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Rev iew A rtic le

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Am J C /in Nut r 1991 :54 :4 38-6 3 . P rin ted in U SA . © 1 991 A m erican S oc ie ty fo r C lin ica l N utrition

Om ega -3 fa tty a c id s in h ea lth and d ise ase

and in g row th and deve lopm en t4

 r te rn is S im op ou lo s

A B S T R A C T S eve ra l sou rces o f in fo rm a tion sug gest tha t

m an evo lved on a d ie t w ith a ratio o fw 6 to w 3 fa tty ac ids o f 1

w hereas today th is ra tio is 10 :1 to 20-25 :1 , ind ica tin g tha t

W es tern d ie ts a re defic ien t in w 3 fa tty ac ids com pared w ith the

d ie t on w hich hum an s evo lv ed an d the ir g en etic pa tte rn s w ere

estab lished . O m ega-3 fatty ac ids inc rease b leed ing tim e; decrease

p late le t aggrega tion , b lood v iscosity , and fib nnog en : and increase

e ry th rocy te defo rm ab ility , thu s d ecreas ing the tend en cy to

th rom bu s fo rm ation . In no c lin ica l tr ia l, inc lud ing coronary ar-

te ry gra ft su rgery , h as the re b een any ev idence of inc reased b lood

lo ss due to ing estion of w 3 fa tty acids . M any s tu d ies sho w tha t

th e ef fects o f w 3 fa tty ac id s on serum lip id s d ep en d on the typ e

of pa tien t and w hether th e am oun t o f sa tu ra ted fa tty ac ids in

th e d ie t is he ld cons tan t. In pa tien ts w ith h yperlip idem ia , w 3

fa tty ac id s decrease low -dens ity -lip opro te in (L D L ) cho les tero l

if the sa tu ra ted fatty ac id con ten t is decreased , o the rw ise th ere

is a sligh t in c rease , bu t a t h igh d oses (32 g ) th ey low er

LD L

cho leste ro l: fu rthe rm ore , they co nsis ten tly low er se rum trig lyc -

e rides in no rm al sub jec ts an d in p atien ts w ith hyp ertr ig ly cer -

id em ia w hereas the ef fect o n h igh -dens ity lip opro te in (H D L )

varies from no effec t to sligh t inc reases . T h e d isc repanc ies be-

tw een an im al an d hum an s tud ies m o st like ly a re due to d iffe r-

ences be tw een an im al and hu m an m etabo lism . In c lin ica l tria ls

e ico sapen taeno ic ac id (E P A ) and do co sahexaeno ic ac id  DHA

in the fo rm of fish o ils a lo ng w ith an tirh eu m atic d rug s im prove

jo in t pa in in p atien ts w ith rh eum ato id arth ritis: have a benefic ia l

e ffec t in pa tien ts w ith u lce ra tiv e co litis: and in com b in ation w ith

drugs, im pro ve the sk in les ions , low er the h yperlip idem ia from

etre tin ates , an d decrease th e to x icity o f cyc losporin in p atien ts

w ith psoriasis. In variou s an im al m ode ls w 3 fatty ac id s decrease

the nu m ber and s ize of tum o rs and increase the tim e e lap sed

befo re app earance oftum ors . S tu d ies w ith n onhum an prim ates

and hum an new b orns ind ica te tha t D N A is essen tial fo r the

norm al func tiona l dev elop m en t o f the re tina and bra in , pa rtic-

u la rly in prem atu re in fan ts. B ecau se w 3 fa tty ac ids a re essen tia l

in g row th and dev elop m ent th rough ou t the life cyc le , they shou ld

be inc luded in the d ie ts o f a ll hum an s. O m ega-3 an d w 6 fa tty

ac ids a re no t in te rcon vertib le in the hum an body and are im -

portan t com pon en ts o fp rac tica lly a ll ce ll m em branes. W hereas

ce llu la r p ro te in s a re gene tica lly de te rm ined , th e po lyu nsa tu ra ted

fa tty ac id (PU FA ) com pos ition ofce ll m em branes is to a g reat

ex ten t depend en t on the d ieta ry in take . T here fo re ap prop ria te

am ou n ts o fd ieta ry w 6 and w 3 fa tty acids need to be co nsidered

in m ak in g d ie ta ry recom m enda tions , and th ese tw o c lasses o f

P U F A s sh ou ld be d istingu ished becau se they a re m etabo lica lly

an d func tiona lly d is tinc t and hav e op pos in g phy sio log ica l func-

tions . T h eir ba lance is im p ortan t fo r hom eos tas is and norm al

d eve lo pm ent. C anada is the firs t coun try to p rov id e sepa ra te

d ieta ry recom m end ations fo r w 6 an d w 3 fa tty acids .

Am J

C lin N u tr 19 9 1:54 :438 -63 .

K E Y W O R D S P o lyun sa tu ra ted fatty acid s, w 3 fa tty ac ids ,

w 6 fa tty ac ids, lip id s, ct- lino len ic acid , e ico sap en taen o ic ac id ,

d ocosah ex aen o ic ac id , essen tia lity in grow th and deve lopm ent,

ca rd io vascu la r d isease , hyp erten sion , in f lam m ation , a rth ritis an d

o ther au to im m une d iso rders , pso riasis, cancer, p ro stag land ins ,

leuk o trien es , in te rleu k ins, p la te let-d er iv ed grow th fac to r, en -

d o the liu m -derived re lax ing fac to r

Conten ts

In t roduc t ion

O m eg a-3 and w 6 fa tty acids : sources , e long a tion ,

a nd d es at ur at io n

E v olu tio nary aspec ts: the w 3 and u6 fa tty acid ba lance

L arge-sca le p rodu c tion of vege tab le o ils

A gribu siness and m odern agricu ltu re

Im ba lan ce of w 6:3

B io lo g ica l ef fec ts o fw 3 fa tty ac ids in re la tion to coro nary

hear t d isease and hypertens ion

E icosano id m etab o lism

M olecu la r asp ects and gene expression :

beyond th e e ico sano ids

H ypo lip idem ic ef fects

E ffec ts o n norm al sub jec ts

E ffec ts o n pa tien ts

A ntia the rom atous ac tio ns

A ntith rom b otic e ffec ts

V ascu la r e ffec ts

A ntia rrhy th m ic effec ts

E ffects on res ten osis

E ffects on lipop ro te in (a )

A d d itio na l e ffec ts

I

F rom the C en te r fo r G ene tics, N u trition and H ea lth , W ash in g ton ,

D C.

2 Sup ported in p art by T h e C o unc il fo r R espons ib le N utritio n (C R N ),

W as hi ng to n, D C.

3 T his rev iew paper w as p repared a t the reques t o f C R N an d w as

sub m itted to the Foo d and D rug A dm in istra tion b y the C R N o n D e-

ce mb er 19 . 1 990 .

4 A d d r e s s

rep rin t requests to A P S im opou lo s, T he C en te r fo r G ene tics,

N u trition and H ea lth . 20 01 S S tree t. N W , S u ite 530 , W ash in g ton , D C

20009 .

R eceiv ed Febru ary 27 , 199 1 .

A ccep ted fo r p ub lication M arch 2 0 , 19 91 .

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w 3 FA T T Y A C ID S IN H E A L T H A N D D ISE A SE

43 9

C oronary heart d isease

H yper tens ion

In flam m ato ry an d au to im m un e d iso rders

Arthritis

Psor ias is

U lce ra tiv e co litis

C ancer

D iabe tes

O m eg a-3 fa tty ac ids as an ad ju van t to d rug therapy

E ssen tia lity : the ro le o f w 3 fa tty ac ids in gro w th

a nd d ev elo pm en t

A nim al s tud ies

Human studies

Pregnancy

F eta l deve lopm en t, hum an m ilk , and in fan t feed ing

C h ild ren , ad u lts , an d eld erly adu lts

D ie ta ry im plic atio ns

C onc lus ions

Addendum

R eferences

In t roduc t ion

In th e 195 0s m an y investiga to rs stu d ied th e e ffec ts o fco rn o il

and fish o il in hum ans prim arily by de te rm in ing the ir e ffec ts on

se rum cho leste ro l concen tra tions in pa tien ts w ith a th e rosc le ros is

(1 -5 ). C orn o il (w 6 fatty ac id ), an odo rless, clea r o il, w as foun d

to low er ch o les te ro l, pa rticu la rly w hen it rep laced b u tter o r la rd

in the d ie t. A lth ough sard ine o il (w 3 fa tty ac id ) had s im ila r e ffec ts

and in add ition lo w ered se rum trig lyceride concen tra tions, it

w as no t g iven the a tten tion it d ese rved

(2 ) .

V eg etab le o ils r ich

in w 6 fa tty ac id s d isp laced o th er fats in th e U S d ie t and even tua lly

in the d ie t o f W es te rn E uro peans, o n the ev idence of th eir hy-

poch o les te ro lem ic pro pertie s . O m ega-3 fa tty acids w ere no t

con side red as im p ortan t ag en ts in the con tro l o f ca rd iovascu la r

d isease (C V D ) desp ite experim en ta l and clin ica l w ork po in ting

to the ir im portance (6 -9 ). W ith the em phas is on th e lip id hy-

po thes is, the low erin g ofse rum cho les tero l becam e th e dom inan t

facto r fo r the co n tro l o f co ronary heart d isease (C H D ). A s a

result

th e p rim ary con tr ibu tions o fin f lam m ation and th rom bosis

in th e deve lop m en t o f C H D w ere no t adequa te ly inves tiga ted

un til the la te l97 0s and l98 0s and no w .

In the 1 970 s B ang an d D yerberg   10 - 1 2) reported the ir find -

ings tha t E sk im os had low ra tes o fC H D and cancer d esp ite the ir

h igh-fa t d ie t. B ang an d D yerberg (1 3 , 14) em phas ized the im -

por tance of e icosapen taeno ic ac id (E P A ) in the prev en tion of

heart a ttack s because of its an tith rom botic e ffec ts, th e inc rease

in b leed in g tim e , and its e ffec t in low ering se rum ch o les te ro l

con cen tra tions . S ubsequen tly o ther ep idem io lo g ic stud ies con -

firm ed these find in gs and show ed tha t fish -ea ting po pu la tion s

o ther than th e E sk im os had less C V D than d id those w ho co n-

sum ed less f ish

 

1 5-2 0). E v en as little as 3 0-40 g of fish tw ice a

w eek m ade a d iffe rence (1 7 ). In tw o o ther stud ies th is e ffec t o f

h igher fish in take w as no t seen , m os t lik ely because o f s im ul-

taneou s h igh sa tu ra ted fatty acid in take

(2

1,

22) .

A dditiona l c lin ical inves tiga tions and experim en ta l s tud ies

con firm ed the in itia l observa tion s: w hen d ie ts a re supp lem en ted

w ith o3 fa tty ac ids, the la tte r p a rtia lly rep lace the w 6 fa tty ac ids

in th e m em branes of p ractica lly a ll ce lls (ie , ery th rocy tes, p la te -

le ts , endo the lia l ce lls, m o nocy tes, lym ph ocy tes, g ran u locy tes,

neurona l ce lls , f ib rob lasts , re tina l ce lls , h ep atic ce lls , and n eu -

rob las tom a ce lls); o3 fa tty acids m od u la te p ros tag land in m etab-

o lism and decrease trig lycerides ; and in h igh d oses w 3 fa tty ac ids

lo w er cho les te ro l and have an tith ro m botic and an ti-in flam m a-

to ry prop ertie s . T hese stud ies w ere ex tens ive ly rev iew ed and re -

p or te d 2 3- 28 .

