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Human Nutrition and Metabolism

Trans Fatty Acids in Adipose Tissue and the Food Supply Are Associated with Myocardial Infarction^1,2

CSIRO Health Sciences and Nutrition, Adelaide BC, South Australia 5000

³To whom correspondence should be addressed. E-mail: peter.clifton{at}csiro.au.

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Metabolic studies have clearly shown that trans fatty acids (TFAs) elevate LDL and lower HDL cholesterol. Epidemiologic studies showed a relation between TFA intake and the risk of myocardial infarction (MI), but studies examining adipose tissue TFAs have not uniformly confirmed this. We performed a case control study examining both adipose tissue levels and dietary intake of TFAs and first MI. Between 1995 and 1997, 209 cases of first MI completed a 300-item FFQ and 79 had an adipose tissue biopsy; 179 matched controls completed the FFQ and 167 had a biopsy. During the course of the study (mid-1996), TFAs were eliminated from margarines sold in Australia. Cases biopsied before mid-1996 had greater levels of trans 18:1(n-9) (32% P < 0.03) and trans 18:1(n-11) (23%, P < 0.001) than controls biopsied before mid-1996. After June 1996, there were no differences between cases and controls in any of the adipose tissue TFAs measured. Logistic regression showed that trans 18:1(n-11) (P = 0.03) was an independent predictor of a first MI. Cases consumed 0.5 g/d (P = 0.002) more TFAs than controls. Subjects in the highest quintile of TFA intake had an OR for first MI of 2.1 (95% CI, 1.1–4.3), which was not independent of saturated fat intake. Apparent TFA intake from margarine was related to adipose tissue 18:1t[(n-9) and (n-10)] in 1995 (r = 0.66, 0.66, respectively). We conclude that TFAs in adipose tissue are associated with an increased risk of coronary artery disease and rapidly disappear from adipose tissue when not included in margarines.

KEY WORDS: • trans fatty acids • adipose tissue • food intake • myocardial infarction

Trans fatty acids (TFAs)⁴ produced by partial hydrogenation of unsaturated oils to produce margarine and shortening, were shown to elevate LDL cholesterol and, at high intakes, lower HDL cholesterol (1–9). In a composite regression line drawn from nearly all randomized studies, the ratio of total cholesterol to HDL cholesterol was directly related to the percentage of energy obtained from TFAs (10). Lipoprotein(a), another important coronary risk factor, is also elevated to a small extent by TFAs (1–3,7,11,12). Furthermore, TFAs appear to have a more deleterious effect on lipoprotein levels than saturated fat (1,2,5–9).

Given the well-established association between these blood lipid alterations and heart disease it might be expected that high intakes of TFAs would lead to increased rates of coronary artery disease; however, studies in the area are inconsistent. Epidemiologic evidence in cohort studies from the United States (13,14) suggests that a high TFA intake is associated with an increased risk of coronary artery disease. In these studies, an absolute increase in TFAs of 2% of energy was associated with an increase in risk of between 36 and 93% (13,14). Similarly in a case control study from the Boston area (15), the highest quintile of TFA intake was associated with a doubling of the risk of first MI. An Italian case control study in women also demonstrated an increase in risk with medium-to-high margarine intake with a multivariate odds ratio (OR) of 1.5, with margarine intake accounting for 6% of nonfatal cases (16). However, several studies found no relation between margarine consumption and rates of MI (17,18). This may relate to the source of the TFA, in particular whether it is associated with saturated fat in baked goods or with polyunsaturated fat in soft margarines.

Similarly, the evidence linking adipose tissue levels of TFAs and coronary heart disease is conflicting. Adipose tissue samples in two case control studies from Europe demonstrated no association between the TFA content of adipose tissue and risk of first MI (19,20). The British study of men with sudden death found an OR of 0.4 for the highest quintile of adipose tissue TFA level (20), whereas the larger Euramic study (19) found no relation between adipose tissue TFA levels and risk of myocardial infarction. After excluding the two Spanish centers with very low levels, the OR rose to 1.44, but it was not significant. In contrast, Baylin et al. (21) found an association between total adipose tissue TFAs (mostly 18:2t and 16:1t) and risk of nonfatal MI in Costa Rican adults; Pedersen et al. (22) also found an increased risk of MI in the 5th compared with the 1st quintile of adipose tissue TFAs in a Norwegian population. Only one study performed both dietary and adipose tissue measurements at the same time (22), and the issue of the association of TFA consumption with coronary artery disease remains controversial.

