94 Trans-Fatt Acids Intake and Risk of Myocardial Infarction Alberto Ascherio, MD, DrPH; Charles H. Hennekens, MD, DrPH; Julie E. Buring, ScD; Carol Master, MD, ScD; Meir J. Stampfer, MD, DrPH; Walter C. Willett, MD, DrPH Background Concern that trans-fatty acids formed in the partial hydrogenation of vegetable oils may increase the risk of coronary disease has existed for several decades, but direct evidence on this relation in humans is limited. Methods and Results With a case-control design, we studied the association between intake of trans-fatty acids and a first acute myocardial infarction among 239 patients admitted to one of six hospitals in the Boston area and 282 population control subjects. Intake of trans-fatty acids was estimated using a previously validated food frequency questionnaire. After adjustment for age, sex, and energy intake, intake of trans-fatty acids was directly related to risk of myocardial infarction (relative risk for highest compared with lowest T rans-isomers of fatty acids constitute about 5% to 6% of dietary fat in the average US diet,' mostly derived from the partial hydrogenation of vegetable oils.2,3 Trans-fatty acids are also formed in the rumen of cattle and comprise about 5% of dairy and beef fat4; however, the predominant isomer, trans- vaccenic acid, is distinct from those derived from vege- table oils. The trans-fatty acid content of typical mar- garines in the US market ranges from 10% to 30% of total fat5; however, values as high as 60% have been reported.2 Levels of trans-fatty acids of more than 10% of total fat are also frequent in cookies, crackers, breads, pastries, and french fried potatoes.2 Due to the replacement of butter and lard with margarine and vegetable shortening, consumption of trans-isomers in- creased progressively in the United States during the first half of this century, and it has changed little in the past few decades.' Trans-fatty acids can compete with natural fatty acids in enzymatic reactions involved in prostaglandin synthesis and can affect platelet activity and other critical functions.' Concern about an adverse effect of trans-fatty acids was heightened by recent reports that they increase circulating low-density lipo- protein (LDL) cholesterol and reduce high-density li- poprotein (HDL) cholesterol.6,7 However, direct evi- Received March 29, 1993; revision accepted September 19, 1993. From the Departments of Nutrition (A.A., W.C.W.) and Epi- demiology (M.J.S., W.C.W., C.M.), Harvard School of Public Health; Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School (C.H.H., JE.B.); and Channing Laboratory, Department of Medicine, Brigham and Women's Hospital (M.J.S., W.C.W.), Boston, Mass. Correspondence to Alberto Ascherio, MD, Harvard School of Public Health, Department of Nutrition, 665 Huntington Ave, Boston, MA 02115. quintile, 2.44; 95% confidence interval, 1.42, 4.19; for trend P<.0001). This relation remained highly significant after ad- justment for established coronary risk factors, multivitamin use, and intake of saturated fat, monounsaturated fat, linoleic acid, dietary cholesterol, vitamins E and C, carotene, and fiber. Intake of margarine-the major source of trans-iso- mers-was significantly associated with risk of myocardial infarction. Conclusions These data support the hypothesis that intake of partially hydrogenated vegetable oils may contribute to the risk of myocardial infarction. (Circulation. 1994;89:94-101.) Key Words * coronary disease * diet * fatty acids * myocardial infarction dence that intake of trans-isomers affects the incidence of coronary heart disease in humans is limited. In one British case-control study,8 persons dying of coronary heart disease had a higher proportion of trans-fatty acids in their adipose tissue than did those dying of other causes; in that population, the trans-isomers were derived largely from partially hydrogenated marine oils rather than from vegetable oils. An increased risk of coronary heart disease was recently reported in a large prospective study limited to women.9 To address the hypothesis that higher intake of trans-isomers formed in the partial hydrogenation of vegetable oils increases the risk of myocardial infarction, we examined this relation in a case-control study conducted in the Boston area in 1982 through 1983. Methods Study Participants Eligible patients were white men and women less than 76 years of age with no history of previous myocardial infarction or angina who were admitted to the intensive care units of one of six suburban Boston hospitals between January 1, 1982, and December 31, 1983. The diagnosis of myocardial infarction was confirmed from the hospital record, based on clinical history and creatine kinase increase. Informed consent was obtained from the patients after obtaining permission from the admitting physician. For each patient, a control subject of the same age (within 5 years) and sex was selected at random from the resident list of the town in which the patient resided.10 Control subjects were ineligible if they had previously had a myocardial infarction or angina. A total of 450 eligible patients were identified. Of these, 9 could not be approached because of lack of physician consent, 5 could not be contacted after discharge, and 70 (16% of those approached) refused to participate, leaving 366 for the study. Among 741 potential control subjects, 423 (57.1%) agreed to participate and were available for the study. Appropriate by guest on May 11, 2018 http://circ.ahajournals.org/ Downloaded from