T he 1980 s w ere a p e riod ofex pansion in o ur kn ow led ge abo u t

po lyun sa tu ra ted fa tty ac ids (P U F A s) in g en era l and w 3 fa tty

ac id s in particu la r. T oday w e know tha t w 3 fa tty ac ids a re es-

sen tia l fo r no rm al g row th and d ev elop m ent and m ay p lay an

impor tan t

ro le in the p reven tion an d treatm en t o fco ro na ry a rtery

d isease , hypertens io n , a rth ritis, o the r in flam m atory an d au-

to im m une d iso rders , and cancer. R esearch has been carried ou t

in an im al m o de ls , tis su e cu ltu res . and hum ans . T he o rig in a l

observa tion a l s tu d ies hav e g iven w ay to con tro lled c lin ica l tria ls.

A new arena fo r w 3 fatty ac ids has em erged as ad juv an ts to d rug

trea tm en t lead ing to synerg ism (p o ten tia ting the effec ts o f d rugs)

o r to d ecreas in g the ir tox icity . T h is im m ense expans io n in our

k now ledg e is sho w n by th e increase in the num b er of pub lica tion s

from 1 10 in 1984 to 319 in 1989 worldwide based on January

10 , 199 0 , N IH -M E D L IN E search ou tp u t), am o un ting to 154 1

fo r th e 5-year p erio d (F ig I ) (29). In S ep tem b er 1 98 9 the U S

N ation al L ib ra ry ofM edic in e pu b lished a se lec tiv e b ib liog raphy

o n the hea lth benefits o f fish o ils th at inc luded pub lica tions from

January 1985 to M ay 198 9 bu t w as in ten tiona lly lim ited to h u-

m an s tud ies. C ited w ere 576 artic les p ub lished in 1 5 5 jo urna ls

from aro und th e w o rld . T h e b ib liog raph y is in d icativ e o f th e

exp lo sive and expand ing in te res t in the hea lth benefits o f f ish

o ils and w 3 fa tty acids .

A lth oug h a nu m ber o f im po rtan t co nferences had been he ld

befo re 1985 , su ch as th e R ead ing confe rence he ld in 1984 , the

expans ion o fth is im p ress iv e grow th in ou r kno w ledge can a lm os t

be da ted from the 19 85 conferen ce H ealth E ffec ts o f P o lyun -

sa tu ra ted F a tty A c ids in S eafood s, he ld Ju ne 2 4-2 5 , 19 85 , in

W ash in g ton , D C (2 4). T he 1 985 co nference w as the first m aj o r

in terna tion al confe rence to es tab lish th e fact tha t w 3 fa tty ac ids

of m arin e o rig in , E P A and do co sahexaen o ic ac id (D H A ), p lay

im portan t ro les in prostag land in m etabo lism , th rom b osis and

a theroscle ros is, im m unology and in flam m ation , and m em brane

func tion . T h e 19 85 co nfe rence p ar tic ipan ts reco m m ended 1)

the su pport o f resea rch o n the ro le o f w 3 fa tty ac ids in grow th

and d ev e lopm en t and in h ea lth and d isea se and o n th e m ech -

an ism s invo lved and

2) the estab lish m en t o f a te st-m ate r ials

prog ram to spec if ica lly define nu tritio na l requ irem en ts th rough -

ou t the life cyc le , and do se and type of w 3 fa tty ac id in in te r-

ven tion stud ies and in c lin ica l tria ls.

A fte r the confe rence the N a tio na l In stitu te s o f H ealth (N IH )

p ub lished a ser ies o f p rogram an nouncem ents inv iting app li-

ca tions fo r research on th e ro le o f w 3 fa tty ac ids in g row th and

d eve lopm en t and in hea lth and d isea se (T ab le 1 )(2 9 ). T o su ppo rt

th e resea rch , in D ecem ber 1986 the U S D epartm en t o f C orn-

m erce deve lo ped a sp ec ia l p ro g ram , the B iom ed ica l T est M a-

te ria ls (B T M ) prog ram , w hich pro v ides standard ized tes t m a-

te ria ls o f k now n co m pos ition of E P A an d D H A nationa lly and

in te rna tiona lly . T hese tes t m ate ria ls co n tain 0 .2 m g te rtia ry bu-

ty lh ydroq u inone (T B H Q )/g as an an tiox idan t an d 2 m g to -

co phero ls /g (30).

T h e resp onse o f th e scien tific com m un ity m ad e it ob v iou s

fro m the ve ry beg in n ing tha t re sea rch w ith w 3 fatty ac ids w ou ld

d eve lop alo ng tw o avenu es: 1) stud ies on the essen tiality o f th e

w 3 fa tty ac ids tha t w o u ld define the ir ro le in grow th and dev el-

op m ent th rou ghou t the life cyc le based on the defic iency m od el

and im provem en t in va rious func tion s up on sup p lem en ta tion

w ith w 3 fa tty acids and

2)

stud ies inv o lv ing m echan ism s in th e

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Y e a r

440

S I M O P O U LO S

I

-J

z

w

z

-I

0

w

C

C

C

.5

U

C

.5

E

z

FI G I

.

Publications of marine oil and fish oil and w 3 fatty acid studies retrieved from M ED LI N E (N ational L ibrary

of M edicine, N ational I nstitutes of H ealth) from 1984 to 1989. (D ata as ofianuary 10, 1990, from M ED L I N E. B y

June 1989 the total number of publications for 1989 w as 386.) R eproduced with permission from reference 29.

understanding of chronic diseases that w ould use the supple- medical and nutrition journals (27, 28, 35-37). T he most recent

mentation approach by increasing the amount offish in the diet, research advances were extensively discussed at the Second I n-

substituting fish for meat, or using fish oils. ternational Conference on the H ealth Effects ofO mega-3 Poly-

Since 1985 many conferences have been held in various parts unsaturated Fatty A cids in Seafoods, held M arch 20-23, 1990,

of the w orld to review progress in the field, define gaps in the in W ashington, D C (25) .

know ledge, and develop a research agenda (24, 25, 3 1-34) . I n T his paper presents the state ofthe art in w 3 fatty acid research,

addition, major review s and commentaries appeared in leading draw n from the published literature, the N I H database Computer

TABLE I

Requests for applications (R FA s) and program announcements (PA s) by N I H and A D A M HA : D ecember 6, 1985, to A pril 17, l987

D ate T itle T ype I nstitute

D ecember 6. 1985 Biological M echanisms ofw3 Fatty A cids in H ealth and

D i sease S tat es

PA N C C. (N I A D D K , N I N C D S. N I A I D N I CH D ,

N I GM S, N EI , N I EH S, N I A , N I A A A ,

N I M H )

June 1986 Studies ofw 3 Polyunsaturated Fatty A cids in

T hrombosis and Cardiovascular D isease

R FA N H L BI

August 22. 1986

The Role ofw 3 Polyunsaturated Fatty A cids in C ancer

Prevention

PA N CI

A pril 17, 1987

The Role ofw 3 Polyunsaturated Fatty A cid in Cancer

P rev en ti on ( rei ssu ed )

PA N CI

October

22, 1987 Fatty A cid D erived M ediators of Inf lammation

R FA N I A I D

S

R eproduced with permission from reference

29.

N IH : N ational I nstitutes of H ealth: A D AM HA : A lcohol, D rug A buse and M ental H ealth A dministration: N CC: N utrition C oordinating Committee:

N I A D D K : N ational I nstitute of D iabetes and D igestive and K idney D iseases: N I N CD S: N ational I nstitute of N eurological and C ommunicative

D isorders and Stroke: N I A I D : N ational I nstitute of A llergy and I nfectious D iseases: N I C H D : N ational I nstitute of C hild H ealth and H uman D e-

velopment: N I G M S: N ational I nstitute of General M edical Sciences: N EI : N ational Eye I nstitute: N I EH S: N ational I nstitute of Environmental

H ealth Sciences: N I A : N ational I nstitute on A ging: N I A A A : N ational I nstitute on A lcohol A buse and A lcoholism: N I M H: N ational I nstitute of

M ental H ealth: N H LB I : N ational H eart, L ung, and Blood I nstitute: N C I : N ational Cancer I nstitute: and N I A I D : N ational I nstitute ofA llergy and

I n fect io us D i seases.

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w 3 F A T T Y A C ID S IN H E A L T H A N D D ISE A SE

44 1

FI G 3 . E ssen tia l fa tty ac id m eta bo lism d esa tura tio n and e lon ga tion of w 6 a nd w 3 .

O m e g a C a r b o n s

a- t lno len lc H , “ .C O O H

U nols lc H 3

coO) H ,C   R . C O O H

F IG 2 . Stru ctu ral fo rm u las fo r w 3 (a-lino le ic ), 6 (lin o leic ), and w 9

(o le ic ) fa tty acids . T he firs t num ber (befo re th e co lon) g iv es th e n um ber

of ca rbon a to m s in the m olecu le and the secon d g iv es th e n um ber of

do ub le bo nds . w3, w 6, and w 9 ind ica te p osition ofthe first doub le b ond

in a g iv en fat ty a cid m olecu le .

R etrieva l o f In fo rm ation o n S c ien tific P ro jec ts

(C R IS P ), a nd

presen ta tion s a t th e 1 9 90 conferen ce .

O mega-3 and w 6 fat ty acids: sou r ces elongat ion

a nd d esa tu r at i on

U nsatu rated fa tty ac ids co nsis t o fm ono unsatu rates and po ly -

un sa tu ra te s . T he re are tw o cla sse s o f P U F A s, w 3 and w 6 . T he

d is tin ction be tw een w 3 and w 6 fa tty acid s is based

on the lo ca tion

o f the first do ub le bon d , coun ting fro m th e m e thy l end o f the

fa tty ac id m olecu le . M onou nsa tu ra tes a re rep resen ted b y o le ic

ac id , w hich can be syn thes ized b y a ll m am m als inc lud in g hu-

m ans . I ts do ub le bo nd is be tw een th e 9 th and 10 th carbo n a tom s

(F ig 2 ).

O m eg a-3 an d w 6 fa tty acid s a re a lso kno w n as essen tia l fa tty

ac ids (E F A s) because hum ans , lik e a ll m am m als, cann o t m ak e

th em an d m ust o b ta in them in th eir d iet. O m ega -6 fatty ac ids

are rep resen ted b y lino le ic ac id (L A ) and w 3 fatty ac id s b y

a-lino len ic ac id (L N A ).

L A is p len tifu l in na tu re and is fou nd in th e seeds of m o st

p l a n t s e x c e p t f o r c o c o n u t c o c o a a n d p a l m. L NA o n t h e o t h e r

hand is fo und in the ch lo rop las t o fg reen leafy vege tab les. B o th

E F A s are m e tab o lized to lon ge r-cha in fa tty ac ids o f 20 and 2 2

carbo n a tom s . L A is m etabo lized to arach id on ic ac id (A A ) and

L N A , to E P A and D H A , in creas ing the cha in leng th and degree

of unsa tu ra tion b y add ing ex tra d oub le bon ds to the carboxy l

g r o u p F i g 3 .

H um ans an d an im a ls ex cep t fo r ca rn ivo re s such as lions and

ca ts can co nvert L A to A A and L N A to E P A an d D H A (3 8).

T h is co nvers io n w as sho w n by us ing deu te ra ted L N A (39 ). T h ere

is com petitio n b etw een w 3 and w 6 fa tty ac ids fo r the desa tu ra tio n

enzy m es. H o w eve r , bo th 4 and 6 desa tu ra se s p re fer w 3 to

w 6 fa tty ac id s (3 8 , 40 , 4 1 ) . T he re is som e ev idence th at 6

d esa tu rase decreases w ith ag e (38 ). P rem atu re in fan ts (4 2), hy -

pertens iv e ind iv idua ls (43) , and som e diabe tics (4 4) a re lim ited

in the ir ab ility to m ake E P A and D H A from L N A . T hese find ings

a re im portan t and n eed to be cons id e red w h en m ak in g d ie ta ry

recom m enda tio ns. E P A and D H A are foun d in the o ils o f f ish ,

particu la rly fa tty fish (T ab le 2 ) (24) . A A is found predo m in an tly

in th e phospho lip ids o f g rain - fed an im als.

