Historical overview of n-3 fatty acids and coronary heart disease.

The first evidence that fish oil fatty acids might have a beneficial effect on coronary heart disease came from the discovery that Greenland Eskimos, who have a diet high in n-3 fatty acids, have a lower mortality from coronary heart disease than do Danes and Americans. Long-chain polyunsaturated fatty acids are essential in our diets and can be classified in 2 groups: n-6 fatty acids found in plant seeds and n-3 fatty acids found in marine vertebrates. Further evidence of n-3 benefits to human health include a 1989 study demonstrating a 29% reduction in fatal cardiac arrhythmias among subjects with a recent myocardial infarction who had been advised to consume fish oil. The GISSI-Prevenzione Trial found a significant reduction in relative reduction of death, cardiac death, nonfatal myocardial infarction, and stroke in subjects consuming n-3 fatty acids. In a recent study, subjects with implanted cardiac defibrillators (ICDs) at high risk for fatal ventricular arrhythmias were randomly assigned to four 1-g capsules of either an ethyl ester concentrate of n-3 fatty acids or olive oil daily for 12 mo. Subjects receiving n-3 who thus had significantly higher levels of eicosapentaenoic acid and docosahexaenoic acid in their red blood cell membranes showed a longer time to first ICD events and had a significantly lower relative risk of having an ICD event or probable event (P = 0.033). These studies demonstrate that fish oil fatty acids have beneficial effects on coronary heart disease.

Conclusions and recommendations from the symposium, Beyond Cholesterol: Prevention and Treatment of Coronary Heart Disease with n-3 Fatty Acids.

After the symposium "Beyond Cholesterol: Prevention and Treatment of Coronary Heart Disease with n-3 Fatty Acids," faculty who presented at the conference submitted manuscripts relating to their conference topics, and these are presented in this supplement. The content of these manuscripts was reviewed, and 2 conference calls were convened. The objective was to summarize existing evidence, gaps in evidence, and future research needed to strengthen recommendations for specific intakes of n-3 fatty acids for different conditions relating to cardiovascular disease. The following 2 questions were the main items discussed. What are the roles of n-3 fatty acids in primary versus secondary prevention of coronary heart disease? What are the roles of n-3 fatty acids in hypertriglyceridemia, in the metabolic syndrome and type 2 diabetes, and in sudden cardiac death, cardiac arrhythmias, and vulnerable plaque? Each area was summarized by using 2 general categories: 1) current knowledge for which general consensus exists, and 2) recommendations for research and policy. Additional references for these conclusions can be found in the articles included in the supplement.

Fish oil fatty acids as cardiovascular drugs.

Starting in the 1970s the hypothesis that the low mortality from coronary heart disease among the Greenland Eskimos was due to their high consumption of n-3 fish oil fatty acids, initiated many studies to find if the n-3 polyunsaturated fatty acids in fish oils (PUFAs) could prevent cardiac atherosclerosis. To date this possibility has not achieved clinical recognition. The recent literature shows an increase of intervention studies to learn if the fish oil fatty acids can reduce mortality from sudden cardiac death, and the mechanism(s) of such a protective effect. Indeed the most definite beneficial cardiac action of these n-3 PUFAs seems now to be their ability in the short term to prevent sudden cardiac death. It is apparent that over long periods of time the n-3 fish oil fatty acids also prevent atherosclerosis. Definition of the fatty acids to which I will be referring in the text: n-6 (omega-6) polyunsaturated fatty acids; linoleic acid (18:2n-6, LA); arachidonic acid (C20:4n-6, AA). n-3 (omega-3) fatty acids; alpha-linolenic acid (18:3n-3, ALA); eicosapentaenoic acid (20:5n-3, EPA); docosahexaenoic acid (C22:6n-3, DHA). The bold, underlined abbreviation will appear in the text to identify the fatty acid being discussed.

Prevention of sudden cardiac death by n-3 polyunsaturated fatty acids.

