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European Heart Journal Supplements (2001) 3 (Supplement D), D98D105

The electrophysiological basis for the antiarrhythmic

actions of polyunsaturated fatty acids

A. Leaf

Departments of Medicine, Massachusetts General Hospital and the Harvard Medical School, Boston, MA, U.S.A.

Aims To determine whether n-3 polyunsaturated fatty

acids (PUFAs) have cardiac antiarrhythmic effects and, if

so, to determine the basis(es) for such an effect.

Methods and results First, tests were made of the ability

of administering n-3 PUFAs to a reliable dog model toprevent ischaemia-induced sudden cardiac death. Infusion

of an emulsion of fish oil free fatty acids just prior to

coronary artery obstruction prevented ventricular fibril-

lation (VF) (P


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We then tested which PUFAs were antiarrhythmic[8].

Both the n-3 and n-6 classes of PUFAs are antiarrhyth-mic, whereas monounsaturated oleic acid and thesaturated fatty acids (stearic, palmitic and lauric) werenot. However, arachidonic acid (C20n-6, AA) wasanomalous. Cyclooxygenase metabolites of AA (exceptprostacyclin) cause arrhythmias, whereas cyclooxygen-ase metabolites of n-3 EPA do not[11]. This wouldaccount for the remaining fatal arrhythmias observed inthe study by McLennan[4] when he fed his rats avegetable oil, safflower oil, which is rich in n-6 poly-unsaturated fatty acids. To avoid arrhythmias inducedby prostaglandins of n-6 arachidonic acid, we haveadvised that only the n-3 PUFAs should be tested in

clinical trials as antiarrhythmic agents.The structural requirements for an antiarrhythmiccompound that acts in the manner of these PUFAs are along acyl or hydrocarbon chain with two or more C=Cunsaturated bonds and a free carboxyl group at one end.With this guideline we found all-trans retinoic acid alsoto be specifically antiarrhythmic, whereas retinal andretinol were not[12].

The antiarrhythmic action of the PUFAs results fromtheir effects on the electrophysiology of cardiac myo-cytes[13]. They cause slight hyperpolarization of theresting or diastolic membrane potential and thethreshold voltage for the opening of the Na+ channelbecomes more positive. This results in an increased

depolarizing stimulus of about 4050% required to in-duce an action potential. In addition, the refractoryperiod, phase 4 of the cardiac cycle, is prolonged some

threefold. These two effects on every myocyte in theheart would account for the increased electrical stabilityand resistance of the heart to lethal arrhythmias.

This electrical stabilizing effect of the n-3 PUFAs onevery cardiomyocyte can be readily demonstrated invitro[10]. Figure 3 shows the tracing of the rate andamplitude of contractions of a single cardiomyocyte in aclump of cells growing on a microscope coverslip. Whentwo platinum electrodes were placed across the micro-

scope coverslip in a perfusion chamber and connected toan external voltage source, the regular beating rate couldeasily be doubled by stimulating the myocyte by theexternal field of 15 V. When the external voltage sourcewas turned off the myocyte regained its prior beatingrate. When the same cell was exposed to n-3 EPA(15 M) added to the superfusate, the beating rate beganto slow down a highly reproducible effect of thePUFAs on the neonatal rat cardiomyocytes and nowthe myocyte paid no attention to the stimuli from theexternal voltage source at 15 or at 20 V. However,external stimuli delivered at 25 V succeeded in elicitingmyocyte contractions, but only in response to everyother electrical stimulus. When delipidated bovine serum

albumin (2 mg . ml

1) was added to the superfusate ofthe same coverslip to extract the free fatty acid from thecardiomyocytes, the beating rate returned to its control

A

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Ouabain (01 mM)Ca2+ (5 mM)

(EPA 10 prior)

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6 min 6 min 5 min

Ca

2+

(7 mM)EPA (7 M)

Ouabain (01 mM)EPA (7 M)

(EPA 8 M) BSA (2 mg.m1)

'

'

Figure 2 The effects of n-3 PUFAs on the arrhythmicactions of [Ca2+ ]e (5 or 7 mM) and the cardiac glycoside

ouabain (01 mM) on cultured neonatal rat cardiomyo-cytes[8]. Both elevated Ca2+ (A) and ouabain (B) causedcontracture and fibrillation of the myocytes. But when theEPA was added prior to the calcium or ouabain it slowedthe beating rate and prevented the fibrillation (C). Whenboth ouabain and calcium were added to the superfusatethey caused a violent arrhythmia, which was terminated byadding EPA to the same superfusate. The cells resumed afairly regular rhythm, but when the free fatty acid wasextracted from the myocytes by delipidated bovine serumalbumin, still in the presence of the ouabain and elevatedCa2+ , the violent arrhythmia promptly resumed.

