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t,ans FATTY ACID S AND CORONARY ARTERY D ISEASE 1 007Spartially hydrogenated vegetable oils (vanaspathi) are replacingthe traditional ghee (clarified butter) . I t is likely that productionand consumption of these products are increasing w idelythroughout the developing world as populations move fromrelying on subsistence agriculture to being urban societiesdependent on a commercial food supply.

M E T A B O L IC E FFE C T S

For decades concerns have existed that trans fatty acids mayhave adverse physiologic ef fects because they are structurallysimilar to saturated fats, lack the essential metabolic activity ofthe parent compounds, and inhibit the enzymatic desaturationof linoleic and linolenic acid (4). M uch less attention has beenpaid to the cis isomers of oleic and linoleic acid, which alsointerfere w ith the metabolism of the parent compounds andmay be elongated and desaturated to eicosanoids of unusualstructure (5, 6). A comprehensive report issued in 1985 did notfind clear evidence of adverse effects of trans fat, but didindicate the need for further research (2).

I n the past decade, new metabolic studies have providedunequivocal evidence that the partial hydrogenation of vegeta-ble oil creates fatty acids that adversely affect plasma lipidconcentrations relative to the natural oil. I n a rigorous trialconducted in Holland by M ensink and K atan (7), trans fattyacids at 10% of energy in the diet increased low -density-lipoprotein (LD L ) cholesterol and decreased high-density-lipoprotein (HD L ) cholesterol when substituted for oleic acid.I n contrast, saturated fats increased LD L but did not decreaseHDL cholesterol when compared w ith oleic acid. The adverseeffect of trans fatty acids on the ratio of total to H D L choles-terol was about tw ice that of saturated fats. These results,obtained at trans fatty acid intakes well above the averageintake in most populations, were later confirmed in trials ofdiets containing 7.7% (8), 6% (9) , and 3% (9) of energy astrans. Similar effects of trans fatty acids on LD L and HD Lcholesterol have also been reported in men with mild hyper-cholesterolemia (10). W hen the effect of trans fatty acids andsaturated fats on the ratio of total to HD L cholesterol areplotted against the percentage of energy contributed, thereappears to be a linear dose-response relation, with the slope fortrans fatty acids being nearly twice that of saturated fats (theabsolute blood lipid concentrations for Figure 1 are shown inT able 1).

M oreover, in each of these individual studies in which thesefats were compared, the adverse effect of trans fatty acids wassignif icantly worse than that of saturated fat (7-9) as assessedby the ratio of total to H D L cholesterol. W hen the effects oftrans fatty acids on LD L and HD L cholesterol were summa-rized separately, as in Figure 1 , significant adverse effects wereseen for both (for LDL , j3 = 0.39 mmol . L . % of energy95% CI = 0.028, 0.050, P = 0.001; for H DL , 3 = -0.012mmol . L . % of energy , 95% CI = -0.015, -0.009, P =0.02) . I n another metabolic study conducted in A sia, not in-cluded in the above summary, trans fatty acids at 7% of energymarkedly increased LD L and reduced HDL relative to botholeic acid and saturated fat (13). I n addition to having clearadverse effects on HDL cholesterol, intake of trans fatty acidsincreased plasma concentrations of lipoprotein(a), another pu-tative risk factor for coronary artery disease (CAD ), in two ofthree randomized trials (10, 14).

FIG U R E 1. Change in the ratio of total to HD L cholesterol by percent-age of energy from trans fatty acids ( and saturated fat (# {149} )omparedwith natural unsaturated fat ( for trans fat, 3 = 0.059, P < 0.001; forsaturated fat, f3 = 0.029, P = 0. 10; test for differences in slopes, P 0.03).D ata are from Judd et al (9), Z ock and K atan (8), and M ensink and K atan(7). * p < 0.005, ** < 0.0001. Figure adapted from reference 11.

A common assertion is that trans fat reduces blood choles-terol concentrations compared w ith saturated fat ( 1 5) . How-ever, this is highly misleading because trans fat does so pri-marily by reducing HDL cholesterol, which cannot beconstrued as a desirable effect. For example, in the study ofM ensink and K atan (7), trans fat at 10% of energy reducedtotal serum cholesterol by 6% compared w ith saturated fat, butthis was mainly due to a 12% reduction in HD L cholesterol.