There were already several epidemiologic studies that showed eating fish frequently seemed to reduce deaths from coronary heart disease. There were also observational and clinical trials that more specifically showed that the reduction in cardiovascular deaths from eating fish was largely the result of the prevention of sudden cardiac death by n-3 polyunsaturated fatty acids in fish oil. This led me to perform a clinical trial in which all subjects had an implanted cardioverter-defibrillator and were at very high risk of sudden cardiac death. The results of this study and the mechanisms by which n-3 fish oil fatty acids prevent fatal cardiac arrhythmias will be the subject of this review.

Omega-3 fatty acids and prevention of arrhythmias.

PURPOSE OF REVIEW: There is now a considerable factual basis from laboratory and clinical trials that omega-3 fatty acids of fish oil will prevent fatal arrhythmias in animals and humans and this is the focus of the review. RECENT FINDINGS: Several recent trials in humans have strengthened the evidence that omega-3 fatty acids may prevent arrhythmias although this has not been a uniform finding. SUMMARY: Since there are at present some 400 000 deaths annually in the US alone and millions more worldwide, what has been learned about the antiarrhythmic actions of omega-3 fatty acids has considerable potential public-health benefit.

Prevention of sudden cardiac death by n-3 polyunsaturated fatty acids.

There were already several epidemiologic studies that showed eating fish frequently seemed to reduce deaths from coronary heart disease. There were also observational and clinical trials, which more specifically showed that the reduction in cardiovascular deaths from eating fish were largely the result of n-3 polyunsaturated fatty acids in fish oil for the prevention of sudden cardiac death (SCD). This led me to perform a clinical trial in which all subjects had an implanted cardioverter-defibrillator and were at very high risk of SCD. The results of this study and the mechanisms by which the n-3 fish oil fatty acids prevent fatal cardiac arrhythmias will be the subject of this review.

Potent block of inactivation-deficient Na+ channels by n-3 polyunsaturated fatty acids.

A voltage-gated, small, persistent Na(+) current (I(Na)) has been shown in mammalian cardiomyocytes. Hypoxia potentiates the persistent I(Na) that may cause arrhythmias. In the present study, we investigated the effects of n-3 polyunsaturated fatty acids (PUFAs) on I(Na) in HEK-293t cells transfected with an inactivation-deficient mutant (L409C/A410W) of the alpha-subunit (hH1(alpha)) of human cardiac Na(+) channels (hNav1.5) plus beta(1)-subunits. Extracellular application of 5 microM eicosapentaenoic acid (EPA; C20:5n-3) significantly inhibited I(Na). The late portion of I(Na) (I(Na late), measured near the end of each pulse) was almost completely suppressed. I(Na) returned to the pretreated level after washout of EPA. The inhibitory effect of EPA on I(Na) was concentration dependent, with IC(50) values of 4.0 +/- 0.4 microM for I(Na) peak (I(Na peak)) and 0.9 +/- 0.1 microM for I(Na late). EPA shifted the steady-state inactivation of I(Na peak) by -19 mV in the hyperpolarizing direction. EPA accelerated the process of resting inactivation of the mutant channel and delayed the recovery of the mutated Na(+) channel from resting inactivation. Other polyunsaturated fatty acids, docosahexaenoic acid, linolenic acid, arachidonic acid, and linoleic acid, all at 5 microM concentration, also significantly inhibited I(Na). In contrast, the monounsaturated fatty acid oleic acid or the saturated fatty acids stearic acid and palmitic acid at 5 microM concentration had no effect on I(Na). Our data demonstrate that the double mutations at the 409 and 410 sites in the D1-S6 region of hH1(alpha) induce inactivation-deficient I(Na) and that n-3 PUFAs inhibit mutant I(Na).

Prevention of fatal arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake.