15 V

15 V 20 V 25 V

15 V

10 s

EPA (15 M)

BSA (2 mg.ml1)

Figure 3 The effect of EPA on the response of thecultured neonatal rat cardiomyocytes to electrical stimuli

delivered from an external applied electrical voltagesource[10]. The three strips are continuous tracings of thecontraction rate and amplitude of a single myocyte withina clump of myocytes. The spontaneous beating rate andamplitude of contraction is apparent in the top tracing. Anexternal electric field of 15 V delivered stimuli at a ratethat readily doubled the beating rate. The second tracingshows that with EPA (15 M) added to the superfusate thebeating rate slowed, but when an external electrical fieldof 15 V was applied the cells paid no attention to thestimuli, nor did they at 20 V. At 25 V they responded butonly to every other stimulus. Upon addition of delipidatedbovine serum albumin to the superfusate the free EPA wasextracted from the cardiomyocyte, the contractionsreturned to the control rate, and now the cells doubled

their beating rate in response to stimuli delivered at 15 V,just as they had initially.

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Eur Heart J Supplements, Vol. 3 (Suppl D) June 2001

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frequency and now the myocytes responded to theexternal electrical stimuli delivered at 15 V, as they hadinitially. When one considers that this electrical stabiliz-

ation is an effect of the PUFAs directly on every cardiacmyocyte, both atrial and ventricular, in the absence ofneural or humoral effects, one can sense what a potentantiarrhythmic action these n-3 PUFAs may exert.Furthermore, the antiarrhythmic action should beindependent of the pathological condition causing thearrhythmias.

Effects of PUFAs on membrane ioncurrents

These effects in turn result from an action of the PUFAsto modulate the conductance of ion channels in theplasma membranes of the heart cells. The voltage-gatedsodium current, INa, initiates and propagates actionpotentials in most cardiac myocytes. Our finding thatthe PUFAs increased the magnitude of a depolarizingstimulus required to elicit an action potential made itlikely that the PUFAs were affecting the INa. Thus ourexploration of the effects of the PUFAs on membraneion currents and channels began with INa.

Effects on sodium channels

The PUFAs inhibited the INa in a concentration-dependent manner, with an IC50 of 48 M in neonatalrat cardiomyocytes[14] but only 051006 M i n ahuman embryonic kidney cell line, HEK293t, transientlyexpressing human myocardial sodium -subunits,hH1[15] (Fig. 4). Inhibition occurred within seconds of

application of the PUFAs to the myocytes. It wasvoltage-dependent, but not use-dependent, and consist-ent with the lipophilic nature of the PUFAs[16]. In bothpreparations INa in the rat cardiomyocyte and INa inthe human myocardial -subunit transiently expressedin HEK293t cells the PUFAs caused a large voltage-dependent shift of the steady state inactivation potential

to more hyperpolarized values; the shift at V1/2=19 mV with 10 M EPA in the neonatal rat cardio-myocyte and a further 278 mV with 5 M EPA in thehH1. There was no effect of the PUFAs on the acti-vation of the Na+ channels, only on the inactivatedchannel (Fig. 5). The PUFAs prolonged the inactivatedstate of the hH1 channels by speeding the transitionfrom the active to the inactivated state and retarding theslow inactivation phase of the channel. In more recentstudies[17] the 1 subunit has been transiently co-expressed with the -subunit in HEK293t cells and thisshifted the steady state inactivation potential to the right(to more depolarized potentials) returning the electro-physiology of the hH1 channels almost to exactly that

observed for the neonatal rat cardiomyocytes. EPA wasfound to have no effect on the activation but only on theinactivation of INa,, INa and INa,rat. Consistent with

the effects of these fatty acids solely on the inactivatedstate of the Na+ channel, is the finding that the bindingor interaction of these fatty acids to the inactivated stateof the Na+ channels displayed a 265-fold higher affinityfor 5 M EPA than channels in the closed resting, butactivatable, state of hH1.