L A , L N A , an d th eir long -cha in de riva tive s a re im portan t

com po nen ts o fan im al and p lan t ce ll m em branes. In m am m als

and b irds the w 3 fa tty ac ids are d istrib u ted selec tive ly am ong

lip id classes. L N A is found in trig lycerides , in cho les tery l este rs,

and in v ery sm a ll am ou n ts in pho sph o lip id s. E P A is fou nd in

cho les te ry l es ters, tr ig ly cerides , and p hospho lip ids . D H A is foun d

m ostly in p hospho lip ids . In m am m als , inc lud in g hum ans , the

cereb ra l co r tex (45), re tin a (46), and tes tis an d sp erm (47) a re

particu la rly rich in D H A . D H A is o ne o f the m os t abundan t

com p onen ts o fth e b ra in ’s struc tu ra l lip id s. D H A , like E P A , can

be d erived on ly from d irec t ing es tio n or b y syn thesis from d ieta ry

E PA or L N A .

E volu t ionar y aspect s: t he w 3 and w 6 fat t y acid bal ance

O n the basis o festim ates from stud ies in pa leo lith ic nu tr ition

and m o dern -d ay hun ter-ga the re r pop u la tions , hum an s ev o lved

on a d ie t tha t w as m uch low er in sa tu ra ted fa tty ac ids than is

today’s d ie t. Fur th erm ore , the d ie t co n tained sm all bu t rough ly

equa l am ou n ts o fw 6 and w 3 P U F A s (F ig 4 ) (4 8 -50) .

L ino lea te se ries Lino lenat .e series

C 18:2 w 6 L ino leic acid

 

desaturase

4

C 1 8:3w 6 G am m a-lino len ic ac id

4

C 20:3w 6

D ihom o-gam m a-L in o len ic A cid

 

desa tu rase

C 20:4w 6 A rach ido n ic ac id

C 2 2 : 4 w 6

 

4

C 22:5w 6

D ocosapen taeno ic ac id

C 1 8 :3 w 3 A lp ha -Iin ole nic acid

  desaturase

1

C 18:4w 3

1

C 20:4w 3

  desatwase

4

C 20:5w 3 E icosapen taeno ic acid

4

C 22:5 w 3 D ocosapen taeno ic ac id

  desatu rase

4

C 22:6w 3

D ocosahexaenoi c acid

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4 4 2

S IM O P O U L O S

TA B LE 2

C o ntent of w 3 fatty acids and other fat com p onents in selected fish

Total

Fatty acids

Total Total Total

Fish fat

saturated m onounsaturated polyunsaturated 18:3 20:5

22:6 C holesterol

g/iOOg mg/lOOg

A n c h o v y ,

E uropean 4.8 1.3 1.2 1.6

-

0.5 0.9

-

B ass, striped 2.3 0.5 0.7

0.8 Tr 0.2 0.6 80

B luefish 6.5 1.4 2.9 1.6

-

0.4 0.8 59

C arp 5.6 1.1 2.3 1.4 0.3 0.2 0.1 67

Catfish, brown

bullhead 2.7 0.6

1.0 0.8 0.1 0.2 0.2 75

C atfish, channel 4.3 1.0 1.6 1.0 Tr 0.1 0.2 58

C od, A tlantic 0.7 0. 1

0. 1 0.3 Tr 0. 1 0.2 43

C roaker, A tlantic 3.2 1.1

1.2 0.5 Tr 0.1 0.1 61

flounder,

unspecified 1.0 0.2 0.3 0.3

T r 0.1 0.1 46

G rouper, red 0.8 0.2 0.1

0.2 - Tr 0.2 -

H addock 0.7 0. 1 0. 1 0.2 Tr 0. 1 0. 1 63

H alibut,

G reenland 13.8 2.4 8.4 1.4 Tr 0.5 0.4 46

H alibut, Pacific 2.3 0.3 0.8

0.7 0. 1 0. 1

0.3 32

H erring, Pacific 13.9

3.3 6.9 2.4 0.1 1.0 0.7 77

H erring, round 4.4

1.3 0.8 1.5 0.1 0.4 0.8 28

M ackerel,king 13.0 2.5 5.9

3.2 - 1 . 0 1 . 2 5 3

M ullet,striped 3.7 1.2 1.1 1.1 0.1 0.3 0.2 49

O cean perch 1.6 0.3

0.6 0.5

Tr 0.1 0.1 42

Plaice, European

1.5 0.3 0.5 0.4 Tr 0.1

0.1 70

Pollock 1.0

0. 1 0. 1 0.5

-

0. 1

0.4 71

Pom pano,

f l o r i d a

9 . 5 3 . 5 2 . 6 1 . 1

- 0.2 0.4 50

Salm on, C hinook 10.4 2.5 4.5

2.1 0.1 0.8 0.6 -

Salm on, pink 3.4 0.6

0.9 1.4 Tr

0.4 0.6 -

S napper, red

1.2 0.2 0.2 0.4

Tr Tr 0.2 -

Sole, E uropean

1.2 0.3 0.4

0.2 Tr

Tr 0. 1 50

Sw ordfish 2.1 0.6 0.8 0.2

-

0.1 0.1 39

T rout, rainbow 3.4 0.6

1.0 1.2

0. 1 0. 1 0.4 57

Tuna,albacore 4.9 1.2 1.2

1.8 0.2 0.3 1.0 54

Tuna, unspecified 2.5 0.9 0.6

0.5 - 0.1 0.4 -

S Per 100 g edible portion, raw . D ashes denote lack of reliable data for nutrient know n to be present; T r, trace (< 0.05 g/lO O g food). A dapted

from the U n ited S tates D e partm ent ofA g riculture P rovisional T able on the C o ntent ofO m ega-3 F atty A cids and O ther F at C o m ponents in Seafoods

as presented by S im o poulos et al (24).

Large-scale production of vegetable oils

T he increased consum p tion of w 6 fatty acids in the last 100

y is due to the developm ent of technology at the turn of the

century that m arked the beginning of the m o dern vegetable-oil

industry and to m odern agriculture w ith the em phasis on grain

feeds for dom estic livestock (grains are rich in w 6 fatty acids)

(5 1

).

The invention of the continuous screw press, nam ed E x-

pellet#{174}

y V D A nderson, and the steam -vacuum deodorization

process by D W esson m ade possible the industrial production

ofcottonseed oil and other vegetable oils for cooking(5 1). S olvent

extraction of oilseeds cam e into increased use after W orld W ar

I and the large-scale production of vegetable oils becam e m ore

efficient and m o re econom ic. Subsequently, hydrogenation w as

applied to oils to solidify them . T he partial selective hydrogen-

ation of soybean oil reduced the LN A content of the oil w hile

leaving a high concentration of LA . LN A content w as reduced

because LN A in so ybean o il cau sed m an y o rg an oleptic problem s.

It w as recently documented that the hydrogenation process and

particularly the form ation oftrans fatty acids has led to increases

in serum cholesterol concentrations w hereas LA in its regular

state in oil is associated

w ith a reduced serum cholesterol con-

cen tration (52, 53).

A s stated in the introduction, since the 1950s, research on

the effects of PU F A s in low ering serum cholesterol concen-

trations has dom inated the research support on the role of

P U F A s in lipid m etabolism . A lthough a num ber of investiga-

tom contributed extensively, the paper by A hrens et al in 1954

(1) and subsequent w ork by K eys et al (2) firm ly established

the 6 fatty acids as the im portant fatty acids in the field

of C V D . The availability of m ethods for the production of

vegetable

oils and their use in low ering serum cholesterol

concentration led to an increase in both the fat content of the

8/17/2019 5. Acizii Grasi Omega 3 in Sanatate Si Boala Sau in Crestere Si Dezvoltare Am J Clin Nutr-1991-Simopoulos-438-63

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 4 o

 0

  ____._.._._J2t I± ___._

-

2 O

  1 0

 0 L I i i

  -4 x 1 0 y .w t )

 o3 FA T T Y A C I D S I N H EA L T H A N D D I SEA SE

443

5

R eproduced with permission from reference 58.

Hwi le r -Gc f hirer

Agr/cu/ t irc /

/ thistr j/

(10,000 ysort)

1800 1900 2000

T M

ye ta rs

FI G 4. Scheme of the relative percentages of different dietary fatty acids (saturated fatty acids and w 6 and w3

unsaturated fatty acids) and possible changes subsequent to industrial food processing, involving fattening of animal

husbandry and hydrogenation of fatty acids. R eproduced from reference 48.

diet and the greater increase in vegetable oils rich in w6 fatty

acids.

Agr ib usiness and m odern ag ricu ltu re

A gribusiness contributed further to the decrease in w3 fatty

acids in animal carcasses. W ild animals and birds w ho feed on

wild plants are very lean, w ith a carcass fat content ofonly 3.9%

(54), and contain about five times more PU FA s per gram than

is found in domestic livestock (55,

56) .

M ost importantly, 4%

ofthe fat ofw ild animals contains EPA . D omestic beef contains

very small or undetectable amounts of L N A because cattle are

fed grains rich in w6 fatty acids and poor in w 3 fatty acids (57)

whereas deer that forage on ferns and mosses contain more w 3

fatty acids (L N A ) in their meat.

M odern agriculture with its emphasis on production has de-

creased the w 3 fatty acid content in many foods: green leafy

vegetables, animal meats, eggs, and even fish (58-6 1

). Foods

from edible wild plants contain a good balance of w 6 and w 3

fatty acids (T able 3) (58). M odern aquaculture produces fish

that contain less w 3 fatty acid than do fish grow n naturally in

the ocean, rivers, and lakes (T able

4) (60). A s can be seen from

T able S comparing the fatty acid composition of egg yolk from

free-ranging chickens and the standard U S D epartment of A gri-

culture (U SD A ) egg, the former has an w 6-w 3 ratio (w 6:w3) of

1.3 w hereas the U SD A egg

has an w 6:w 3 of 19.4

  59 ) .

Im ba lance o f w 6 .w 3

Before the l940s cod-liver oil w as ingested mainly by children

as a source of vitamins A and D with the usual dose being a

teaspoon. O nce these vitamins w ere synthesized consumption

of cod-liver oil w as drastically decreased. T hus an absolute and

relative change of 6:w3 in the food supply of W estern societies

has occurred over the last 100

y

(Fig 4) (48). A balance existed

betw een w 6 and w 3 for millions of years during the long evo-

lutionary history of the genus Homo , and genetic changes oc-

curred partly in response to these dietary influences (49). H ow -

ever, rapid dietary changes over short periods of time as have

occurred over the past 100-

1 50 y is a totally new phenomenon

in human evolution

H om o sap ien s m ade hi s appearance

 

40 000 y ago and the

human genetic constitution has remained relatively unchanged.