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94
Trans-Fatt Acids Intake and Riskof Myocardial Infarction
Alberto Ascherio, MD, DrPH; Charles H. Hennekens, MD, DrPH; Julie E. Buring, ScD;Carol Master, MD, ScD; Meir J. Stampfer, MD, DrPH; Walter C. Willett, MD, DrPH
Background Concern that trans-fatty acids formed in thepartial hydrogenation of vegetable oils may increase the risk ofcoronary disease has existed for several decades, but directevidence on this relation in humans is limited.Methods and Results With a case-control design, we studied
the association between intake of trans-fatty acids and a firstacute myocardial infarction among 239 patients admitted toone of six hospitals in the Boston area and 282 populationcontrol subjects. Intake of trans-fatty acids was estimatedusing a previously validated food frequency questionnaire.After adjustment for age, sex, and energy intake, intake oftrans-fatty acids was directly related to risk of myocardialinfarction (relative risk for highest compared with lowest
T rans-isomers of fatty acids constitute about 5%to 6% of dietary fat in the average US diet,'mostly derived from the partial hydrogenation
of vegetable oils.2,3 Trans-fatty acids are also formed inthe rumen of cattle and comprise about 5% of dairy andbeef fat4; however, the predominant isomer, trans-vaccenic acid, is distinct from those derived from vege-table oils. The trans-fatty acid content of typical mar-garines in the US market ranges from 10% to 30% oftotal fat5; however, values as high as 60% have beenreported.2 Levels of trans-fatty acids of more than 10%of total fat are also frequent in cookies, crackers,breads, pastries, and french fried potatoes.2 Due to thereplacement of butter and lard with margarine andvegetable shortening, consumption of trans-isomers in-creased progressively in the United States during thefirst half of this century, and it has changed little in thepast few decades.' Trans-fatty acids can compete withnatural fatty acids in enzymatic reactions involved inprostaglandin synthesis and can affect platelet activityand other critical functions.' Concern about an adverseeffect of trans-fatty acids was heightened by recentreports that they increase circulating low-density lipo-protein (LDL) cholesterol and reduce high-density li-poprotein (HDL) cholesterol.6,7 However, direct evi-
Received March 29, 1993; revision accepted September 19,1993.From the Departments of Nutrition (A.A., W.C.W.) and Epi-
demiology (M.J.S., W.C.W., C.M.), Harvard School of PublicHealth; Division of Preventive Medicine, Brigham and Women'sHospital, Harvard Medical School (C.H.H., JE.B.); and ChanningLaboratory, Department of Medicine, Brigham and Women'sHospital (M.J.S., W.C.W.), Boston, Mass.
Correspondence to Alberto Ascherio, MD, Harvard School ofPublic Health, Department of Nutrition, 665 Huntington Ave,Boston, MA 02115.
quintile, 2.44; 95% confidence interval, 1.42, 4.19; for trendP<.0001). This relation remained highly significant after ad-justment for established coronary risk factors, multivitaminuse, and intake of saturated fat, monounsaturated fat, linoleicacid, dietary cholesterol, vitamins E and C, carotene, andfiber. Intake of margarine-the major source of trans-iso-mers-was significantly associated with risk of myocardialinfarction.
Conclusions These data support the hypothesis that intakeof partially hydrogenated vegetable oils may contribute to therisk of myocardial infarction. (Circulation. 1994;89:94-101.)Key Words * coronary disease * diet * fatty acids *
myocardial infarction
dence that intake of trans-isomers affects the incidenceof coronary heart disease in humans is limited. In oneBritish case-control study,8 persons dying of coronaryheart disease had a higher proportion of trans-fattyacids in their adipose tissue than did those dying ofother causes; in that population, the trans-isomers werederived largely from partially hydrogenated marine oilsrather than from vegetable oils. An increased risk ofcoronary heart disease was recently reported in a largeprospective study limited to women.9 To address thehypothesis that higher intake of trans-isomers formed inthe partial hydrogenation of vegetable oils increases therisk of myocardial infarction, we examined this relationin a case-control study conducted in the Boston area in1982 through 1983.