A lthough it seems likely that the effects on blood cholesterolfractions are not the same for all the trans isomers, there are nodata on the relative potency of individual compounds. In two ofthe above experi ments (7, 9), the trans diet contained a mixtureof cis and trans isomers similar to that of commercially avail-able margarine; in the others (8, 10), elaidic acid (9t- l8:l, thetrans isomer of oleic acid) contributed most of the total transf atty aci ds.

E PID E M IO L O G IC ST U D IE S

The prediction, based on the metabolic studies, that intake ofpartially hydrogenated fats increases the risk of coronary dis-ease has been supported by several epidemiologic investiga-tions. Intake of partially hydrogenated fats has paralleled therise in CAD mortality in the U nited States and other countries(16). A lso, among the seven countries studied by K eys and hiscolleagues, average intake of trans fatty acids, assessed byanalysis of replicate food sample, was strongly associated withregional incidence of CAD (17). M ore detailed investigationsthat allow for the control of individual risk factors are desirablebecause many other variables besides dietary fat compositiondiffer among countries and may account for at least some of thedifference in CA D incidence.

D irect associations have been reported between concentra-tions of trans isomers in adipose tissue and risk of death frommyocardial infarction ( 1 8) and between plasma concentrationsof trans fatty acids and the presence of atherosclerosis (19). I nthe above investigations, however, other dietary factors thatmay affect the risk of CAD were not considered. This limita-tion was addressed in the N urses H ealth Study (20), a longi-tudinal study of 90 000 US women. In that investigation,women in the highest quintile of intake of trans fatty acids

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1008S A SC H ER IO A N D W ILLETF

T A BL E 1C oncentrations of serum total and H D L cholesterol and ratio of total to H D L cholesterol w ith isoenergetic intakes of saturated, unsaturated, and t r ansfatty acids

Percent of energyT otal cholesterol H D L cholesterol Total-t o-H D L cholesterol2

Sat t r ans U nsat Sat t r ans U nsat Sat t r ans U nsat% mmoL /L mmo / I L

Judd et a! (9) 3.0 - 5.46 5.26 - 1.40 1.42 - 3.90 3.96Lichtenstein et a! (l2) 3.7 - 5.30 5.02 - 1.1 1 1.14 - 4.77 4.40N estel et al (10) 4.2 5.84 5.92 5 .56 1.09 0.98 0.98 5.36 6.04 5.67Judd et a! (9) 6.0 5.61 5 .52 5.26 1.47 1.38 1.42 3.82 4.00 3.70Zock and K atan (8) 7.7 4.89 4.90 4.74 1.41 1.37 1.47 3.47 3.58 3.22M ensink and K atan (7) 10.0 5.00 4.72 4.46 1.42 1.25 1.42 3.52 3.78 3.14

Sat, saturated fatty acid; Unsat, unsaturated fatty acid.2 C alculated as m e an total cholesterol/m e an H D L cholesterol because not all studies reported m e an total-to-H D L cholesterol ratio.3 U nsaturated fat w as ci s polyunsaturated; otherw ise saturated fat w as prim a rily cis m onounsaturated.4 S aturated fat w a s stearic acid; in o th er studies, saturated fat w a s a m ix tu re of satu rated fats considered to be ch olesterolem ic.

from partially hydrogenated vegetable fats at baseline (m edianintake = 3.2% of total energy) had a 35% higher risk ofcoronary disease than w om en in the low est quintile (m edian1 .3% of total energy), after stand ard cardiov ascu lar risk facto rsw ere adjusted for. T he association rem ained significant afterfurther adjustm ent for intake of other types of fat, cholesterol,vitam ins, and fiber. The positive association w as lim ited tot rans fatty acids from partially hydrogenated vegetable fat. T heassociation w as stronger w hen w om en w ho had changed theirconsum ption of m argarine during the past 10 y w ere excluded,suggesting that the association w as not due sim ply to a sw itchto m argarine by w om en w ith a suspicion of preclinical coro-nary disease. A lso, the positive association w ith intake of t ransfatty acids w as due to high consum ption of cookies and w hitebread, as w ell as a higher intake of m argarine, indicating thatthe association w as not sim p ly the result of healthier behaviorby w om en w ith a perceived higher risk of C A D . A positiveassociation betw een intake of t rans fatty acids and risk ofm y ocardial infarction w as also observed in a case-control studyam ong m en and w om en (21); the dose-response findings sug-gested a possible J-shaped relation, but a form al statistical testindicated that the data did not depart significantly from linear-ity. In both studies the risk w as quantitatively higher thanpredicted by the effect of t rans fatty acids on blood LD L andH D L concentrations, w hich is com patible w ith the suggestionthat t rans fatty acids m ay have other adverse physiologiceffects perhaps m e diated by lipoprotein(a) or a prothrom b oticm echanism .