T hen, 10

000

y ago, agriculture began to bring changes slowly

in food consumption. I t is only since the industrial revolution

that changes in food consumption have occurred rapidly. T hese

changes are reflected in increased consumption of animal fat

and in imbalances in w 6:w 3. T he ratio that was 1 from veg-

etable and animal sources during the evolutionary

period for

humans is now estimated by H unter (6 1) to be 10-1 1 : 1 from

vegetable sources. From evidence that the

per capita consump-

tion of major foods in 1987 w as 61.4 kg red meat, 28.6 kg

chicken, and 6.8 kg fish plus the increases in w 6 fatty acids from

vegetable oils, the ratio is closer to 20-25: 1 from vegetable and

T A BL E 3

Fatty acid content of plants*

Fatty

acid Purslane Spinach

Buttercrunch

lettuce

Red leaf

lettuce M ustard

m g /g w e t

W

14:0 0. 16 0.03 0.0 1

0.03 0.02

16:0 0.81 0.16 0.07

0.10 0.13

18:0

0.20 0.01 0.02 0.01

0.02

18:1w 9 0.43 0.04

0.03 0.01 0.01

18:2w6 89 14

  1 12 12

18:3w 3 4.05

0.89 0.26 0.31

0.48

20:5w 3 0.01 0.00

0.00 0.00 0.00

22:6w 3 0.00 0.00

0.001 0.002 0.001

O ther I

.9 5

0.43 0. 1 1 0. I 2

0.32

T otal 8.50 1.70 0.60

0.702 1.101

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4 4 4

S IM O P O U L O S

TA B LE 4

Fat content and fatty acid com p osition of w ild and cultured trout, eel, and

Trout

  almo gairdneri

a n d

  a lm o tru tta fario)

Eel

  A ngu i /l a angui ll a)

Salm o n (S

a/mo sal ar )

W ild C ultured W ild

C ultured

W ild

C ultured

 n= 2) n= 9) n= 4) n= 4)

  n= 2) n= 2)

F a t (g/lO O g) 5

±

3 6

±

1 21

±

6 30

±

2 t 1 0

±

0.1 16

±

0 . 6 4

Fatty acids

(g/ 100 g fatty acid)

l8:3w 3 3±2 1 ±0.34 2±2 1 ±0.3 1 ±0.1

1 ±0.1

2 0 : 5 w3 7 ± 0 . 6 4 ± 14 4±2 3 ±0.6 5 ±0.2 5 ±0.1

2 2 : 6 w3 1 5 ± 2 1 3 ± l t

4 ± 2 6 ± 0 . 4 1 0 ± 2 7 ± 0 . l t

O ther w 3 5 ± 0.6 2 ± 0.74

3 ± 1 2 ± 0.2t 3 ± 0.5 4 ± 0.1

l8:2w 6 4±3 9 ±24 2±2

5 ±0.34 1 ±0.1 3 ±0.1

O ther w 611

I ± 0.4 0.6 ± 0.14 2 ± 0.3 0.4 ± 0.14 0.2 ± 0.1 0.5 ± 0.1

Total w 3 30 ± 0 . 2 2 0 ± 3 4 1 4 ± 3

1 2 ± I 20 ± 2 1 7 ± 0.2

T otal w 6 5 ± 3 9 ± 2 t

3 ± 1 6 ±

0.34 2

± 0 . 1 3 ±

0.14

w 3:w 6 7±5 2 ± 0 . 6 4

5 ± 2 2 ± 0 . 3 t 1 1 ±2 6 ± 0 . l t

 

R eproduced from reference 60. ± SD ;

n,

num b er of lots; each lot consisted of about six trout or eel or one or tw o salm o n.

tt Significantly different from w ild:

tP

 

0.05, 4P

  0.01.

§

18:4w 3 + 2 0 : 3 w3 + 22:5w 3.

II

2 0 : 4 w6 + 2 2 : 4 w6 .

anim al sources. From per capita quantities of foods available

for consum ption in the U S national food supply in 1985, the

am ount of EPA is reported to be 50 m g - cap ita I d ‘ and

the am ount of D H A is 80 m g - capita

‘

- d

‘.

T he tw o m ain

sources are fish and poultry (62).

B iological effects of w f tty cid s in rel tion

to C H D  nd hypertension

Ei cosanoi d metabol i sm

A A and EPA are

precursors

of m etabo lic p rod ucts that consist

of 20 carbon atom s and are know n collectively as eicosanoids

(prostaglandins, throm boxanes, and leukotrienes) (Fig 5) (63,

64). T he discovery of prostaglandins and subsequently the rec-

ognition that A A is the precursor of the 2-series of prostanoids

(prostaglandins and throm boxanes) and of leukotrienes of the

4-series expanded the horizons of research on w 6 and w 3 fatty

acids because LA , the precursor ofA A , is the predom inant PU FA

in the W estern diet. EPA and D H A are precursors ofthe pros-

tanoids of the 3-series and leukotrienes of the 5-series. T he dis-

covery in 1979, by N eedlem an et al (65), that prostaglandins

derived from E PA have different biological properties than do

those

derived from A A stim ulated further research on fish oils

and on the nutrition al aspects o f prostagland in s.

C om petition betw een the tw o different classes of PU FA s oc-

curs in prostaglandin form ation: EPA com petes w ith A A for

prostaglandin and leukotriene synthesis at the cyclooxygenase

and lipoxygenase level. W hen hum ans ingest fish or fish oil, the

E PA and D H A from the diet partially replace the w 6 fatty acids,

especially A A , in the m em branes of probably all cells but es-

pecially in the m e m branes of platelets, erythrocytes, neutrophils,

m onocytes, and liver cells. A s a result, ingestion of EPA and

D H A from fish or fish oil leads to

1)

a decreased production of

p ro stag lan din E 2 (P O E 2 ) m etab olites;

2)

a decrease in throm -

boxane A 2 , a potent platelet aggregator and vasoconstrictor; 3)

a decrease in leukotriene B 4 form ation, an inducer of inflam -

m ation and a pow erful inducer of leukocyte chem otaxis and

adherence; 4 ) an increase in throm boxane A 3 , a w e ak platelet

aggregator and a weak vasoconstrictor; 5) an increase in pros-

tacyclin P G 3 , lead in g to an o verall in crease in to tal p rostacyclin

by increasing PG I3 w ithout a decrease in PG 2

.

B oth P012 and

P G 3

are active v asodilators an d inhibitors ofplatelet agg regation ;

and 6) an increase in leukotriene B 5 , a w eak inducer of inflam -

m ation and a w eak chem otactic agent (63, 64).

M olecular aspects and gene expr ession:

beyond the eicosanoids

The phospholipid class and fatty acid com position and cho-

lesterol content of biom em branes are critical determ inants of

physical properties of m em branes and have been

show n to in-

fluence a w ide variety of m em brane-dependent functions, such

a s integral enzym e activity, m em brane transport, and receptor

function. The ability to alter m em brane lipid com position and

function in vivo by diet, even w hen EFA s are adequately sup-

plied, dem onstrates the im portance of diet in grow th and m e-

tabolism (66).

C om plex interactions and displacem ents of the w 3 and w 6

fatty acids take place in plasm a and cellular lipids after dietary

m anipulations. E arly steps ofcell activation, such as generation

of inositol phosphates, are induced by dietary fatty acids (67).

T he effects ofdietary fatty acids on the inositol phosphate path-

w ay indicate that diet-induced m odifications of PU FA s at the

cellular level affect the activity of the enzym es responsible for

the generation of lipid m ediators in addition to the form ation

of products (eicosanoids) directly derived from their fatty acid

precursors. T his show s that dietary fats affect key processes in

cell function.

The role of w 3 fatty acids in the control of gene expression is

an area that is expected to expand over the next 5 years as w e

begin to understand the role of nutrients in gene expression. It

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S uperm arke t eg g

m g /g yolk

0 . 7 0

0 . 0 7

5 6 . 6 6

0 . 3 4

2 2 . 8 8

8 0 . 6 5

4 . 6 7

1 0 9 . 9 7

0 . 6 8

0 .04

I 1 5. 3 6

2 6 . 1 4

0 . 2 5

0 . 3 6

0 . 4 7

5 . 0 2

0 . 3 7

1 . 2 0

3 3 . 8 1

0 . 5 2

0 . 0 3

0 .09

I .0 9

I . 7 3

0 . 4 4

19 .4

1 . 1 0

7 7 . 6 0

0 .66

2 1 . 3 0

100 .66

2 1 . 7 0

1 2 0 . 5 0

0 . 5 8

1 4 2. 7 8

16 .00

0 . 1 7

0 .46

5 . 4 0

0 . 7 0

0 . 2 9

2 3 . 0 2

6 .90

0 . 1 6

1 . 2 0

2 . 8 0

6 .60

1 7 . 6 6

0. 4

1 . 3

l 8 : 2 w6

1 8 : 3 w6

2 0 : 2 w6

20 :3w 6

20 :4e6

2 2 : 4 w6

2 2 : 5 6

T ota l

w3

1 8 : 3 w3

2 0 : 3 w3

2 0 : 5 w3

2 2 : 5 w3

2 2 : 6 w3

T ota l

P:S t

w6 : w3 4

w 3 FA T T Y A C ID S IN H E A L T H A N D D ISE A SE

4 4 5

T A B L E 5

F atty ac id co ncen tra tion s in ch icken eg g yo lk s*

F a tty ac id G reek eg g __ ____ _____ ___

Sa tu ra ted

I 4 : 0

1 5 : 0

I 6 : 0

I 7 : 0

I 8 : 0

T ota l

Monounsa tu ra ted

1 6 : l w7

I 8 : 1

2 0 : 1 w9

2 2 : l w9

24 :1w 9

T ota l

w6

S

R eprodu ced w ith perm iss io n from referen ce 59 . Fa tty ac id com -

po sitio n and lip id co n ten t w ere de te rm ined in h ard -bo iled egg s.

t R a tio o f

po lyunsa tu ra ted fa tty ac id s to satu rated fa tty ac ids.

:1:

R atio of w 6 to w 3 fa tty ac ids .

is k now n tha t nu trien ts, like ho rm ones , in fluen ce and con tro l

gen e expre ssion , and resea rch is no w p ro v id in g m ore exam ples

(68 ). O m ega-3 fa tty ac ids in the fo rm o f m enh aden o il low er

the enzym e fa tty ac id sy n the tase in th e live r, p resum ably as a

consequence ofa la rge decrease in fa tty ac id sy n the tase m R N A

concen tra tion (69) .

O m eg a-3 fa tty ac ids have been ex ten sive ly stu d ied in te rm s

of th eir h ypo lip idem ic , an tiath erom ato us, an ti- in f lam mato ry ,

an tith rom bo tic , vascu la r, an d o th er effec ts d esc ribed be low . In

fac t, m o re is kn ow n abo u t the effec ts o fw 3 fa tty acids in hum an

m etabo lism th an any o ther c lass o f fatty ac id s.

Hi’polipidemic effects

A rev iew o fth e c lin ica l inv estig atio ns pub lished u p to F ebrua ry

1988 in p ee r-rev iew ed E ng lish -lang uage jo u rna ls w as earned ou t

by H am s (37) on the ef fects o f fish o ils on lip ids and lipopro teins

in n orm al vo lu n teers an d in p atien ts w ith prim ary hyperlip id -

em ia , iso la ted h ypercho leste ro lem ia (type Ila ), com bined h y-

perlip idem ia (type IIb ), and iso lated h ypertrig lyceridem ia (typ es

IV an d V ) . H ypercho les te ro lem ia w as defined as low -dens ity -

lipo pro te in (L D L )-cho leste ro l co ncen trations

>

4 . 14 m m ol/L

an d hypertrig lyceridem ia w as defined as p lasm a trig lyceride

concen tra t ions > 2 .26 m m ol/L . T here w ere m arked v ar ia tions

in the des ig n of the s tu d ies. T h e am o unt o f fish o il va ried from

a low of 1 .6 g /d to > 100 g /d

and th e w 3 fa tty ac ids va ried from

0 .5 to 25 g /d . T he leng th of in te rven tion v aried from 2 w k to

>

2 y . T h e w 3 fa tty ac id in take w as in th e fo rm of w ho le fish ,

cod -liv er o il, fish -o il concen tra te , fa tty ac id e thy l este rs , o r pu -

ri f led

E P A eth y l e ste rs .