MethodsStudy Participants
Eligible patients were white men and women less than 76years of age with no history of previous myocardial infarctionor angina who were admitted to the intensive care units of oneof six suburban Boston hospitals between January 1, 1982, andDecember 31, 1983. The diagnosis of myocardial infarctionwas confirmed from the hospital record, based on clinicalhistory and creatine kinase increase. Informed consent wasobtained from the patients after obtaining permission from theadmitting physician. For each patient, a control subject of thesame age (within 5 years) and sex was selected at random fromthe resident list of the town in which the patient resided.10Control subjects were ineligible if they had previously had amyocardial infarction or angina.A total of 450 eligible patients were identified. Of these, 9
could not be approached because of lack of physician consent,5 could not be contacted after discharge, and 70 (16% of thoseapproached) refused to participate, leaving 366 for the study.Among 741 potential control subjects, 423 (57.1%) agreed toparticipate and were available for the study. Appropriate
control subjects were interviewed for 340 patients, so 340matched pairs were available for analysis. In the present study,we excluded subjects who reported a history of diabetes- 46patients (including 15 women) and 26 control subjects (includ-ing 3 women) -or a history of high cholesterol- 60 patients(including 8 women) and 36 control subjects (including 9women) -because their diet was likely to have been modifiedas a consequence of the disease and may not be representativeof their long-term intake. Eight men and one woman reportedboth diabetes and high cholesterol. As a result, 521 subjects(407 men and 114 women) were included in the study: 197matched pairs, plus an additional 42 patients and 85 controlsubjects.
Data CollectionEligible and willing patients and control subjects were
interviewed in their homes by one of two nurses approximately8 weeks after hospital discharge of the patients. Informationwas obtained on coronary risk factors related specifically to thetime period before the infarction for the patients and beforethe interview for the control subjects. This information in-cluded history of diabetes, high blood pressure, and hypercho-lesterolemia; family history of myocardial infarction; weight;height; level of physical activity; cigarette consumption; pres-ence of type A personality; alcohol consumption; and diet. Aphysical activity index, expressed in kilocalories per week, wasobtained by summing stairs climbed, blocks walked, activity atwork, and recreation and leisure time activity.1" Body massindex was calculated as weight (in kilograms) divided by height(in meters squared). Fasting venous blood samples wereobtained from patients approximately 8 weeks after hospitaldischarge and from control subjects at about the same time asthe matching patient. HDL and LDL cholesterol concentra-tions in serum were determined by Lipid Research Clinicsmethods, as previously described.10
The Semiquantitative Food Frequency QuestionnaireInformation on dietary intake was collected using a semi-
quantitative food frequency questionnaire, which was an ex-tended and refined version of a previously validated question-naire.12-15 The questionnaire included 116 food items plusvitamin supplements. For each food, a commonly used unit orportion size was specified, and participants were asked howoften on average over the previous year they had consumedthat amount. Nine responses were possible, ranging from "lessthan one time per month" to "six or more times per day." Forseveral foods, including margarine, we also asked whetherintake had greatly increased or greatly decreased over the past10 years. In addition, we inquired about the type of margarineusually used (stick or tub) and types of fat used in frying andbaking. Distinction of the type of margarine is importantbecause stick margarine has a higher proportion of trans-isomers. The intake of trans-isomers of fatty acids and of othernutrients was computed by multiplying the frequency of con-sumption of each unit of food by the nutrient content of thespecified portions. Composition values for total trans-isomerswere obtained based on analyses by Enig and colleagues2 andSlover and colleagues.5 In these calculations, we included alltrans-isomers of carbon-18 fatty acids, and we assumed anaverage trans-isomers content equal to 32.5% of total fat forstick margarine and 17.5% of total fat for tub margarine. Inaddition to calculating total intake of trans-fatty acids, wepartitioned this total into trans-isomers from vegetable fat andfrom animal sources. Data for other dietary variables wereobtained primarily from US Department of Agriculture sourc-es.16 We adjusted nutrient values for total energy intake usingregression analysis.15"17The validity of trans-fatty acid intake estimated from the
dietary questionnaire has been assessed by comparison to theproportion of trans-fatty acids in aspirates of adipose tissue
measured by gas-liquid chromatography. Two studies havebeen conducted-one among 115 women selected as controlsubjects in a case-control study of breast cancer18 and oneamong 118 male participants in a cohort study.19 In bothinvestigations, trans-isomer intake was estimated using a ver-sion of the food frequency questionnaire adopted in this study.Among women, trans-isomers constituted 4.4% of adiposefatty acids and 5.8% of fatty acids calculated from the dietaryquestionnaire; comparable values for men were 4.2% and5.4%. The Spearman correlation coefficient between calcu-lated intake and measured level in adipose tissue was .51 inwomen and .34 in men (P<.001 for both). To assess thereproducibility of the measurement of trans intake, the samegroup of men was asked to complete a second food frequencyquestionnaire 1 year after the first; the correlation between thetwo measurements was .63 (unpublished data).