These effects of the n-3 PUFAs (and DHA and LNAdo the same as EPA) we think are pertinent to theantiarrhythmic actions of these fatty acids. Our currenthypothesis is that this voltage-dependent shift of thesteady state inactivation potential to more negative,hyperpolarizing voltages is important to the observed

antiarrhythmic action of the PUFAs in ischaemia-induced fatal arrhythmias. With a coronary thrombosisa gradient of depolarizations of cardiomyocytes occurswithin the ischaemic tissue. Cells in the central core ofthe ischaemic tissue quickly depolarize and die due tolack of oxygen and metabolic substrates. Depolarizationresults from the dysfunctional state of Na, K-ATPaseand the rise of interstitial K+ concentrations in theischaemic tissue. At the periphery of the ischaemic zonemyocytes may be only partially depolarized. They be-come hyperexcitable since their resting membranepotentials become more positive, approaching thethreshold for the gating of the fast Na+ channel. Thus,any further small depolarizing stimulus (e.g. currents of

injury) may elicit an action potential, which, if it occursout of phase with the electrical cycle of the heart,may initiate an arrhythmia. In the presence of the n-3

AControl EPA Washout

2 ms1nA

0

100

EPA, M

B

Inhibition,%

50

1001010.10.011E-30

Figure 4 Inhibitory effects of EPA on INa of hH1channels transiently expressed in HEK293t cells[15]. (A)Whole-cell voltage-clamp traces are superimposed. Theywere elicited by 10 ms test pulses from 90 mV to 55 mVwith 5 mV decrements at 02 Hz for control, 5 M EPAand washout. The cells were held at 80 mV and hyper-polarized to 160 mV for 200 ms before a test pulse. (B)Suppression of INa is concentration-dependent with anIC50 of 051006 M. INa was elicited by single voltagepulses from 120 to 30 mV. Each value represents612 individual preparations exposed to different concen-trations of EPA.

Cardiac antiarrhythmic effects of polyunsaturated fatty acids D101




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PUFAs, however, a voltage-dependent shift of thesteady-state inactivation potential to more hyperpolar-ized resting potentials occurs. The consequence of this

voltage-dependent, hyperpolarizing shift is that thenegative potential necessary to return these Na+ chan-nels from an inactive state to a closed resting, but

activatable state, requires a physiologically unobtainablehyperpolarized resting membrane potential. These par-tially depolarized cells also have Na+ channels which,

within milliseconds, can slip into resting inactivationfrom the closed resting state without eliciting an actionpotential[15]. The result of these two effects of the n-3PUFAs is that these partially depolarized myocytes arequickly eliminated from function, and their potentialarrhythmic mischief is aborted. By contrast, myocytes inthe non-ischaemic myocardium, with normal restingmembrane potential, will not be so drastically affectedby this voltage-dependent action of the PUFAs andcontinue to function normally[17].

Effects on calcium channels

Disturbed regulation of cytosolic free calcium concen-trations is another cause of malignant arrhythmiasoccurring in ischaemia or resulting from a variety ofcardiac toxins. Elevations of cytosolic calcium concen-trations can result in increased frequency and amplitudeof contraction of myocytes leading to tachyarrhythmiasand delayed after-potentials.

The effects of the n-3 PUFAs on arrhythmias inducedby some cardiac toxins shown in Fig. 2 [8] are examples ofarrhythmias induced by excessive cytosolic Ca2+ fluc-tuations. Figure 6 is another example in which thecytosolic free Ca2+ fluctuations were recorded simul-taneously with the contractile activity of the neonatal

cardiomyocytes[10]. In this experiment lysophophatidyl-choline (LPC), an amphiphile, was the toxic agent. It hasbeen incriminated as one of the endogenous chemicalmediators of ventricular arrhythmias in ischaemic myo-cardium, which accumulates very early in the ischaemicheart. In Fig. 6A[10] are shown the simultaneous tracingsof myocyte contraction (top) and cytosolic free Ca2+

levels, as estimated by 360/380 nm fluorescence intensityratio of Fura 2 (lower tracing) in a spontaneouslycontracting control myocyte before and after the ad-dition of EPA (10 M) to the superfusate. The contrac-tion of the myocyte results from the spike in cytosolicfree Ca2+ which precedes the contraction spike by some

50 ms. The time-averaged cytosolic free Ca

2+

levelsremain very low, normally about 100 nM. EPA reducedthe beating rate without altering the amplitude of con-tractions, as reported[8]. On another myocyte, which hada slow endogenous beating rate, Fig. 6B shows the effectof LPC (5 M) on increasing the cytosolic free Ca2+

concentrations and fluctuations and the resulting tachy-arrhythmia. The presence of EPA (10 M) added to thesuperfusate reduced the cytosolic [Ca2+]i, sufficiently toterminate the tachyarrhythmia, though not to normalconcentrations in this experiment.