E ffects on norm al subjects. H arr is (3 7) fo und tha t w 3 fa tty

ac ids d id no t in fluence L D L cho les te ro l concen tra tio n , bu t a

s ligh t rise (‘-3% ) occu rred in h igh -dens ity - lipo pro te in (H D L )-

cho les tero l con cen tra tions and a

25 % dec rease o ccurred in

tn -

g ly ceride concen tra tion s. In o ther w ell-co n tro lled stud ies us in g

re lative ly low er doses o ffish o il (< 20 g /d ), s im ila r find ings w ere

reported by Sanders and H och land (70), Z ucker e t a l (7 1 ), and

M ortensen e t al (72). N agakaw a et al (73) used purified E P A

w ith no o ther d ieta ry change . T hey found m odes t decreases in

to ta l cho le ste ro l and L D L con cen tra tions , no changes in H D L

concen tra tions , and a m arked decrease in tr ig ly cerid e concen-

trations.

Effects on patients. In pa tien ts w ith ty pe ha h yperlip idem ia,

d ie ta ry 0)3 fatty acids d id no t chang e to ta l o r L D L ch o leste ro l,

s l ight ly

inc reased H D L , and low ered trig lyceride concen tra tions .

In pa tien ts w ith com bined h yp erlip idem ia , ty pe IIb , to tal cho -

les tero l concen tra tion d id n o t change . L D L and H D L cho les te ro l

concen tra tio ns rose by 5-7% an d trig lycer id e con cen tra tions de-

c reased by 38% . S im ila r resu lts w ere reported in o ther w ell-con-

tro lled , low -dose , c rossov er tria ls (7 1 , 74-7 6). In pa tien ts w ith

iso la ted hy pertrig lyceridem ia , to ta l ch o les te ro l and trig lyceride

concen tra tio ns d ecreased by 8 % an d

52 ,

resp ec tive ly , and L D L

and H D L inc reased by 3 0% and 10 % , re spec tive ly . T h e decrease

in to ta l cho leste ro l resu lted from a fa ll in very -low -dens ity Ii-

popro te in (V L D L ). In pa tien ts w ith typ e IV hy perlip id em ia , L D L

cho leste ro l con cen tra tion increased by 2 0%  75 ,

77) .

T hese stud ies sug gest tha t the type o f pa tien t s tud ied de ter -

m ines the hyp o lip idem ic resp onse to w 3 fa tty ac id supp lem en-

ta tion . In pa tien ts w ith h ypertrig lyceridem ia the fa ll in to ta l ch o-

leste ro l is du e to the decrease in V L D L . S anders (7 8) in an u p-

da ted rev iew reported sim ila r find ings . In add ition , he fou nd

th at in type III pa tien ts fish o il lo w ers trig lycerides and cho les -

te ro l. S anders a lso rev iew ed the stud ies in w hich w 3 fa tty acids

lo w ered trig ly cerides in pa tien ts w ith hyp ertrig lyceridem ia and

fo und tha t these e ffec ts o f w 3 fa tty ac ids a re indeed su sta in ed ,

co n tra ry to rep orts by S chec tm an e t a l (79 ). Schec tm an e t a l

(79) sug gested , on the basis o fa s tudy on a sm all g roup of pa tien ts ,

th at trig lyceride -low ering effects o ff ish o ils canno t be su sta in ed .

T h is sugg estion is no t su pported by o ther la rger con tro lled tr ia ls .

M ille r e t a l (80 ), in a rand om ized con tro lled tria l fo r 3 m o ,

show ed tha t the tr ig ly ceride -low ering effec t o f 10 g M axE P A #{ 174} /

d (3 .2 g o ,3 fa tty ac ids) w as sus tain ed . M o reov e r, S ayno r Ct al

(8 1) show ed tha t the e ffec t is sus tained fo r years . T h e s tu dy of

S chec tm an e t a l (79 ) em p loyed an este r con cen tra te . T he fa ilu re

to susta in th e tr ig ly ce ride -lo w erin g e ffec t in tha t s tudy cou ld w ell

b e re lated to p oor pa tien t com p lian ce (7 8 ) . S ande rs fo und th at

as little as 6 g fish o il/d (2 g w 3 fa tty ac ids ) has a trig lyceride -

low er in g effec t in h ypertrig lyceridem ic p atien ts. T h e m ore com -

m only used d ose is 3 g /d fo r E PA and D H A .

In ad d ition to the type o f p atien t, ano ther fac to r tha t a ffec ts

L D L co ncen tra tion is w he the r sa tu ra ted fa tty ac ids are he ld

con stan t o r decreased during su pp lem en tation . In n orm al sub-

jec ts w hen sa tu ra ted fa tty ac ids w ere he ld con stan t, L D L ten ded

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P L A N T

M E T A B O L I S M

M A M M A L I A N M E T A B O L I S M

02

P ro sta g lan d tn G 2

02

Le n4

L e uko tn ien es 5

C O O ”

Cl 3

)X A

E ic osa pe n tae no ic acid

C O O l

# { 1 4 9 } C H 3

Prostaglandin

G3

FI G 5 . O ri gi n of w 3 a nd w 6 u nsa turated fa tty a cid s, b io sy n th esis o f e ico san oid s from arac h id on ic ac id (C 20 :4w 6)

a nd e ico sap en taen o ic ac id (C 20 :5w 3) . R e pro du ced w ith p erm iss ion f rom refe ren ce 6 3 .

446 S IM O P O U L O S

A c e t y l # { 1 4 9 } C o A

Plast ids

O leic ac id

E n d o p l a sm i c

1. re tIcu lum

H 3 C C O O H vegetab le

  Hf

  * *S C O O H

L ino Ieic ac id (w - 6 ) foo ds A rach ido nic a cid

  Chlorop last

C O O H

a-L ino ien ic a cid (w -3 )

M arin e alg ae

 l t tOfl \ O2 4

ma r ine

H 3 C ,,,,C O o H foods

E ic osape n ta eno ic a cid

l

Ma r ine

algae

7 P la nk to n

j

Fish

I-IC

7

  cC O O H

D oc osa hex aen oic a cid

to r ise bu t w hen sa tu ra ted fatty acids w ere reduced , the L D L

tended to decrease . In pa tien ts w ith hy perlip id em ia in w ho m

sa tu ra ted fatty ac ids w ere he ld cons tan t, L D L increased excep t

in the stud y by P h illip son e t a l (82 ), w ho used a very h igh dose

o ffish o il. In g en eral, a h igh do se o ffish o il (10 g w 3 fatty ac ids

d ) m ay low er L D L w hereas low er doses do no t. W hether E P A

or D H A is m ore effec tive in low ering L D L is und er investiga tion

w ith m ore-pu rified prepara tions of the in d iv idua l fa tty ac ids .

In sum m ary , the e ffec ts o fw 3 fa tty ac ids on serum cho leste ro l

concen tra tio ns a re sim ila r to tho se o f o th er PU F A s. W h en w 3

fatty ac ids rep lace satu rated fa tty ac ids in the d iet, they lo w er

se ru m cho les te ro l concen tra tio ns. O m ega-3 fa tty ac id s have the

added benefit o f co nsis ten tly low ering se rum trig lyceride con-

cen tra tion s w h ereas the w 6 fa tty ac ids do no t and m ay even

in crease them (82).

In con side ring these aspec ts o fw 3 fa tty ac ids on L D L -cho les -

te ro l co ncen tra tion s, th e issue is w he ther th is inc rease in L D L

is indeed s ig n ifican t in inc reasing the risk fo r a the roscle ros is in

pa tien ts w ith type II an d IV h yperlip idem ia in v iew of the an-

tith rom b otic , an ti-in flam m ato ry , and an tivaso restric tive asp ec ts

o f w 3

fa tty ac ids . Fu rth e rm ore , th e p oss ib ility tha t th is new L D L

m ay n o t be a th erogen ic , o r as a the rogen ic , n eed s to be cons id ered

b ecause fish -o il d iets have p roduced changes in lipo pro te in

co m pos ition in an im al s tud ies (8 3-85). T heore tica lly , E PA and

D H A m ay a lte r the ra te o r fo rm of L D L o x ida tion in v iv o and

th ereb y cause a reduced a therogen ic po ten tia l no t re flec ted in

an ac tua l low ering of, o r even desp ite an increase in , L D L co n-

c e n t r t i o n

A nother im por tan t cons ide ra tio n is the find in g tha t dur in g

chron ic fish -o il feed in g there is a decrease in po stp rand ia l tri-

g lyceride

con cen tra tions . Fu rthe rm ore , N este l (8 6) repor ted tha t

fish -o il feed in g b lun ted the expec ted rise in p lasm a cho les te ro l

concen tra tions w hen la rg e am o unts o f cho leste ro l w ere fed to

hum ans . T h ese fin d ings are con sis ten t w ith a red uced ra te o f

coro nary arte ry d isease in fish -ea ting popu la tions . S tud ies in hu-

m ans have show n tha t fish o ils red uce the ra te o fh epa tic sec re tion

of V L D L trig lycerid e (77 , 8 7-89 ). In n orm olip idem ic sub jec ts

w 3 fa tty ac id s p rev en t and reverse rap id ly th e carboh ydra te -in -

d uced hypertrig lycen idem ia (8 7). T here is a lso ev iden ce from

kine tic stud ies tha t fish o ils inc rease the frac tiona l ca tabo lic ra te

(F C R ) ofV L D L (77 , 88 , 89 ).

.4

nt iat /n’ronatoi i .s act ions

T he an tia the rom atous ac tio ns ofw 3 fa tty ac ids a re supp orted

by a num b er o fan im al stud ies . In dogs fed a d ie t h igh in sa tu ra ted

fa tty ac ids an d cho leste ro l, supp lem en ta tion w ith fish o ils p re -

ven ted in tim al hyperp las ia tha t is ind uced on venous a llog ra fts

in se rted in to the ir a rte ries (9 0). In hyp erlip idem ic sw ine m o de l,

d ie ta ry s up pl em e nt ati on w ith co d-live r o il reduced the d ev el-

opm ent o f co ronary a therosc le ro sis w ith ou t any sign ifican t

changes in p lasm a lip id concen tra tio ns b etw een the sup p le-

m en ted an im als and th e con tro ls (9 1). In the pr im ate m o de l,

d ietary

fa t subs titu tion w ith w 3 fa tty acids in h ib ited a therogen es is

in the aorta , ca ro tid , and fem o ra l a rter ies (92). H o llander e t a l

(9 3) co nfirm ed D av is e t a l’s (92) find ings in ano ther p rim ate

spec ies w ithou t s ign ifican t d ifferen ces in se ru m lip id leve ls . U sing

the rab b it athe ro genesis m o de l, T h ie ry and S e ide l (9 4) fou nd

tha t fish -o il feed ing resu lted in an enhancem ent o f cho leste ro l-

indu ced a therogenes is w hereas Z hu e t a l (95) found tha t a th -

ero sc le ros is w as inh ib ited by fish o ils in cho leste ro l-fed rab b its .

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w 3 FA T T Y A C ID S IN H E A L T H A N D D ISE A SE

44 7

T hese co nflic ting resu lts w ere observed in the rabb it a the rog enesis

m ode l w hereas in a ll o the r m o de ls (dog , sw ine , an d tw o prim ate

spec ies ) fish o ils w ere found to h ave an tia the rog en ic e ffec ts even

if th ey d id no t low er serum lip ids.

A ntithrom ho tic effects

In add itio n to a p ro lon ga tion of b leed in g tim e , the re is su b -

stan tia l ag reem en t tha t p la te let aggrega tion to ep inephrine an d

co llagen is in h ib ited , th rom b oxane A 2 pro duc tion is d ecreased ,

w ho le -b lood v iscos ity is reduced , and ery th rocy te m em bran e

flu id ity is inc reased (24 , 33 , 34 , 6 4 , 96) . Inc reased co ncen tra tion s

of p lasm in ogen activa to r and d ecreased concen tra tion s o f a

p lasm ino gen inh ib ito r a fte r fish -o il in gestion w ere repor ted (97).