Statistical AnalysisThe association of trans-isomers with myocardial infarction
was calculated using data from both unmatched subjects andthe 197 matched pairs. Quintiles of nutrient intakes and otherrisk factors were defined according to the distribution of eachvariable among control subjects. Multivariate modeling wasdone using unconditional logistic regression analysis for theunmatched data and conditional logistic regression for thematched pairs. Because the results were virtually identical,only results of the unmatched analyses are included in thisreport. Potential confounders were initially added to themultiple logistic regression models as categorical variables,which were then replaced by continuous variables if the datasuggested a linear association with myocardial infarction.
Tests for trend were performed by adding to the logisticregression models the intake of trans-fatty acids as a contin-uous variable. Reported P values are two tailed; values lessthan .05 were considered significant.
ResultsThe mean intake of total trans-fatty acids was 4.36
g/d (SD, 2.33) in men, corresponding to 1.5% of totalenergy and 4.3% of total fat intake, and 3.61 g/d inwomen (SD, 2.24), corresponding to 1.7% of totalenergy and 4.8% of total fat intake. The higher absoluteintake of trans-isomers in men was explained by theirhigher total energy intake; the energy-adjusted intakeof trans-fatty acids was similar in the two sexes, withmedians of the lowest and highest quintiles of 3.1 g/dand 6.7 g/d in men and of 3.0 g/d and 6.8 g/d in women.The mean values of several dietary and nondietaryvariables across quintiles of intake of energy-adjustedtrans-fatty acids for the control group are shown inTable 1. Intake of energy-adjusted trans-fatty acids wasinversely associated with alcohol consumption and di-rectly associated with number of cigarettes per day andfat intake, including monounsaturated fat, linoleic acid,saturated fat, and cholesterol. Physical activity andintakes of carotene, dietary fiber, vitamin E, and vita-min C were somewhat lower but not significantly loweramong individuals in the top quintile compared withthose in the bottom quintile of energy-adjusted transintake.
Differences between patients and control subjects inmajor risk factors for coronary disease are shown inTable 2. Potential confounding by these factors hasbeen addressed in multivariate analyses (see below).When adjusted only for age and sex, intake of trans-
fatty acids was associated with an increased risk ofmyocardial infarction (Table 3). The relative risk for the
HDL indicates high-density lipoprotein; LDL, low-density lipoprotein.Risk factors are directly standardized by age and sex to the distribution of control subjects.*n=244.
highest compared with the lowest quintile of trans-fattyacid intake was 2.14 (95% confidence interval [CI], 1.24,3.68; for trend P<.0001); the comparable relative riskfor intake of energy-adjusted trans-fatty acids was 2.44(95% CI, 1.42, 4.19; for trend P<.0001). The increasedrisk was evident only among individuals in the topquintile of intake of energy-adjusted trans-fatty acids.These relations changed only slightly after adjustmentfor standard risk factors, including cigarette smoking,history of hypertension, and family history of ischemicheart disease (all of which were independently associ-ated with increased risk of myocardial infarction inthese data) as well as alcohol intake and physicalactivity (both independently associated with decreasedrisk of myocardial infarction) and body mass index. Nomaterial change in the association between trans-fattyacid intake and risk of myocardial infarction was ob-served if smoking, alcohol, body mass index, or physicalactivity was added to the models as a categorical ratherthan a continuous variable.