Such excessive cytosolic-free Ca2+ fluctuations asshown in Fig. 6B after LPC can induce delayed after-potentials, which may trigger fatal arrhythmias if the

after-potential occurs at a vulnerable moment in theelectrical cycle of the heart. Because both ICa,L andsarcoplasmic reticulum Ca2+-release underlie many

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Figure 5 The activation and inactivation of INa ofhuman cardiac Na+ channel alpha-subunits, hH1,expressed in human embryonic kidney cells, HEK293t, inthe absence ( ), presence ( ), and washout ( ) of EPA(5 M)[15]. (A) Averaged and normalized current-voltagerelationships (n=6) of INa are plotted, showing the inhi-bition of the peak Na+ current in the presence of EPA andpartial recovery following washout of EPA. (B) Theaveraged relative activation of INa (right) was unaffectedby EPA and the three curves control, EPA andwashout of normalized activation were superimposable.By contrast (left), EPA produced an impressive shift of thesteady state inactivation to more hyperpolarized potentialsand this was largely reversible on washout of the EPA.The same unchanged activation curves were also found forthe complete hH1 sodium channel with both alpha andbeta-1 units co-expressed[17], and for the neonatal ratcardiac myocyte[14]. The shift of the steady state inacti-vation potential to more negative potentials also occurredwith hH1 and for the rat myocyte. The shifts weresimilar for both but not as large as seen in hH1.

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cardiac arrhythmias, we examined the effects of thePUFAs on ICa,L and Ca

2+ sparks, together with A. M.Gomez and W. J. Lederer[18]. Whole-cell voltage clamptechniques and confocal Ca2+ imaging were used todetermine the effects of PUFAs on the voltage-gatedL-type Ca2+ current (ICa,L), elementary sarcoplasmicreticulum Ca2+-release events (Ca2+-sparks), and[Ca2+]i transients in isolated adult rat ventricular myo-cytes. Extracellular application of eicosapentaenoic acidand the other antiarrhythmic polyunsaturated fatty

acids, but not saturated or monounsaturated fatty acids,produced a prompt and reversible concentration-dependent inhibition of ICa,L. The concentration of EPAto produce 50% inhibition of ICa,L was 08 M inneonatal rat heart cells and 21 M in adult rat ventricu-lar myocytes. Although the EPA-induced suppression ofICa,L, did not significantly alter the shape of the currentvoltage relationship, it produced a small, but significant,negative shift of the steady-state inactivation curve(V1/2=3 to 5 mV). The suppression of the ICa,L bythe PUFAs was voltage- and time-dependent butnot use-dependent. The effects of the PUFAs on ICa,Lresemble their effects on INa, except that the steady stateinactivation potentials for ICa,Lwere shifted to the left to

a much lesser degree.When heart cells become overloaded with Ca2+, they

become arrhythmogenic and produce arrhythmogenic

ITI currents and waves of elevated [Ca2+]i that propagate

within the heart cell. During the Ca2+ overload theryanodine receptors (RyRs) become more sensitive to

the triggering process, produce an increased number ofspontaneous Ca2+ sparks, and produce propagatingwaves of elevated Ca2+, all of which can be viewed withthe confocal microscope while measuring membranecurrent. Thus it seems our finding that the n-3 PUFAsare potent inhibitors of ICa,L and that this prevents thecytosolic Ca2+ overload[18] appears to be the majormechanism by which this cause of triggered arrhythmiasevoked by ischaemia or cardiac toxins are prevented bythe PUFAs.

Effect on other sarcolemmal ion currents

Although at present we think that inhibitory effects ofthe PUFAs on INa and ICaL seem the major effectsaccounting for their antiarrhythmic actions, we are notunmindful that they affect other sarcolemmal ion cur-rents as well. By whole-cell voltage-clamp measurementswe and others (Y-F. Xiao. unpublished results) havefound that the PUFAs also inhibit K+ currents thetransient outward current, Ito, and the delayed rectifiercurrent, IK, but not the inward rectifying current, IK1.However, these influences on the important repolarizingK+ currents would have the effect of prolonging theaction potential duration, whereas the PUFAs, if any-thing, slightly shorten the action potential duration[13].

