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Transcript of 5. Acizii Grasi Omega 3 in Sanatate Si Boala Sau in Crestere Si Dezvoltare Am J Clin...
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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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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
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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