When intakes of saturated fat, monounsaturated fat,linoleic acid, and cholesterol were also added simulta-neously to the model, the associations of trans- andenergy-adjusted trans-fatty acid intakes with myocar-dial infarction were slightly weakened, but the tests fortrend remained significant. No material changes inthese relations were observed after further adjustmentfor intakes of carotene, vitamin E, vitamin C, or dietaryfiber; use of multivitamins or aspirin; marital status;education; occupation; and personality type.To assess the effect of excluding men and women with
diabetes and high cholesterol on the association be-tween trans-fatty acid intake and risk of myocardialinfarction, we estimated this association among the 680subjects in the original study. After adjusting for stan-dard risk factors and intakes of saturated fat, monoun-saturated fat, linoleic acid, and cholesterol, the relativerisk for the highest compared with the lowest quintile ofenergy-adjusted trans-fatty acid intake was 2.75 (95%CI, 1.64, 4.66; for trend P<.00001).
Vitamin E, IU/dCarotene, IU/dVitamin C, mg/dLDL cholesterol, mg/dLtHDL cholesterol, mg/dLt
78.2 78.0
25.7
15.3
16.2
4.0
25.4
21.8
47.3
25.5
19.8
1.0
4.0 .63
27.2
7.6 14.1
29.1
34.3 19.5
42.3
26.2 13.9
31.6
20.9
50.6
32.6
14.2
58.7
23.5
2 819
2 507
36.5
4.68
257
113
37.3
36.4
15.5
456
21.0
45.1
10 887
257.8
142.4
34.8
2 667
965
6.4
3 698
2 384
34.0
2.57
112
41
18.2
16.4
8.0
224
10.1
179.7
10 791
308.2
34.2
9.2
LDL indicates low-density lipoprotein; HDL, high-density lipoprotein.*Not energy adjusted.tPatients, 214; control subjects, 244.
3.78
251
106
33.2
32.2
13.9
429
21.9
47.3
11141
303.7
137.0
42.2
.05
.0001
.00003
.001
.009
.04
.08
.03
3087 .0005
797 .12
6.2 .0001
2.02 .0001
99 .52
35 .04
15.2
13.9
.006
.002
6.9 .02
195 .14
11.4
128.9
9905
366.3
33.6
11.3
.35
.88
.78
.12
.0001
.0001
In analyses stratified by sex, we observed an associa-tion between risk of myocardial infarction and intake ofenergy-adjusted trans-fatty acids among both men andwomen. After adjustment for standard risk factors, therelative risk comparing the highest with the lowestquintile was 3.65 (95% CI, 0.90, 14.70; for trend P=.02)among women and 2.17 (95% CI, 1.11, 4.24; for trendP=.001) among men.To explore the possibility that the observed associa-
tions between trans-fatty acids and myocardial infarc-tion were due to a change from butter to margarineconsumption among subjects who suspected they mightbe at increased risk of ischemic heart disease, werepeated the analyses excluding (from our study popu-lation of 521 subjects) men and women who increased(n=75) or decreased (n=27) their consumption of
margarine during the previous 10 years and those whowere on a special diet at the time of the interview(n=100). A total of 344 subjects remained after theexclusions. The relative risk of myocardial infarction forthe highest compared with the lowest quintile of energy-adjusted trans-isomer intake increased from 1.97 to 2.48(95% CI, 1.0, 6.16) after adjustment for standard riskfactors and intake of other types of fat. The comparablerelative risk was 5.16 (95% CI, 1.65, 16.07) after furtherexclusion from the analyses of subjects who reportedchange in the consumption of butter, beef, or vegetablesduring the previous 10 years. Only 187 subjects, how-ever, met the inclusion criteria for this analysis.Because partially hydrogenated vegetable fats and
animal fat contain different positional and configura-tional trans-isomers, which have been shown to have
RR indicates relative risk; Cl, confidence interval.*Age, sex, smoking (number of cigarettes per day), history of hypertension (yes, no), body mass index, alcohol intake, family history
of ischemic heart disease (yes, no), and physical activity entered as continuous variables unless otherwise specffied.tAdditionally adjusted for intake of saturated fat, monounsaturated fat, linoleic acid, and cholesterol (categorized in quintiles).