Also the concentrations of EPA required to affect therepolarizing K+ currents were considerably larger thanthose required to affect the INa and the ICa,L, as de-scribed above. However, Xiao has found other cardiactransmembrane ion currents are also affected by thePUFAs. All ion currents that he has examined in cardiacmyocytes have been found to be inhibited by the samePUFAs (Y-F. Xiao, unpublished data) including thecardiac chloride current and the ligand-activated acetyl-choline potassium current.

Toxicity questions

When we found that the n-3 PUFAs inhibited thevoltage-dependent sodium current, INa, as potently as dothe class I sodium channel-blocking drugs, we wereconcerned that the antiarrhythmic fatty acids mightprove to be as toxic clinically as the class I drugs. Thereason for the toxicity of the sodium channel-blockingdrugs does not yet seem to be understood. Duff andCatterall suggested one interesting possibility from theirexperiments[19,20]. They found that administration ofmexiletine, a class I antiarrhythmic drug to rats resultedin an up-regulation of cardiac Na+ channel expression,as shown by increase in both the level of mRNAencoding Na+ channel alpha-subunits and the number

of sodium channels per cell. It was suggested that theincreased number of sodium channels caused by chronictreatment by these drugs may secondarily itself cause

Prior to EPA 7 min after EPA (10 M)

Control 7 min after LPC (5 M) 7 min after EPA (10 M)

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tion

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Figure 6 Simultaneous measurements of [Ca2+ ]i (as in-dicated by 360/380 fluorescence ratio of Fura 2) and cellcontractions showing the effects of EPA and arrhyth-mogenic lysophosphatidylcholine in cultured neonatal ratcardiomyocytes[10]. (A) A representative recording illus-trates the [Ca2+ ]i transients (lower trace) and cell contrac-tions (upper trace) before and after perfusion of EPA(10 M) in the absence of LPC (n=6). (B) In another cell,tracings show that LPC (5 M) induces an elevation ofbasal [Ca2+ ]i levels with chaotic transients as cell contrac-ture or tachyarrhythmias occur. Addition of EPA (10 M)results in return to the initial slow control beating rate and

[Ca2+ ]i transients with the basal level reduced, but not tonormal.





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arrhythmias. Whether or not their proposal is correct, J.Kang tested the effects of EPA, mexiletine, and the twoagents together on cultured neonatal rat cardiac myo-

cytes. He found, as had Duff and Catterall, a two-tofivefold increase in the number of Na+ per cell andsimilar increase in mRNA encoding the Na+ channelprotein in the myocytes cultured with mexiletine, but noincrease over control levels in the myocytes cultured inthe presence of n-3 EPA[21]. Combining the two agentsreduced the Na+ channels and mRNA per cell by aboutone-third. Chronic treatment with potent calciumchannel-blocking drugs probably results in similarup-regulation of L-type Ca2+ channels per cell, sincecardiac myocytes are competent nucleated cells. Whenagents block an important cellular function, the affectedcell can respond by making more of the elements that

are responsible for that function. That the n-3 PUFAscan produce blockage of channels while obviating thecells, response to generate more channels, suggests somequite fundamental difference in the actions of the twoion channel-blocking agents on the myocytes. Perhapsover the millennia that these fatty acids have been partof the human diet[22], Nature has adapted importantphysiological functions for them in ways that were safefor humans.

Once we found that these fatty acids modulated theion channels in the heart excitable tissue, we stronglysuspected they would similarly affect other excitabletissues, namely muscles and the nervous system as theyall utilize highly homologous electrical communicating

systems and they do. Vreugdenhil et al.[23] determinedthe effect of these n-3 fatty acids on the sodium andcalcium channels of the hippocampal CA1 neurons ofrats and found they were both modulated very similarlyto their effects in the heart cells. A functional conse-quence of this action on the sodium and calciumchannels was tested with Voskuyl[24], who found thepolyunsaturated free fatty acids to have anticonvulsanteffects in rats, using the cortical stimulation model toinduce seizures. There has not been time to pursue thenervous system effects of these antiarrhythmic fattyacids further, but the effects we have found, I think,support our findings in the heart and hopefully will bepursued by others.