T w o recent studies have been published that w ere interpretedby som e as refuting an association betw een intake of t rans fattyacids and risk of C A D (22, 23). T he study of R oberts et al (23),based on adipose fatty acid analysis of only 66 cases of suddendeath and m atched control subjects, w as sim ply too sm all to beinform ative. This can be appreciated by the fact that the 95%C Is for the relative risks in highest quintiles of both 18: 1 t rans(0.18, 1.83) and 18:2 t rans (0.85, 2.84) easily included therelative risks seen in the N urses H ealth Study. In this sm allstudy, neither diabetes nor hypertension w as significantly as-sociated w ith outcom e, w hich w ould lead no reasonable personto conclude that they w ere not causes of coronary disease. Inthe EU R A M IC study, a case-control study of nonfatal m yocar-dial infarction that also sam p led adipose tissue for fatty acidanalysis, the Spanish centers had by far the low est concentra-

tions of t rans fatty acids (22). Inasm uch as Spain also has verylow C A D rates, this is certainly com patible w ith a causalrelation. W hen the outlying Spanish data w ere appropriatelyexcluded, the adjusted relative risk of C A D w as 1.44 (95% C I :9.94, 2.20) in the highest versus the low est quartile of t rans fat.A lthough not quite statistically significant, this w as alm o stidentical to the relative risk of 1.47 seen for the N urses H ealthStudy. A s the authors concluded, these findings do not excludethe possibility that t rans fatty acids have a significant effect onrisk of C A D ; indeed, the data tend to support such a relation.In a report from the Fram ingham H eart Study (24), consum p-tion of m argarine w as significantly associated w ith risk offuture C A D , although use of butter w as not.

ESTIM A TIO N O F D EA TH S A TTR IB U TA B LE TO t ransFA TTY A C ID S

A lthough confounding by unm easured factors rem ains apossible explanation of the results of the epidem iologic inves-tigations, the com b ined evidence from m etabolic and epidem i-ologic studies strongly supports a causal interpretation. W ehave elsew here estim ated that current intake of partially hy-drogenated fats m ay account for > 30 000 deaths from C A Dper year in the U nited States (25). T his estim ation w as basedonly on the effect of t rans fatty acids on blood concentrationsof total and H D L cholesterol from m etabolic studies and on therelation of the blood total-to-H D L cholesterol ratio to risk ofC A D repeatedly docum ented in m any studies. B y this m ethod,w e calculated that 7% of C A D deaths w ere attributable tot rans fatty acid consum p tion; m u ltiplying this by the 50 0 00 0C A D deaths that occur annually in the U nited States yields> 30 000 deaths. W e have also estim ated the num ber of deathsdue only to the effects of t rans fatty acids on L D L cholesterolw ith the use of a sum m ary of the m etabolic studies show n inFigure 1 to estim ate the change in LD L corresponding to 2% ofenergy from t rans fatty acids. This gives an estim ate of 1 6 000deaths annually. A ll of these are conservative estim ates forseveral reasons: they assum ed only 2% of energy from t ransfatty acids for the population average, w hich is probably low ;the relation betw een plasm a total to H D L cholesterol and C A Drisk is based on only one blood sam ple per subject, w hich w illsubstantially underestim ate the m agnitude of association; and