different physiological properties, we examined the as-sociation of myocardial infarction with intake of trans-isomers from different sources (Table 4). Hydrogenatedvegetable fats contributed 74% of the total intake oftrans-fatty acids in the population. The overall associ-ation between trans-fatty acid intake and risk of myo-cardial infarction was almost entirely accounted for bytrans-isomers from hydrogenated vegetable fats. Nosignificant association was observed between intake oftrans-isomers from animal fats and myocardialinfarction.To understand this relation further, we examined the
contribution of individual food items to the differencesin total trans-isomer intake among the study partici-pants. In stepwise regression with energy-adjusted transas the dependent variable and individual food items aspotential predictors, margarine was the first variable toenter the model (R2=.64). Other food items contributedonly modestly to the intake of trans-isomers. Intake ofmargarine was directly associated with risk of myocar-dial infarction, but the increased risk was significantonly among participants consuming more than 2.5 patsof margarine per day compared with those consumingless than 1 pat per day (relative risk, 3.22; 95% CI, 1.63,6.38; for trend P=.0002). The association of margarinewith myocardial infarction did not change appreciablyafter adjustment for butter intake.To evaluate whether the association between intake of
trans-isomers and myocardial infarction was mediated by
their effect on plasma lipids, we further adjusted therelative risk for plasma concentrations ofHDL and LDLcholesterol in addition to standard risk factors. Bloodsamples were obtained from patients approximately 8weeks after hospital discharge and from control subjectswithin 1 week of the day of the matching patient.Concentrations of plasma lipids were available for 458participants. Among these subjects, the relative risk ofmyocardial infarction comparing the highest with thelowest quintile of intake of trans-isomers was 2.23 (95%CI, 1.19, 4.18) before and 2.12 (95% CI, 1.09, 4.11) afteradjustment for plasma HDL and LDL cholesterol.
DiscussionIn this case-control study, we found a significant
association between intake of trans-fatty acids and riskof myocardial infarction. This association could not beexplained by other established risk factors or otherdietary variables. Because we excluded from the studysubjects with a previous diagnosis of ischemic heartdisease, diabetes, or hypercholesterolemia, it is unlikelythat the observed association was due to a shift frombutter to margarine by subjects at high risk of myocar-dial infarction. Further evidence against this explana-tion is provided by the stronger association betweentrans-isomers and myocardial infarction among men andwomen who did not change their dietary pattern duringthe past 10 years. Also, history of hypercholesterolemiawas associated with a decreased intake of eggs but not
Cl indicates confidence interval.*Adjusted for age, sex, smoking, history of hypertension, body mass index, alcohol intake, family history of ischemic heart disease,
physical activity, and intake of saturated fat, monounsaturated fat, linoleic acid, and cholesterol.
with an increased intake of margarine, suggesting that,in this sample, an increase in margarine intake was notpart of the dietary changes induced by a diagnosis ofhigh coronary risk (data not shown).The association between intake of trans-fatty acids
and myocardial infarction in our data could theoreti-cally be due to a biased selection of control subjects intothe study. This explanation, however, is unlikely be-cause it implies a strong association - independent ofage, sex, educational level, occupation, area of resi-dence, and other variables that were controlled for inthe analyses -between trans intake and refusal to par-ticipate in the study. We cannot exclude the possibilitythat patients overreported (or control subjects underre-ported) their margarine consumption, perhaps becauseuse of margarine rather than butter may have beenperceived as a healthy habit. Some indirect evidenceagainst this interpretation comes from the fact thatintake of other foods usually considered as healthy, suchas apples, carrots, spinach, and other fresh fruits andvegetables, was not directly associated with an increasedrisk of myocardial infarction. Such association would beexpected if attitudes toward food caused a recall bias.On the other hand, some nondifferential misclassifica-tion of dietary intake of margarine and trans-fatty acidsis likely to have occurred and could only have dilutedthe strength of the observed association.The results of our study are similar to those recently
reported from the Nurses' Health Study9 and suggestthat an association between intake of trans-fatty acidsand risk of myocardial infarction exists among men.