An aspect of human nutrition

Finally, for those of you who may share the scepticism Ihave had about the veracity of this presentation untilI saw the data unfold let me try to put this into thelarger picture of human nutrition. This was an attemptwith Weber to utilize the methods of evolutionarymedicine to find the place of n-3 PUFAs in humannutrition[22]. Admittedly the method in this case is verycrude, but our best estimates suggest that these fattyacids were once present in human diet in amounts nearly

as large as were the other, or n-6 class, of polyunsatu-rated fatty acids. This was during the 24 million yearsof human existence during which our genes were

adapted to our environment, including our diets (Fig. 7).Deviation began some 1015 thousand years ago (tooshort a time to affect genetic adaptation significantly)with adoption of agriculture and animal husbandrymainly of ruminants. The agriculture introduced grainsand n-6-rich vegetable oils into the diet and the rumi-nants, partially hydrogenated polyunsaturated fattyacids depriving the PUFAs of their special benefits. Thesituation was aggravated further by the Industrial Revo-lution with further hydrogenation of PUFAs formargarine and increased consumption of animal fat. n-3

Fatty acids have been declining in our diets while the n-6vegetable oils have increased. No one is surprised todaythat the n-6 fatty acids have been adapted by Nature toprovide, via the arachidonic acid cascade, a host ofpotent cell messengers: prostaglandins, leukotrienes,lipoxins and epoxygenase products. But if one suggeststhat during this same period the n-3 class of PUFAs mayalso have been adapted for important functions, some ofwhich may antagonize the effects of excesses of arachi-donic acid in our bodies, disbelief is the commonresponse. I think that we are just at the modest begin-nings of comprehending what these safe and interestingPUFAs may do for human health.

Conclusions

It is apparent that there exists a basic control of cardiacand other excitable tissues by common dietary fattyacids which has been largely overlooked. With some250 000 sudden cardiac deaths annually, largely due toventricular fibrillation, in the U.S.A. alone and millionsmore worldwide, there may be a potential large publichealth benefit from the practical application of thisrecent understanding. Initial reports suggest that the n-3PUFAs are producing beneficial effects in the treatmentof depression[25], bipolar and other behavioural dis-

eases[26]. The knowledge that these fatty acids havedirect physical effects on the fundamental property ofthe nervous system, namely its electrical activity, should

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Figure 7 Hypothetical scheme of the relative percent-ages of fat and different fatty acid families in humannutrition as extrapolated from cross-sectional analyses ofcontemporary hunter-gatherer populations. The relationto coronary heart disease (CAD) was obtained fromlongitudinal observations and the putative changes during

the preceding 100 years.

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encourage further exploration of potential beneficialeffects on brain functions both normal and pathological.It seems likely that we are just scratching the surface of

the potential health effects of these interesting dietarypolyunsaturated fatty acids.

Studies from the authors laboratories have been supported inpart by research grants DK38165 from NIDDK and by HL62284from HLBI of the National Institutes of Health of the U.S. PublicHealth Service.

The author would like to acknowledge the contributions of DrsJing X. Kang, Yong-Fu Xiao, Robert A. Voskuyl and George E.Billman to this study, without which it would not have been done.

The author regrets that because of limited space, many import-ant studies on which this work is based could not be referencedhere, but the references to the authors studies herein include thefull references to others.

References

[1] Gudbjarnason S, Hallgrimsson J. The role of myocardialmembrane lipids in the development of cardiac necrosis. ActaMed Scand 1975; (Suppl 587): 1726.

[2] Murnaghan MF. Effects of fatty acids on the ventriculararrhythmia threshold in the isolated heart of the rabbit. Br JPharmacol 1985; 73: 90915.

[3] McLennan PL, Abeywardena MY, Charnock JS. Influence ofdietary lipids on arrhythmias and infarction after coronaryartery ligation in rats. Can J Physiol Pharmacol 1985; 63:14117.

[4] McLennan PL. Relative effects of dietary saturated, mono-unsaturated, and polyunsaturated fatty acids on cardiacarrhythmias in rats. Am J Clin Nutr 1985; 57: 20712.

[5] Billman GE, Hallaq H, Leaf A. Prevention of ischemia-induced fatal ventricular arrhythmias by fatty acids. ProcNatl Acad Sci USA 1994; 91: 442730.

[6] Billman GE, Kang JX, Leaf A. Prevention of ischemia-induced cardiac sudden death by n-3 polyunsaturated fattyacids. Lipids 1997; 32: 11618.

[7] Billman GE, Kang JX, Leaf A. Prevention of ischemia-induced cardiac sudden death by pure n-3 polyunsaturatedfatty acids. Circulation 1999; 99: 24527.