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trans FA T tY A C ID S A N D C O R O N A R Y A R TE R Y D ISEA SE 1 0 0 9 Sw e have no t tak en in to accou n t o ther po ss ib le adverse e ffec ts o fpartia lly h ydrog en ated fa ts , in c lu d ing effects on lip opro te in (a )or th rom bo tic tend en cy . Ind ep enden t o f ou r ca lcu latio n ,Grundy (2 6) estim ated tha t 8% o f p rem atu re CA D dea ths in theU n ited S ta te s can be attr ibu ted to co nsum ption of trans fattyac ids , w hich is very m uch in line w ith ou r estim ate o f 7% . O ilindu stry rep resen tativ es have a rg ued tha t cau sa tion can on ly b epro ven by rand om ized tria ls (2 7), b u t these w ould b e un e th ica lan d log istica lly unfeasib le and w ill a lm os t su re ly never b eco nduc ted . B ecause there a re no know n nutritiona l ben ef its o fpartia lly h ydrog en ated fa ts an d w ell-docum ented adv erse m et-ab o lic e ffec ts, th e re appears to be no jus tifica tio n fo r ad d ingthe se syn the tic substan ces to the foo d supp ly .

PUBL I C H EA L T H APPROACH T O REDUC I NG I N T AK EO F trans FA T T Y AC I DS

Som e have a rg ued tha t d ie tary adv ice sho u ld still fo cus onlow ering in take o f to ta l fat, m a in ta in in g tha t a dec rease in fatin take w ill a lso cause a dec rease in satu ra ted an d trans fatsconsum p tion (12 ) . H ow eve r , reduc ing to ta l fa t in take is n o tlike ly to be the m ost e ffec tiv e w ay to red uce trans fatty ac idsco nsum ption . D uring the p as t d ecade in th e U n ited S ta tes , to ta lfa t in take has dec lined from 38% to 34% o f energ y , w ith on lym ino r ch anges in trans fa tty ac id co nsum ption . M uch grea te rreduc tio ns can be ach ieved by chang ing m anu factu r in g pro -cesses and sp ec ific food cho ices. A lso , th is con ten tion ign oresth e po ss ib ility tha t trans fa tty ac ids m ay have a w orse effec t(o n a p er-un it b asis ) than sa tu rated fa t, as su ggested by theef fects on th e ra tio o f to tal to H D L cho leste ro l in m etabo lics tud ies .

A t presen t, in d iv id ua ls w ho d esire to reduce the ir b loodch o leste ro l m ay see the ir e ffo rts h am pered by an increasedco nsum ption of trans fa tty ac ids as a resu lt o f choos ing food slow in satu ra ted fat. T h is pa rad ox is alread y a conseq uence o ffo od labe ling regu la tions in the U nited S ta te s and C an ad a,w h ich do no t requ ire m anufactu re rs to revea l the trans con ten tof the ir p rodu c ts and a llow labe ling of p rod uc ts a s low insa tu ra ted fa t and low in cho les tero l regard less o f the ir transfa tty ac id con ten t. Th is p o licy prov id es a s trong incen tiv e torep lace sa tu ra ted fa ts w ith partia lly hydro gena ted fa ts , andprodu cts w ith these labe ls a re , in fac t, those w ith th e h igh es tam oun ts o f trans fa tty ac id s (28 ). In a m eta -ana lysis com paringthe e ffec ts o f va rio us m arga rin es and bu tter on b lo od lip id s,Zock an d K a tan (2 9 ) fou nd th at th e sa tu ra ted fa t con ten t o fm argarines w as un re la ted to the ra tio o f to ta l to H D L cho les -tero l. H ow eve r , th e trans fa t con ten t o f m arg ar in es w asstron g ly assoc iated w ith th e to ta l-to -H D L cho les te ro l ratio andm argarines w ith h igh trans fa t con ten t w ere s im ila r to bu tte r.These d ata p rov id e ind ep en den t confirm atio n of the re latio nsdescribed in F igure 1 . In the U nited S tate s , ev en m od era teconsum p tion of fo ods rich in trans fa tty ac ids m ay increaseco nsum ption to 5% of en ergy , a leve l th at w ou ld be pred ic tedto nega te the b en e fits o f a redu ctio n in 10% o f ene rg y fromsa tu ra ted fat (25 , 30). F in ally , av erag e consum ption d ata ignoreth e fact th at a subs tan tia l p ro portion o f th e po pu la tio n con-sum es h igh am ounts o f trans fa tty ac ids . Fo r exam ple , con-sum p tion m ay be 27 g /d in the U nited K ing dom for m d i-v idua ls w ith a d ie t h igh in fa t, w ith hydro gena ted f ish o ils asth e m ajo r source (31 ). A w ork ing g roup of W H O IFA O re-