F ib rin ogen a lso d ecreases a fte r w 3 fa tty ac id inges tio n . A lth ough

so m e s tud ies fa iled to show a decrease in fib r in ogen concen tra -

tions , a rando m ized , do ub le -b lind c lin ical tria l d id sho w a d e-

c rease a fte r in gestion ofw 3 fa tty ac ids in adu lts w ith typ e lIb or

IV hyp erlipop ro tein em ia (9 8 ). A decrease in f ib r ino gen w as a lso

fou nd in ano ther dou b le-b lin d tria l w ith 64 m en aged 35 -40 y

rando m ly ass igned to tw o grou ps (99 ). In th e stud ies tha t fa iled

to show an effec t, th e s tudy by Sand ers e t al (100) used a sm all

d ose ofcod -liv er o il an d the study by R o gers e t a l (101) in clud ed

hea lth y v o lun tee rs and w as of short du ra tion .

A lthoug h a decrease in p la te let co un t o ccurs w ith an increase

in p la te le t s ize af te r ingestion ofw 3 fa tty ac ids (espec ially in v ery

la rge q uan titie s) , c lin ica l ev idence of b leed ing has y et to be re -

por ted . P la te le t su rv iva l has been fou nd to be norm al. B ecause

there is an increase in p la te let s ize w ith a decrease in p la te le t

cou n t, the re is no ov erall d ec rease in p la te le t m ass (102 ). W hen

fish o ils a re d iscon tinued , the p la te let coun t re tu rns to norm al.

In so m e cases p la te let coun t rebou nds to supe rno rm a l be fo re

retu rn in g to no rm al. T h e m echan ism s ofthese e ffec ts o ffish o il

o n p late le ts and on m egakaryocy tes a re un know n. T hese ef fects

o f fish o ils lead ing to an increase in b leed ing tim e has raised

q uestions : W h at is the c lin ica l sign ificance of the pro lon ged

b leed ing tim e? A re there an y adverse e ffec ts?

T h e e ffec ts o f d iffe ren t d oses o f fish o ils o n the p ro lo nga tion

o f b leed ing tim e w ere investiga ted b y S aynor e t a l (8 1

).

W i t h

1 .8 g E PA th ere w as no t any pro lon ga tio n in b leed in g tim e . A t

4 g the b leed ing tim e increased an d the p la te let cou n t d ecreased

w ithou t an y ad verse e ffec ts . In stud ies in hum ans there has never

b een a case of c lin ica l b leed ing , ev en in pa tien ts un dergo ing

an g iop lasty w h ile they w ere on f ish -o il supp lem en ts (10 3).

D eC ate rina e t a l (10 4) recen tly repo rted on the preopera tive

u se off ish o ils in I 3 m en and 2 w o m en w ho und erw en t coron ary -

ar te ry -bypass g raf t su rgery . T h e da ily dose w as 3 g E P A an d 1 .3

g D H A in pu rif ied fish o il tha t w as taken fo r 28 d b efo re su rgery .

T h e co n tro l sub jec ts w ere 1 4 m en an d 1 w o m an perfec tly

m atched fo r age an d severity o fd isease w ho w ere sch ed u led fo r

su rg ery by the sam e surgeon . T h e co n tro l sub jec ts d id no t receive

an y f ish o ils. D esp ite changes in p late le t fun c tion , inc reases in

b leed in g tim e , and increases in vascu la r PG 2 . th e periop era tive

b lood loss w as no t inc reased in sub jec ts rece iv ing fish -o il sup-

p lem en ts . T here is no ev idence tha t the inc rease in b leed in g

tim e is c lin ica lly sign ifican t o r has any adverse ef fects .

Vascular effects

It w as recen tly show n tha t w 3 fatty ac ids inh ib it the pro duc tion

ofp la te le t-den iv ed g row th fac to r (PD G F )

  105) and inc rease en -

do the lium -derived re lax ing fac to r (E D R F )(l06) . O m ega-3 fa tty

acids red uce prod uc tion of a P D G F -like pro te in in bov ine en-

do th elia l ce lls , w h ich leads to in h ib itio n in the m igra tion and

pro life ra tion of sm o oth m usc le ce lls , fib ro b lasts, and m acro -

p hages in th e arter ia l w a ll

 105 .

T he endo the lium re leases an E D R F , p resum ably n itric ox id e.

W hen an im als a re fed cod -liv er o il o r fish o ils (E PA plus D H A ),

they increase the re lease of re lax ing facto rs, w h ich fac ilita tes

re laxa tio n in la rge arte ries and in res istance v esse ls (106). A lso

in the presen ce of E P A , end o the lia l ce lls in cu ltu re inc rease the

re lease of re lax ing fac to rs in d icating a d irect e ffec t o f the fa tty

ac id on th e cells. E D R F presum ably con tribu tes to an tith rom -

b o tic and an tia the rosc lero tic e ffec ts o fw 3 fa tty ac ids by re lax ing

vascu lar sm o oth m usc le and in h ib iting p la te let aggreg ation .

Inc reases in PG I2 w ere show n in tissue fragm en ts from th e

a trium , aorta , an d sap henous ve in ob ta ined a t su rgery in pa tien ts

trea ted w ith w 3 fatty ac id s (104) . T h is find ing is very im portan t

b ecause it en hances our u nderstand in g ofthe effec ts o fw 3 fatty

ac ids o n vesse l w a lls in h um ans an d d if fers from the resu lts o f

som e an im al stud ies (1 07 , 10 8). R ats do no t fo rm PG I3 after

d ie ta ry E PA (10 7 , 108) w h ereas hum an s do (10 9). T here fo re ,

the im portance of hu m an stud ies is obv io us.

Antiarrhvthmic effects

S udden card iac d ea th is frequ en tly a conseq uence of severe

v en tr icu la r fib rillation or te rm ina l ca rd iac ar rhy thm ia . E xperi-

m en ta l s tud ies w ith iso la ted pap illa ry m usc les fro m eithe r rats

o r m arm ose t m o nkeys ind ica te m uch less suscep tib ility to ca t-

ech o lam ine-ind uced arrhy th m ia in the m uscles from an im als

fed fish -o il sup p lem en ts than from th ose on w 6 o r low -fa t d iets

 1 10 ). In dom ethac in abo lishes these e ffec ts in v itro , sugg es ting

a m echan ism op era ting v ia the e icosano ids (p ro stag land in s). In

stud ies w ith ad u lt m arm ose t m on keys fed d ie ta ry fish o il fo r

severa l m onths, ca rd iac func tio n im pro ved , and the vu lnerab ility

o f th e heart to deve lop card iac a rrhy thm ia w as reduced w hen

sub jec ted to ischem ic s tress . B urr e t a l (23) stud ied the effec ts

o fd ie ta ry in te rven tion in the seco ndary prev en tio n of m yocard ia l

in farction . A m odes t in tak e of fa tty fish tw o-to -th ree tim es p er

w eek (o r 3 g fish o ils /d ) reduced all-cau se m orta lity b y 2 9% o ver

a 2-y period , po ss ib ly by preven ting sud den d eath from an -

rhy thmia .

E ffects on r estenosi s

T he an tia the rom atous aspec ts o f w 3 fa tty ac ids show n in an-

im al exp er im en ts sugges ted th e use o f w 3 fa tty ac ids to prev en t

restenos is in pa tien ts un dergo ing ang iop lasty . T he cause of re -

steno sis is unk now n. H ow ev er p la te let aggrega tion , p ro life ra tion

ofsm ooth m uscle ce lls , an d coron ary vasosp asm are con side red

to be im portan t co n trib u to rs to restenos is. A lthoug h the success

ra te o f ang iop las ty is h igh , restenos is occu rs in 25-40 % in the

d ila ted lesion s

 

6 m o afte r the proced ure . M ost stud ies show ed

a bene fit w hen

c o3 fa tty

ac ids supp lem en ted the s tan dard reg im en

befo re and after su rg ery (103 , 1 1 1, 1 12 ). D ehm er e t a l (10 3)

p ro v ided ev idence tha t w hen w 3 fa tty ac ids w ere g iven to the

pa tien ts a long w ith asp irin and d ipy rid am ole 7 d befo re ang io -

p lasty an d co n tinued fo r 6 m o afte rw ard , the re w as a redu ction

in the ra te o f restenos is o n ca th ete riza tio n 3-4 m o afte r an g io -

p lasty . O thers report no b en ef it

 

1 1 3, 1 1 4). T here w as no c lin ica l

ev idence of b leed ing com plica tio ns in any trea ted p atien t re-

por ted in th ese s tu d ies . T he ro le o fw 3 fa tty ac ids in the p reven-

tion ofea rly restenos is a fte r co ron ary an g iop lasty is a m ajo r a rea

of resea rch b ecause percu taneous trans lu m in al co ronary an g io -

p lasty is an im portan t trea tm en t fo r se lected p atien ts w ith C H D .

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44 8 S I M O P O U L O S

T A B L E 6

E ffe cts ofd ietary w 3 fatty acid s o n facto rs an d m ec han ism s in volved

in th e de velopm en t of in flam m atio n , ath ero sclero sis, and im m un e

disea ses

R educe or in h ib it risk and /o r p rec ip ita ting facto rs

A rach ido nic a cid

P la te le t a gg re ga ti on

T hro m boxane A 2 fo rm ation

M o no cyte a nd /or m a cro ph age func tion

L euko triene fo rm ation (L T B 4 )

Fo rm ation of p la te le t ac tiv ating fac to r (P A F )

T o xic o xyg en m e tab o li tes

In te rleuk in I fo rm atio n (IL - 1 )

F o rm atio n o f tum or nec ros is fac to r (T N F )

P la te le t-d erived gro w th fa cto r-lik e p ro tein (P D G F )

I nt im a l h yp er pl as ia

B lood pressu re and /o r b lood pressu re respo nse

V e ry- low -de nsi ty an d low -de nsi ty l ipo pro tein s (V L D L , L D L )

Triglycerides

L ip op ro tein (a) [L p (a)]

Fibr inogen

B lo od v is co sit y

Increase beneficia l and /o r p ro tective fac to rs

P ro sta cyc lin form ation (P G I2 + P G I3)

L euko triene B 5 (L T B 5)

In te rleuk in 2 ( IL-2)

E n do the lia l-de rive d re lax ing facto r (E D R F )

F ibrino ly tic ac tiv ity

R e d- ce ll d ef or m ab il it y

H igh -de nsi ty lipo pro tein (H D L )

  R eprod uced w ith perm iss io n from refe rence 29 .

Effects on l ipopr otein a)

L ipopro tein (a ) [L p (a )] is a g ene tica lly de te rm ined p ro te in

tha t has a the rogen ic and th rom b ogen ic p roperties . T he m olecu lar

s tru c tu re o fL p(a) apopro te in is s trik in g ly s im ila r to tha t o f p las -

m inog en . O m eg a-3 fa tty ac ids w ere reported to in h ib it th e in -

h ib ito r o f p lasm inogen ac tiva to r and thus con tribu te to fib ri-

no ly sis (97). T h us it w as o n ly na tu ra l to test th e e ffec ts o f w 3

fa tty acids o n L p(a) con cen trations   1 1 5). H errm ann e t a l (1 15)

repor ted on such a s tudy a t the po ste r sess ion of the N A T O

A dvan ced R esearch W ork sho p on D ie ta ry w 3 and w 6 F atty A c-

ids : B io lo g ical E ffec ts and N u tr itiona l E ssen tia lity . T hese in ves-

tiga tons stud ied 62 m ale p atien ts w h o had m yocard ia l in fa rc tion

6 m o befo re the s tudy . Inges tion o f fish o il reduced the con cen-

tration of trig lycerides, reduced b loo d pressu re , and led to a

sig n ifican t redu ction in L p(a). T h is s tud y pro v id ed the firs t e v-

idence tha t w 3 fa tty ac ids low ered L p(a). R ecen tly , S chm id t e t

a l (1 16) sho w ed tha t w 3 fatty ac ids low ered se rum L p(a) co n-

cen tra tion s w h en L p (a) con cen trations w ere > 2 00 m g/L b ut

had no effec t < 20 0

m g / L .