[8] Kang JX, Leaf A. Effects of long-chain polyunsaturated fattyacids on the contraction of neonatal rat cardiac myocytes.Proc Natl Acad Sci USA 1994; 91: 988690.

[9] Kang JX, Leaf A. Prevention and termination of the-adrenergic agonist-induced arrhythmias by free polyunsatu-rated fatty acids in neonatal rat cardiac myocytes. BiochemBiophy Res Comm 1995; 208: 62936.

[10] Kang JX, Leaf A. Prevention and termination of arrhythmiasinduced by lysophosphatidyl choline and acylcarnitine inneonatal rat cardiac myocytes by free omega-3 polyunsatu-rated fatty acids. Eur J Pharmacol 1996; 297: 97106.

[11] Li Y, Kang JX, Leaf A. Differential effects of various eicosa-noids on the production or prevention of arrhythmias incultured neonatal rat cardiac myocytes. Prostaglandins 1997;54: 51130.

[12] Kang JX, Leaf A. Protective effect of all-trans-retinoic acidagainst cardiac arrhythmias induced by isoproterenol, lyso-phosphatidylcholine or ischemia and reperfusion. J Cardio-vasc Pharmacol 1996; 297: 87106.

[13] Kang JX, Xiao Y-F, Leaf A. Free long-chain polyunsaturatedfatty acids reduce membrane electrical excitability in neonatalrat cardiac myocytes. Proc Natl Acad Sci USA 1995; 92:39974001.

[14] Xiao Y-F, Kang JX, Morgan JP, Leaf A. Blocking effectspolyunsaturated fatty acids on Na+ channels of neonatal ratventricular myocytes. Proc Natl Acad Sci USA 1995; 92:110004.

[15] Xiao Y-F, Wright SN, Wang GK, Morgan JP, Leaf A. N-3fatty acids suppress voltage-gated Na+ currents in HEK293tcells transfected with the -subunit of the human cardiac Na+

channel. Proc Natl Acad Sci USA 1998; 95: 26805.

[16] Hille B. Local anesthetics: hydrophilic and hydrophobic path-ways for the drug-receptor reaction. J Gen Physiol 1977; 69:497515.

[17] Xiao Y-F, Wright SN, Wang GK, Morgan JP, Leaf A.Coexpression with the 1-subunit modifies the kinetics andfatty-acid block of hH1

Na+ channels. Am J Physiol 2000;

279: H3546.[18] Xiao Y-F, Gomez AM, Morgan JP, Lederer WJ, Leaf A.

Suppression of voltage-gated L-type Ca2+ currents by poly-unsaturated fatty acids in adult and neonatal rat cardiacmyocytes. Proc Natl Acad Sci USA 1997; 94: 41827.

[19] Taouis M, Sheldon RS, Duff HJ. Upregulation of the ratcardiac sodium channel by in vivo treatment with a class 1antiarrhythmic drug. J Clin Invest 1991; 88: 35778.

[20] Duff HJ, Offord J, West J, Catterall WA. Class 1 and 1Vantiarrhythmic drugs and cytosolic calcium regulate mRNAencoding the sodium channel subunit in rat cardiac muscle.Mol Pharmacol 1992; 42: 5704.

[21] Kang JX, Leaf A. Regulation of sodium channel gene expres-sion by class 1 antiarrhythmic drugs and n-3 polyunsaturatedfatty acids in cultured neonatal rat cardiomyocytes. Proc NatlAcad Sci USA 1997; 94: 27248.

[22] Leaf A, Weber PC. A new era for science in nutrition. Am JClin Nutr 1987; 45: 104853.

[23] Vreugdenhil M, Breuhl C, Voskuyl RA, Kang JX, Leaf A,Wadman WJ. Polyunsaturated fatty acids modulate sodiumand calcium currents in CA1 neurons. Proc Natl Acad SciUSA 1996; 93: 1255963.

[24] Voskuyl RA, Vreugdenhil M, Kang JX, Leaf A. Anticonvul-sant effects of polyunsaturated fatty acids in rats, usingthe cortical stimulation model. Eur J Pharmacol 1998; 31:14552.

[25] Hibbeln JR. Fish consumption and major depression. Lancet

1998; 351: 12103.[26] Stoll AL, Severus E, Freeman MP et al. Omega 3 fatty acids

in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 1999; 56: 40712.





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