al., 2005). For Omega-3 (n-3 fatty acids), the terminal double bond is on C3 counting from the methyl end of the hydrocarbon chain. "
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    ABSTRACT: Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice with growing prevalence in developed countries. Several medical and interventional therapies, such as atrial specific drugs and pulmonary vein isolation, have demonstrated prevention of recurrences. However, their suboptimal long-term success and significant rate of secondary effects have led to intensive research in the last decade focused on novel alternative and supplemental therapies. One such candidate is polyunsaturated fatty acids (PUFAs). Because of their biological properties, safety, simplicity, and relatively cheap cost, there is a special clinical interest in omega-3 PUFAs as a possible antiarrhythmic agent. Obtained from diets rich in fish, they represent one of the current supplemental therapies. At the cellular level, an increasing body of evidence has shown that n-3 PUFAs exert a variety of effects on cardiac ion channels, membrane dynamic properties, inflammatory cascade, and other targets related to AF prevention. In this article, we review the current basic and clinical evidence pertinent to n-3 PUFAs in AF treatment and prevention. We also discuss controversial outcomes among clinical studies and propose specific subsets of AF patients who will benefit most from n-3 PUFAs.
    Frontiers in Physiology 09/2012; 3:370. DOI:10.3389/fphys.2012.00370 · 3.53 Impact Factor
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    • "Independent of PG biosynthesis, LC n-3 PUFAs have been shown to exert their cardioprotective [34] and immunosuppressive [35], [36] effects at the level of the plasma membrane. Docosahexanoic acid (DHA)-induced changes in the membrane structure and architecture leading to modulation of ion channels and the displacement of key proteins from lipid raft signaling platforms appear to be the mechanisms of action [37]–[39]. "
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    ABSTRACT: Epidemiological studies and interventional clinical trials indicate that consumption of long chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) such as docosahexaenoic acid (DHA) lengthen gestational duration. Although the mechanisms are not well understood, prostaglandins (PG) of the 2-series are known to play a role in the initiation and progress of labor. In animal studies, modest DHA provision has been shown to reduce placental and uterine PGE(2) and PGF(2α), matrix metalloproteinase (MMP)-2 and MMP-9 expression, and placental collagenase activity. However, modulation of PG biosynthesis may not account for all the effects of LC n-3 PUFAs in labor. We investigated one potential PG-independent mechanism of LC PUFA action using cultured pregnant human myometrial smooth muscle cells. Our goal was to characterize the effect of LC PUFA treatment on oxytocin signaling, a potent uterotonic hormone involved in labor. The addition of 10 µM-100 µM DHA or arachidonic acid (AA) to the culture media for 48 h resulted in dose dependent enrichment of these fatty acids in membrane lipid. DHA and AA significantly inhibited phosphatidylinositol turnover and [Ca(2+)](i) mobilization with oxytocin stimulation compared to bovine serum albumin control and equimolar oleic acid. DHA and AA significantly reduced oxytocin receptor membrane concentration without altering binding affinity or rate of receptor internalization. These findings demonstrate a role for LC n-3 PUFAs in regulation of oxytocin signaling and provide new insight into additional mechanisms pertaining to reports of dietary fish and fish oil consumption prolonging gestation.
    PLoS ONE 07/2012; 7(7):e41708. DOI:10.1371/journal.pone.0041708 · 3.23 Impact Factor
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