M o re recen tly , K os tner and H errm ann (1 17) com pared the

effec ts o ffish -o il co ncen trate (12 g F E N IC O #{17 4}/d , con ta in ing 70 %

w 3 P U F A s) in

35 pa tien ts w ith co ro na ry d isease and a con tro l

g rou p rece iv ing an equ iva len t am o un t o frapeseed o il. In add ition

to m easu ring L p(a ), th ese inves tig ato rs ca rried ou t s tan dard

p lasm a lip id an d lipop ro te in de te rm ina tion s an d h em osta tic in -

d ices. P lasm a L p(a) concen tra tio ns w ere reduced in the fish -o il

g rou p bu t w ere unaffec ted in th e rap eseed-o il g roup . T he to ta l

cho leste ro l, L D L cho leste ro l, and apo lipopro te in B (apo B ) co n-

cen tra tion s fe ll s ig n ifican tly in bo th gro ups . H D L cho leste ro l

in c reased and trig ly cerides d ecreased s ign ifican tly on ly in the

fish -o il g roup . N ot ev ery body in the fish -o il g roup show ed a

decrease in p lasm a L p(a) co ncen tra tion s. T he inves tig ato rs

the re fo re sub d iv ided the p ar tic ipan ts in the s tudy in to tw o grou ps,

resp onders an d n onresp onders . T w o -th irds o f the p eo p le stud ied

w ere respo nders and th ey sho w ed an average L p(a ) decrease of

24% . In th is s tudy , tissue p lasm inogen ac tiva to r concen tra tio ns

w ere reduced sign ifican tly in bo th grou ps by 16% . T here w as

a con com itan t bu t no t s ig n ifican t in c rease of p lasm a ac tiva to r

inh ib ito r, P A l5 .

In a recen t stu dy b y S eed e t a l (1 1 8) on the rela tion o f serum

L p(a ) c on ce ntra tio n

an d apo lip opro te in A (apo A ) p heno ty pe

to C H D in pa tien ts w ith fam ilial hyp ercho le ste ro lem ia , it w as

show n tha t “ th e m ed ian lip opro te in (a ) leve l in th e 54 p atien ts

w ith C H D w as 5 7 m g/d l, w h ich is s ig n ifican tly h igher th an the

correspon d ing va lue of 18 m g /d l in the 6 1 pa tien ts w ith ou t C H D .

A ccord ing to d isc rim inan t-func tion ana lysis , the lipopno te in (a )

leve l w as th e bes t d isc rim in ato r be tw een the tw o g roup s (as

co m pared w ith a ll o the r lip id and lipopro te in leve ls, age , sex ,

an d sm oking s ta tus ).” T he au thors conc lude tha t “an e leva ted

leve l o f lip op ro te in (a ) is a stro ng risk facto r fo r C H D in pa tien ts

w ith fam ilia l h ypercho les te ro lem ia , an d the increase in risk is

indep en den t o f age , sex , sm oking sta tus, and serum leve ls o f

to ta l cho les te ro l.” In ano ther stu dy on apo A and is ch em ic h eart

d isease in fam ilia l h ypercho les te ro lem ia , W ik iund e t a l (119)

a lso co nc luded tha t L p(a ) is a g en etic trait th at m ay be u sefu l

in iden tify in g pa tien ts w ith fam ilia l hyp erch o leste ro lem ia a t h igh

r isk fo r C H D (1 1 9). C lin ica l inv es tiga tion s a re u rgen tly needed

to de te rm ine if lo w ering L p(a ) by w 3 fa tty ac ids low ers th e r isk

fo r C H D in these pa tien ts.

Addi ti onal effects

O m ega-3 fa tty ac id s have been show n in hum an m onocy tes

to inh ib it th e prod uc tio n of p la te le t ac tiv ating fac to r (P A F). O ne

of the adverse e ffec ts o f PA F is th e activa tion of p late le ts , thus

con tribu ting to a therog en esis (1 20). ln te rleu k in and tum o r ne-

c rosis fac to r (T N F) are reduced by feed in g fish -o il supp lem en ts

to h um ans (121 ). B o th in te rleuk in 1 (IL -I) and T N F are co n-

side red a therog en ic because they s tim ulate the syn thesis o f

adh esion m ole cu le s, thu s cau sin g m on ocy tes to

adh ere to en -

do th elia l ce lls . T hey a lso activa te p la te lets , neu trop h ils , and

m onocy tes (1 21).

In conc lusio n , m any s tud ie s ind icate tha t w 3 fatty ac ids appea r

to d ecrease or in h ib it risk and prec ip ita ting fac to rs in the de-

ve lopm ent o f C V D S. T hese fac to rs a re sum m arized in T ab le

6 (29) .

T he new find ings in re latio n to in te r leu k in m e tab o lism and

g en e expressio n in d ica te tha t, in add ition to the ir m ajo r e ffec ts

on pros tag land in m etab o lism , w 3 fa tty acids have o th er fa r-

reach in g effec ts o n in trace llu la r ce ll com m unication . T hese

f ind in gs ind ica te tha t it is v ery im p ortan t to kno w and even tu a lly

un derstand the num erou s in te r- and in trace llu la r fac to rs th a t

a re in f lu en ced by w 3 fatty ac ids as w ell as the sp ecific m ech an ism s

invo lv ed . It is th is typ e o f in fo rm ation tha t w ill enab le us to

d es ign ap propr ia te c lin ica l tria ls to p rec isely define the dose of

(& ,3 fa tty ac id s to b e u tilized and the ty pe of fa tty ac id and leng th

o fin te rv en tio n requ ired fo r e ffec tive the rapy w hile avo id ing any

p oss ib le adverse reac tions .

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T A B L E 7

G ene tic de te rm inan ts and en v ironm enta l risk fac to rs fo r C H D *

G en etic de term in an ts

F am ily h isto ry o fC H D at an ea rly a ge

T ota l se rum cho les tero l, L D L , and ap o B co ncen tration s

H D L cho leste ro l, apo A -I, an d apo A -Il co ncen trations

Lp(a )

L D L recep to r activ ity

T hrom bos is and coagu lation v ariab les

T rig lycerides and V LD L concen tra tio ns

R F L Ps in D N A at the ap o A -I/apo C -Ill and ap o B loc i

O ther D N A m arkers

B lo od p res su re

D iabe tes

Obesi ty

Insu lin concen tra tion and insu lin respo nse

H ete ro zy go sity fo r h om oc ys tin uria

E n v ironm enta l risk fac to rs

S m o k i n g

S ed en ta ry l if es ty le

(lack of ae rob ic exerc ise)

D ie t (ex cess energ y in take)

H ig h satu rated fatty acid in take

L o w w 3 fa tty ac id in take

P sy cho so cial facto rs

T ype A persona lity

S ocial c lass

m ost- im por tan t p ape r o n a therosc le ros is en titled “A th erosc le -

ros is: A prob lem o fthe b io logy ofthe ar te ria l w a ll ce lls and the ir

in te rac tion w ith b lo od com p onen ts,” in w hich th e m odern con -

cep ts o f a the rosc le ros is w ere presen ted . R oss in 1986 (1 26) and

S te inberg e t a l in 19 89 (127 )

upda te d

the con cep ts o f th e resp onse

to in ju ry hypo th es is in th e pa thog en es is o fa the rosc le ro sis, w h ich

can be su m m arized as fo llow s. T he fir st step in the fo rm ation

of a th erosc le ros is is a non spec ific (func tiona l) in ju ry to endo -

the liu m fo llo w ed b y an accu m ula tion o f m ono cy tes and m ac-

rophages , foam ce ll fo rm ation , and p la te le t aggrega tion . T he

p la tele ts re lease grow th fac to r, w h ich leads to sm o oth m usc le

m igra tio n an d

p ro life ra tion . A t th is po in t ch o les te ro l is d ep osited

in the sm oo th m usc le ce lls and m ono cy te m acro phages in th e

vesse l w a ll. T hese even ts fu rthe r lead to the fo rm a tion of g ro und

sub stance an d ev en tua lly to p laq ue fo rm ation . A s seen in T ab le

6 , w 3 fa tty ac id in gestion m ay be ab le to preven t the inc rease in

ce llu la r co m ponen ts genera ted by these ce lls and in te rfe re a t

m an y s teps in the d ev e lo pm ent o f the a the rog en ic p ro cess (F ig

6

(2 7 , 48 ).

V eg etab le o ils r ich in the w 6 L A have been prom o ted as lo w -

er in g b lood cho les tero l con cen tra tions of peop le in the U n ited

S ta tes . S o m uch em phasis h as been pu t on the lip id hypo th esis

an d on low ering se ru m cho les te ro l concen tra tions th rou gh d ie t

an d drugs tha t the co n tribu tions ofin flam m atio n and th rom bos is

in the deve lopm en t o f C H D have no t been fu lly app rec ia ted .

A n inc rease in ou r u nde rstan d in g of the p a thop hysio logy o f

co ronary arte ry th rom b osis has led to the h ypo thes is tha t p re -

ven tin g p la te le t activa tion and aggreg ation are essen tia l steps in

th e preven tion of coronary th ro m botic co m plica tions . C u rren t

ev idence sugges ts tha t th e pa tho phys io logy of u nstab le an g ina

in vo lves p late le t rec ru itm en t an d th rom bos is. B urr’s stud y re -

fe rred to earlie r (2 3) is the firs t p rosp ec tive d ie ta ry -in terven tio n

tr ia l fo r secon dary preven tion ofC H D tha t dem ons tra tes c lin ica l

benefi t in th ose g iven adv ice to ea t fa tty fish or fish -o il capsu les.

O m ega-3 fa tty acid s a lo ne c lea rly w ill n o t lead to the u n iversa l

erad ica tion of a the rosc le ro sis. H ow ev er , it is inc reas in g ly ev id en t

th at d ie ta ry f ish -o il su pp lem en ta tion m ay he lp in the preven tion

of a the rosc lerosis o r its

th ro m bo tic co m plica tions . T he fav orab le

ef fects show n b y D eC ate rina e t a l (104) p rov id e fu rthe r supp ort

/

/

/

I

I M o n o c y tes T h ro m b o sis - - -*

Fibrino l,sis

I/I (circulating)

 X //

_ _ _ _ _ _ _ _ _

I M . S m o oth m u sd e

(m 6 ,aI

  -

f

‘\

.   .

I

E a rlie s t A th ero sc le ro tic L e ss on L D L Ih ole st e ro l

\

\

\ \ F o a m C e lls C o n n e c t iv e T is s u e T h ro m bo s is

------ Atheroma

F IG 6 . S ite s of po ten tia l in te rven tions fo r p rev en ting deve lopm ent o f

a the roscle ros is. N o te tha t severa l o f these possib ilitie s w o u ld abort the

d isease b efo re the co ncen tra tion of p lasm a L D L cho les te ro l cou ld co n-

tr ib u te to the a theroscle ro tic p rocess . R eprodu ced from refe rence 48 .

C

R eproduced w ith perm iss ion fro m refe rence I 23 .