Joossens and coworkers20'21 have reported that coronarymortality in Belgium is lower in the North, wheremargarine consumption is high, than in the South,where butter is used more commonly and margarineconsumption is low. However, northerners also have ahigher intake of polyunsaturated fatty acids and fish anda lower intake of saturated fats and cholesterol, whichmay contribute to their lower coronary risk. Also, intakeof trans-fatty acids was not measured in the Belgianstudy. Because several margarines have a low content oftrans-fatty acids, the contribution of margarine to totaltrans intake may be much smaller in Belgium than in ourstudy population.Numerous potential mechanisms exist by which in-
take of trans-fatty acids could adversely affect the riskof myocardial infarction. The effects of trans-isomers ontotal serum cholesterol have been inconsistent in 14studies that examined this relation.22 However, in ran-domized trials, diets containing 10% or 7.7% of energyas trans-fatty acids from partially hydrogenated vegeta-ble fat increased LDL cholesterol and decreased HDLcholesterol compared with similar diets containing sat-urated or monounsaturated fats.6,7 Persistence of astrong association between trans intake and myocardialinfarction even after controlling for plasma levels ofLDL and HDL in this study suggests that higher transintake may increase the risk of myocardial infarctionindependent of its effect on these lipoproteins. How-ever, this result should be interpreted with cautionbecause plasma lipids among patients may havechanged after the disease. The increased levels of
lipoprotein[a]- an independent risk factor for coronarydisease23- caused by diets containing 7% or 10% trans-monounsaturated fatty acids compared with similardiets containing saturated fats or oleic acid24,25 suggestan alternative mechanism by which trans-fatty acidintake might increase the risk of myocardial infarction.Hydrogenated vegetable oils contain several geomet-
rical and positional isomers of fatty acids with 18 atomsof carbon and 1 or 2 double bonds, each with specificproperties related to the position and configuration ofthe double bonds. Because of their effects on themetabolism of gamma-linoleic and arachidonic acid,26ingestion of trans-fatty acids can affect the metabolismof prostaglandin and other eicosanoids and may alterplatelet aggregation and vascular function. In addition,incorporation of trans-isomers into membrane phospho-lipids may influence the physical properties of themembrane as well as the activities of the membrane-associated enzymes.27 In vitro, trans-isomers have aweaker inhibitory effect on collagen-induced plateletaggregation than do cis-isomers,28 and trans-isomershave been reported to inhibit the activities of Na+,K+-ATPase and adenylate cyclase and reduce the den-sity of P-adrenergic receptors in rat heart membranes.29The lack of association between intake of trans-fatty
acids from animal sources and myocardial infarction inour study may be due to the lower intake and narrowerrange of intake of trans from animal sources comparedwith vegetable sources. Alternatively, this observationmay result from the different composition of transderived from different sources. In human fibroblastcultures, trans-vaccenic acid (trans 11, 18:1), which isthe predominant trans-fatty acid in ruminant fat, has aless inhibiting effect on the d6 desaturase and fatty acidssynthesis than does elaidic acid (trans 9, 18:1), thepredominant monounsaturated trans-isomer in hydro-genated vegetable oils.30Most of our knowledge of the effect of trans-isomers
is based on experiments in rats. Those studies generallyfound little effect on the growth and general health ofrats fed high doses of trans, whereas biochemical analy-ses revealed several dramatic changes in cell membranestructure and enzymatic activity.' Because of differ-ences in the metabolism of trans between rats andhumans,' the effects of trans-isomer intake may bedifferent in the two species. Human studies on thelong-term effect of trans intake are difficult to conductbecause of the changing compositions of the foods thatprovide most of the trans-fatty acids in the diet andbecause of the almost universal exposure to at leastsome level of dietary trans in industrialized countries.
In summary, we observed a positive association ofintake of trans-fatty acids with myocardial infarction.This finding was due to a positive association betweenmargarine intake and myocardial infarction and couldnot be explained by other risk factors for coronary heartdisease. These data support the hypothesis that intakeof partially hydrogenated vegetable oils may contributeto myocardial infarction. If the observed associationwere causal, individuals in the top quintile of trans-fattyacid intake could halve their risk of myocardial infarc-tion- a benefit comparable to that expected from a 20%reduction in plasma cholesterol-by reducing their in-take of trans-isomers.
AcknowledgmentsWe thank the six Boston-area hospitals that participated in
this study: Emerson Hospital (Marvin H. Kendrick, MD),Framingham Union Hospital (Marvin Adner, MD), LeonardMorse Hospital (L. Frederick Kaplan, MD), Mount AuburnHospital (Leonard Zir, MD), Newton-Wellesley Hospital(James Sidd, MD), and Waltham Hospital (Solomon Gabbay,MD). We also thank Marty Vandenburgh and Mary Johnson,who assisted in the research.
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