BACKGROUND: The long-chain n-3 fatty acids in fish have been demonstrated to have antiarrhythmic properties in experimental models and to prevent sudden cardiac death in a randomized trial of post-myocardial infarction patients. Therefore, we hypothesized that these n-3 fatty acids might prevent potentially fatal ventricular arrhythmias in high-risk patients. METHODS AND RESULTS: Four hundred two patients with implanted cardioverter/defibrillators (ICDs) were randomly assigned to double-blind treatment with either a fish oil or an olive oil daily supplement for 12 months. The primary end point, time to first ICD event for ventricular tachycardia or fibrillation (VT or VF) confirmed by stored electrograms or death from any cause, was analyzed by intention to treat. Secondary analyses were performed for "probable" ventricular arrhythmias, "on-treatment" analyses for all subjects who had taken any of their oil supplements, and "on-treatment" analyses only of those subjects who were on treatment for at least 11 months. Compliance with double-blind treatment was similar in the 2 groups; however, the noncompliance rate was high (35% of all enrollees). In the primary analysis, assignment to treatment with the fish oil supplement showed a trend toward a prolonged time to the first ICD event (VT or VF) or of death from any cause (risk reduction of 28%; P=0.057). When therapies for probable episodes of VT or VF were included, the risk reduction became significant at 31%; P=0.033. For those who stayed on protocol for at least 11 months, the antiarrhythmic benefit of fish oil was improved for those with confirmed events (risk reduction of 38%; P=0.034). CONCLUSIONS: Although significance was not achieved for the primary end point, this study provides evidence that for individuals at high risk of fatal ventricular arrhythmias, regular daily ingestion of fish oil fatty acids may significantly reduce potentially fatal ventricular arrhythmias.

Inhibitory effect of n-3 fish oil fatty acids on cardiac Na+/Ca2+ exchange currents in HEK293t cells.

Abnormal activity of the cardiac Na+/Ca2+ exchanger (NCX1) can affect intracellular Ca2+ homeostasis and cause arrhythmias. The n-3 polyunsaturated fatty acids (PUFAs), however, may prevent arrhythmias. To test the effect of PUFAs on the cardiac NCX1 current (I(NCX1)), the canine NCX1 cDNA was expressed in human embryonic kidney (HEK293t) cells. The average density of I(NCX1) was 10.9+/-2.6 pA/pF (n=44) in NCX1-transfected cells and eicosapentaenoic acid (EPA, C20:5n-3) significantly inhibited I(NCX1) The suppression of I(NCX1) by EPA was concentration-dependent with an IC50 of 0.82+/-0.27 microM. EPA had a similar effect on outward or inward I(NCX1). Docosahexaenoic acid (DHA, C22:6n-3) and arachidonic acid (AA, C20:4n-6) also significantly inhibited I(NCX1), whereas the saturated fatty acid, stearic acid (SA, C18:0), did not. Our data demonstrate that the n-3 PUFAs significantly suppress cardiac I(NCX1), which is probably one of their protective effects against lethal arrhythmias.

Electrophysiologic properties of lidocaine, cocaine, and n-3 fatty-acids block of cardiac Na+ channels.

Lidocaine and cocaine, two local anesthetics, and n-3 polyunsaturated fatty acids in fish oils, inhibit the voltage-gated Na(+) channels of cardiomyocytes. This inhibition by lidocaine and n-3 fish oil is associated with antiarrhythmic effects, whereas with cocaine lethal arrhythmias may occur. These electrophysiologic studies show that at the concentrations tested, the n-3 fish oil fatty acids and lidocaine share three actions on I(Na): a potent inhibition of I(Na); a strong voltage-dependence of this inhibition; and a large shift of the steady-state inactivation to hyperpolarized potentials. By contrast cocaine shares only the potent inhibition of I(Na). The voltage-dependence of the inhibition is much decreased with cocaine, which produces only a very small leftward shift of the voltage-dependence of inactivation. The large leftward shift of the steady-state inactivation seems very important in the prevention of fatal arrhythmias by the n-3 fatty acids. Thus, we suggest that it is lack of this effect by cocaine, which is one factor, that eliminates its ability to prevent fatal cardiac arrhythmias. Further we report that in cultured neonatal rat cardiomyocytes n-3 fish oil fatty acids terminate the tachycardia induced by the alpha(1) adrenergic agonist, phenylephrine, whereas cocaine accelerates the tachycardia and causes bouts of tachyarrhythmias.

In vivo characterization of fatty acids in human adipose tissue using natural abundance 1H decoupled 13C MRS at 1.5 T: clinical applications to dietary therapy.