C orna ry h ea rt d isea se

M u ch m o re is k now n abou t the effec ts o f w 3 fa tty acid s on

C V D th an o n

any o ther d isease en tity . C H D is a m ultifac to rial

d isease w ith gene tic de te rm inan ts tha t in te rac t w ith m any en-

v ironm enta l fac to rs , in c lu d ing d ie t an d o ther lifes ty le changes

tha t con tribu te to its de ve lop me nt. A ll the hyp erlipo pro te ine mia s

described so fa r have a s ign ifican t gene tic co m ponen t. I t has

been es tim ated tha t 50% o f the variance in se rum cho leste ro l

concen tra tio n and 1 5 of the v ar iance in the fib rinog en co n-

cen tration are du e to gen etic fac to rs.

A n ex ten sive a rray of genes invo lved in n orm a l reg u la tion

and func tio n of the card iovascu la r sys tem have been iden tified

w ith m od ern gene tic techn iques [D N A m ark ers, restric tion -

fragm ent-leng th po ly m orph ism s (R FL P s) and in s itu hyb rid iza -

tio n stud ies ]. T h ese n ew gene tic m arkers a re b eing used to pred ic t

risk fo r C H D , a m ost im p ortan t aspec t fo r deve lop ing s tra teg ies

fo r the preven tion ofC H D . T he ear ly iden tifica tion of in d iv idua ls

in ch ild hood and yo ung adu lt life w ho are a t h igh gene tic r isk

cons titu tes a very p ow erfu l h ealth ca re s tra tegy fo r the preven tion

ofC H D . C om mo n g en etic l ipo p ro te in d iso rde rs a sso cia te d

w ith

prem atu re C H D inc lude fam ilia l com b in ed h yperlip idem ia

(15% ), fam ilial hypen trig ly ceridem ia (5% ), and fam ilia l hyper-

cho leste ro lem ia (5% )   I 22 ) (T ab le 7 )   1 23). In the U n ited K in g-

do m , 5 g M ax E PA #{1 74} ( 1 8% E PA , I 2% D H A ) tw ice a day h as b een

ap proved fo r the trea tm en t o f seve re hyp ertr ig lyce rid em ia in

pa tien ts at risk of ischem ic heart d isease or p an creatitis.

A therosc le ros is is a co m plex d isease of the arte ries and th e

arter ia l w a ll. M an y ce llu la r b iochem ica l and phy sica l co m po-

nen ts in te rac t a t and w ith in th e arte ria l w all. T he ce llu la r dy -

nam ics in a the rosc lerosis w ere rev iew ed by F agg io tto   1 24) w h o

sta tes tha t “a the roscle ros is en co m passes a n um ber of pa tho log ica l

p rocesses and has m any o fth e featu res o fdeg en erative d iso rd ers,

in flam m ation and neop las ia .” In 198 1 R oss (125) pub lish ed a

w 3 F A T T Y A C ID S

IN H E A L T H A N D D IS E A S E

44 9

- -   “Endothelial I n j u r y ”

Platelet Aggregation

PD G

Fac tor

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45 0

S I M O P O U L O S

th a t w 3 fatty ac ids cou ld m odify th e occurrence and th e course

o f a t he r os c le r os i s.

R ecen tly , D o lecek and G rand its (2 0) investiga ted the 24-h

d ie ta ry -reca ll da ta in the usu al-ca re g roup of the M ultip le R isk

Fac to r In terven tio n T ria l and d is tin gu ish ed be tw een w 3 an d t6

fa tty ac id in take and th eir re la tionsh ip to fo ur m orta lity ca te-

gor ies : C H D , to ta l C V D , a ll-cause m orta lity , and cancer. A n alys is

o f the com bin ed fa tty ac ids p redom inan tly fo und in fish (E PA

and D H A ) dem ons tra ted sign ifican t inverse assoc ia tion s w ith

C H D , C V D , a nd all-ca use

mortal i ty gro ups . T he benefit ap -

pea red to b e in the h igh es t in take qu in tile w ith a m ean ingestio n

of -6 64 m g/d o f E P A and D H A . W hen com pared w ith zero

in take , m orta lity from C H D , C V D , and-a ll cau se m orta lity w as

4 0% , 41% , and 24 % low er, re spec tive ly . A n in ve rse asso cia tion

w as no ted b etw een the ra tio o f 1 8 :3w 3 to 1 8 :2 w 6 and can ce r

m orta lity . T h irty -th ree percen t few er cancer death s occurred in

the h ighes t in take qu in tile w hen com pared w ith the low est.

P opu lations w ith h ig h consum ption of f ish , such as the E s-

k im o s and Japanese , have low er ra tes o f m y ocard ia l in fa rc tio n

(T ab le 8) (128) .

T h e ep idem io lo g ic stu d ie s o f K rom h ou t et al

(1 7) and the in te rven tion s tud ies o f B urr et a l (23) sh ow ed a

d ecrease in C H D m orta lity in peop le consum ing re lative ly sm all

am o un ts o f fish (0 .5 g w 3 fa tty ac id s/d or 1 .5 g fish o il/d ) ov er

a lo ng p eriod o f tim e (19 y and 2 y , respec tive ly ). T h is su ggests

th a t sm all

d oses over lon g periods of tim e m ay h av e benefic ial

e ffec ts , possib ly by redu c in g b lood pressu re and o ther risk fac to rs.

C ertain ly m ore stud ies a re needed to define the prec ise d ose of

w 3 fa tty acids based on the to tal lon g-te rm die t o f the sub jec ts

in te rm s o f w 3 , w 6 , w 9 , an d sa tu ra ted fatty ac ids. T he un ique

p harm acok ine tics o f w 3 fa tty acids in te rm s of tim e and dose-

dependen t accum ula tio n in ce ll m em branes shou ld h elp define

the o p tim u m am ount o fw 3 fa tty acids an d leng th oftim e of th e

in te rven t ion .

T he vast m ajo rity o f su rv ivors o f m yocard ia l in fa rc tion have

one or m ore of four lipopro tein abnorm alities . T hese inc lude

increased

L D L -cho les te ro l co ncen tra tion s, decreased H D L -

cho leste ro l co ncen tra tion s u sua lly acco m pan ied by increased

trig ly ceride or V L D L co nce n tratio ns , in cre ase d c onc en tration

of chy lo m icro n rem nan ts and in term ed ia te -dens ity lipo pro te in

(ID L ), a nd the p resence in p lasm a of inc reased co ncen tration s

of L p(a ). T he exact m echan ism w hereby each of these abn or-

m alities causes C H D is an area of ac tive investiga tion and the

gene tic con tr ib u tio n to each ofthese abnorm al lipopro te in phe-

n o typ es is com in g in to focus (1 29) . A s w e b eg in to un rave l the

gene tic s o f a the ro sc lerosis and iden tify in d iv id ua ls w ith g en e tic

suscep tib ility to C H D , m o difica tion o fd ie t ear ly in life and the

prov is ion o f inc reased am o unts o f w 3 fa tty ac ids sh ou ld be ben-

e fic ia l in the prev en tio n of C H D .

H ypertension

H ypertensio n is a lso a m ultifacto r ia l d iso rd er invo lv in g g en e-

nu trien t in te rac tions and o ther fac to rs (1 30). D iffe ren t m echa-

n ism s app ear to be in vo lved , opera ting a t v ar iab le p ropo rtio ns

b ased o n th e o rgan invo lved or th e cau se of hy perten sion .

C hanges w ere repo rted in e ico sano id m etabo lism , ren in con-

cen tra tions , vascu la r reac tiv ity , b lood v iscos ity , lo ss o f sod ium ,

inc rease in po tass iu m in ce lls , and a decrease in in trace llu la r

ca lc iu m , am ong o thers (130 ).

In 1 983 tw o grou ps o f in vestiga to rs , S ing er e t a l (1 3 1) an d

L oren z e t al (1 32) , w e re the

firs t to show tha t ad d ing m ack erel

to the d iet o fpa tien ts w ith m ild hy perten sion low ered the b lo od

T A B L E

8

E thn ic d iffe rences in fatty ac id con cen tra tions in th rom bo cy te

p hospho lip ids and frequency o f card iovascu la r d iso rders

E urope ,

U nited S tates Japan

G reen land

E s k i m o s

A rach idon ic ac id ,

C 20 :4w 6 (% ) 26 21 8 .3

E ico sap en taen o ic ac id ,

C 20:5w 3 (% ) 0 .5 1 .6 8 .0

w 6 :w 3 50 1 2 1

C ard iovascu la r m orta lity

  )t

4 5 1 2 7

a

A dapted from refe rence I 28 .

t Percen t o fa ll dea ths .

p ressu re . M any stud ies since then have u sed w 3 fa tty ac ids in

th e fo rm o f fish o ils w ith s im ila r resu lts in no rm al and hyp er-

ten sive su b jec ts (72 , 1 33-137) bu t n o t in a ll in te rven tion trials

(138 , 13 9).

M ore recen tly K n ap p and F itzG era ld (1 3 5) rep orted on a

con tro lled s tudy o f P U F A supp lem en ts in essen tia l hy perten sion .

T h ese investiga to rs s tud ied b loo d p re ssu re and eicosan o id p ro -

duc tion during supp lem en ta tio n of d ie ta ry fa t fo r 4 w k in 32

m en w ith m ild essen tia l hyp erten sion . G rou ps ofe igh t sub jec ts

rece ived e ithe r 3 or 1 5 g w 3 fa tty ac ids /d in the fo rm of 10 or

5 0 m L M ax E PA #{1 74}, 39 g w 6 fa tty ac ids/d in the fo rm of 50 m L

sa ff low er o il, o r 50 m L /d o f an o il m ix tu re tha t approx im a ted

the typ es o ffa t p re sen t in th e A m erican d iet. U rin ary m e tabo lite s

w ere m easured to assess b iosyn thes is o f e icosano id s. T he m en

w ho rece ived the h igh d ose of fish o il had a m ean decrease in

sy sto lic b loo d p ressu re of6 .5 m m H g and a decrease of4 .4 m m

H g

in d iasto lic b lood pressu re . T he group rece iv ing th e low d ose

of fish o il (10 m L /d) d id no t have any sign ifican t change in

b lood pressu re from base line dur in g the sup p lem en ta tion period

nor d id the u ,6 -supp lem en ted o n the con tro l g rou ps. In th e group

rece iv ing the h ig h d ose offish o il, th e fo rm ation of vasod ila to ry

pro sta cyc lins (P G 2 and P G I3) inc rea sed in itia lly bu t th is increase

w as n o t m ain tained as b loo d pressu re fe ll. T he concen tra tion of

th rom b oxane A 2 m etabo lite s fe ll and m etabo lite s o f th ro m box-

ane A 3 w ere d etec ted in the g roups rece iv ing fish o il. T he fo r-

m ation ofP G E 2 increased d uring supp lem en ta tio n w ith sa fflow er

o il an d tended to decrease w ith fish o il bu t n o PO E 3 metaboli te

w as d etec ted . T h ese da ta ind ica te tha t h ig h d oses o f f ish o il can

reduce b loo d pressu re in m en w ith essen tia l hypertens ion .

B o naa et a l ( 1 40) , in a p opu latio n -b ased in terven tio n tria l

from T ro m s#{ 248} ,recen tly repor ted decreases o f6 m m H g in systo lic

b lood pressu re and 3 m m H g in d iasto lic b lo od pressu re w ith

fish -o il sup p lem en ta tion . T h ese inves tiga to rs m on ito red d ie t and

assessed co ncen tra tion s of p lasm a ph osp ho lip id fa tty ac ids to

determine the re la tion am ong d ie t, fa tty ac ids, and b loo d pres -

su re . D ie ta ry supp lem en ta tio n w ith fish o il d id no t ch an ge m ean

b lo od pressu re in

th e sub jec ts w ho a te fish th ree or m o re tim es

per w eek as part o fthe ir usu al d iet o r in th ose w h o