v iew ed the hea lth e ffec ts o f trans fa tty ac ids and conc luded tha th ig h in takes o f trans fa tty ac ids are undesirab le and the irco nsum p tio n shou ld be red uced (32). A ltho ugh the U S foodindu stry has resis ted chang e ( 1 5 ), the m ajo r E u ropean m arga-r im e and o il m anu factu rers have acknow ledged the adversee ffec ts o f trans fa t and have e lim ina ted or g rea tly redu cedam ounts in m arg arin es (33). F rom the changes in m argarinea lon e, it w as es tim ated tha t ra tes fo r C A D w ould be reduced by5% . If such changes w ere m ad e in the U n ited S ta tes, th is w ou ldred uce prem atu re dea th s by 25 000 /y .

W ithou t g reate r ava ilab ility o f in fo rm a tion on the trans fattyac id con ten t o f fo ods , hea lth -consc ious consum ers a re like ly tob e particu larly m is lead by c laim s of low sa tu ra ted fat andcook ed in vege tab le o il, as tho se produc ts m ay con tain up to35 % trans fa tty ac ids. P ruden t d ie tary adv ice shou ld a im tored uce spec ifica lly the am ount o f bo th sa tu rated an d trans fattyac ids. T h is can b e ach iev ed by us ing vege tab le o ils in the irn atu ra l, u nhydro gena ted fo rm fo r fry in g , bak in g , and a t th etab le and avo id ing an im a l fa ts and com m erc ia l p rod uc ts bakedo r fr ied in hy dro gena ted fats , w h ich inc lud e m os t fr ied fa stfo ods , b ran ds o f p o ta to and to rtilla ch ips , do nu ts, c rackers,co ok ies, and o ther bakery item s . I t is d ifficu lt to a rgu e tha tco nsum ers shou ld n o t be a llow ed to m ake in fo rm ed cho ices,w hich w ould requ ire tha t food lab els in d ica te the am oun t o ftrans fa tty ac id s and th at sp ec ia l labe ls b e created fo r fast foodsand o the r p ro duc ts w ith v ery h ig h trans fa tty ac id con ten ts andth at are p re sen tly exem pt from labe ling requ irem en ts . N

W e thank M eir S tam pfer fo r h elp fu l com m ents.

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acid isom ers in hy dro genated o ils . A nnu Rev Nu ts l984 ;4 :339 -76 .2 . Sen ti FR . H ealth aspec ts. B ethesda, M D : Fede ration of A m eric an

Soc iet ies for Exper im enta l B io logy , 198 8 . (C on tra ct no . FDA223-83-2020 .)

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5. Anderson RL , F ullm er C SJ, H ollen bach E l. E f fects o f trans isom ers oflino leic ac id o n th e m etabo lism o f lino leic acid in rats. J N utr1 97 5 ; 1 0 5: 39 3 -4 0 0.

6 . R atnay ake W M N , C hen Z Y , P elle tier G , W ebe r D . O ccurren ce o f5c,8c, 1 1 C, I 5 t-e ic osa tetraen o ic an d oth er unu su al po lyu nsa tura ted fa ttyacids in rats fed p artia lly hy drogenated canola o il. L ip id sI 9 9 4 ; 2 9 : 7 0 7- l 4 .

7 . M ensink RPM , K atan M B . E ffect o f d ie tary trans fa t ty acids o nhig h-d en sity an d low -d ens ity lip opro te in cho les tero l le vels in he alth ysub jec ts. N E ng l J M ed 1990 ;32 3:4 39-45 .

8 . Zo ck PL , K a tan M B . H ydro gen atio n altern ativ es: effe cts of trans fa t tyacids and ste aric a cid v ersu s lino leic a cid o n serum lip ids an d lip opro-te ins in hum ans . J L ip id R es l99 2;3 3 :3 99-4 l0 .

9 . Ju dd JT , C lev idence BA , M uesing RA , W ittes J, S unk in M E , P odczasyJ J. D ie ta ry trans fa tty acids: ef fects of p lasm a lip ids an d lip op ro tein sof hea lth y m en and wom en. Am J C lin N u tr 1 994 ;59 :86 1-8 .

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