Natural abundance proton-decoupled (13)C magnetic resonance spectroscopy was used to establish the in vivo lipid composition of normal adipose tissue and the corresponding effects of altered lipid diets. Experiments were performed on a standard 1.5 T clinical MR scanner using a double-tuned (1)H-(13)C coil. Peaks from double-bonded and methylene carbons were analyzed. Normal lipid composition was established in 20 control subjects. For comparison, five subjects on altered lipid diets were studied. Four subjects were on a fish oil supplement diet or predominantly seafood diet (polyunsaturated fatty acids), and one subject was on a Lorenzo's oil diet (monounsaturated fatty acids). Well-resolved (13)C spectra were obtained from the calf adipose tissue with a total acquisition time of 10 min. Model oil solutions were used to identify specific (13)C resonances. Subjects on lipid diets showed significantly elevated levels of monounsaturated and polyunsaturated fatty acids for Lorenzo's and fish oil diets, respectively. We conclude that (13)C MR spectroscopy can readily detect changes in lipid composition due to medium- and long-term therapeutic lipid diets. Since the examination is rapid, robust and noninvasive, opportunities arise for large clinical trials of preventive or therapeutic diets to be performed with (13)C MRS on a clinical MR scanner.

Prevention of sudden cardiac death by n-3 polyunsaturated fatty acids.

This is a review of our present understanding of the mechanism by which the n-3 polyunsaturated fatty acids (PUFA) in fish oils prevent fatal ventricular arrhythmias in animals and cultured heart cells. A brief review of three clinical trials that suggest that these PUFAs prevent sudden cardiac death is also included in order to emphasize the potential importance of these fatty acids in human nutrition. The PUFAs act by stabilizing electrically every cardiac myocyte by modulating conductance of ion channels in the sarcolemma, particularly the fast, voltage-dependent sodium current and the L-type calcium currents, though other ion currents are also affected. Work in progress suggests that the primary site of action of the PUFAs may be on the phospholipid bilayer of the heart cells in the microdomains through which the ion channels penetrate the membrane bilayer in juxtaposition with the ion channels rather than directly on the channel protein itself. These PUFAs then allosterically alter the conformation and conductance of the channels. Both potential benefits and possible adverse effects of the PUFAs in man will be discussed. Knowing that the ion channels have been structurally conserved among all excitable tissues, we tested their effects on the electrophysiology of rat hippocampal CA1 neurons and found that the sodium and calcium ion channels in these neurons were also affected by PUFAs. An attempt to show the place of the PUFAs in human nutrition during the 2-4 million years of our evolution will conclude the review.

Effects of polyunsaturated fatty acids on cardiac voltage-activated K(+) currents in adult ferret cardiomyocytes .

This study was carried out in adult ferret cardiomyocytes to investigate the effects of the n-3 polyunsaturated fatty acids (PUFAs) on voltage-gated K(+) currents. We report that the two outward K(+) currents: the transient outward K(+) current (I(to)) and the delayed rectifier K(+) current (I(K)), are both inhibited by the n-3 PUFAs, while the inwardly rectifying K(+) current (I(K1)) is unaffected by the n-3 PUFAs. Docosahexaenoic acid (C22:6n-3, DHA) produced a concentration dependent suppression of I(to) and I(K) in adult ferret cardiomyocytes with an IC(50) of 7.5 and 20 micromol/L, respectively; but not I(K1). In addition, eicosapentaenoic acid (C20:5n-3, EPA) had the effects on the three K(+) channels similar to DHA. Arachidonic acid (C20:4n-6, AA) at 5 or 10 micromol/L, after an initial inhibitory effect on I(K), caused an activation of I(K),AA which was prevented by pretreatment with indomethacin, a cyclooxygenase inhibitor. Monounsaturated and saturated fatty acids, which are not antiarrhythmic, lack the effects on these K(+) currents. Our results demonstrate that the n-3 PUFAs inhibit cardiac I(to) and I(K) with much less potency compared to their effects on cardiac Na(+) and Ca(2+) currents as we reported previously. This inhibition of the cardiac ion currents by the n-3 PUFAs may contribute to their antiarrhythmic actions.