Dietary TFAs come from both animal and vegetable sources, and the primary TFAs are the same, i.e.,18:1 monoenes, (n-9), (n-10), and (n-11) from both sources (23). In Australia, the total intake of TFAs is lower than in the United States because of the limited use in food service and commercial sectors of highly hydrogenated fats, which are commonly used in the United States. Soft margarines, which are also low in saturated fat and high in unsaturated fat, are the predominant vegetable source of TFAs (24). Thus, it is possible that the intake of TFA-containing foods in Australia may be associated with protection from coronary artery disease because of the associated unsaturated fat, which might outweigh the harmful effects of the TFAs.

The aim of this study was to clarify the relations between TFAs and their isomers in adipose tissue, TFA intake, and first MI by performing a case control study in an Australian population with a first heart attack with no preceding history of coronary artery disease or hyperlipidemia.

During the study, a unique opportunity to investigate the temporal relationship between TFAs intake and adipose tissue levels was presented when the margarine supply, which before 1996 contributed 50% of the dietary intake of TFAs, unexpectedly became TFA-free after food manufacturers withdrew TFAs from popular brands of margarine. Consequently, there was a rare opportunity to obtain data on the effect of changes to the food supply on adipose tissue TFA levels.

	SUBJECTS AND METHODS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Subjects. Cases of first admission for heart disease were recruited from 4 major hospitals in Adelaide between 1995 and 1997. Both men and women were included, but all cases with a previous diagnosis of MI, angina, hypercholesterolemia, hypertriglyceridemia, or diabetes were excluded because this might have caused the subject to change his/her diet. These exclusions were particularly important to avoid confounding by the adoption of perceived healthy diets such as margarine in place of butter after the diagnosis of dyslipidemia or coronary artery disease. Consequently, >50% of potential subjects were excluded. Subjects were identified by the dietitian working in the Coronary Care Unit and interviewed in the general ward just before discharge. MI was confirmed from the notes on the basis of clinical history plus ECG or creatine kinase increase. The subjects were told that the study was examining the association between diet and coronary artery disease. Written, informed consent was obtained from each patient and approval for the study was obtained from the ethics committee of each hospital and of the Commonwealth Scientific and Industrial Research Organization (CSIRO).

Drug intake (including aspirin and vitamin supplements), smoking, exercise, past and family history, occupation, blood pressure, and BMI were also recorded. Lipid levels were obtained from a blood sample taken on the day of admission. Because all blood samples were taken within 4 h of the development of chest pain, no acute phase effects on lipids would have occurred. HDL cholesterol was not routinely requested in the emergency room, and patients were not seen 3 mo after discharge when a further test could have been taken. Cases were subsequently contacted by CSIRO within 2 wk of discharge to obtain an adipose tissue biopsy. Cases were generally reluctant to have a biopsy and only 30% agreed to the procedure. Although cases may have changed their diet after myocardial infarction, we decided that changes in adipose tissue TFA levels would have been minimal in 2 wk.

Control subjects were drawn from a random sample from the electoral roll, which was matched with the cases for age, sex, and postal code (to minimize bias due to social class). A detailed questionnaire including nature of employment was administered after recruitment. Controls were excluded if they had a personal history of coronary artery disease and other criteria as per the cases. Blood was taken from nonfasting subjects for assays of lipid levels, and an adipose biopsy was also obtained at the CSIRO nutrition clinic.

    Adipose tissue biopsy and analysis. Adipose tissue biopsies were obtained from the abdominal subcutaneous fat level with the umbilicus with a 21-gauge needle attached to a 20-mL syringe. The needle and syringe and their contents were frozen at -20°C until analysis. After thawing, lipid was extracted using 2 mL of hexane, which was then evaporated. The lipids were methylated using 0.18 mol/L H₂SO₄ in dry methanol, and the methyl esters extracted with petroleum spirit. The extract was chromatographed on Florosil minicolumns and the eluate was dried under nitrogen, taken up in isooctane, and an aliquot injected onto a vitreous silica check 30 m x 0.53 mm i.d. cross-linked FFA phase GC column for separation of FAME using a Hewlett-Packard 5711A gas chromatograph. Results are expressed as g/100 g TFAs. The CV for fatty acids at the 1% level was 4%.

    Laboratory methods. Plasma total cholesterol and triglyceride concentrations were determined by commercial enzymatic methods (Cholesterol kit 2016630, Triglyceride kit 2016647,Roche Diagnostics) on an automated analyzer (Cobas Bio, Hoffmann-La Roche).

    Dietary methodology. Each subject was given a 300-item FFQ modified to include more detailed questions on margarine intake; the FFQ was checked by the dietitian using photographs of commonly available margarines to correctly define the type of margarine usually used. Metric spoons were also used to quantify how much margarine was consumed. Each control subject was sent the same FFQ as the cases before their clinic visit. This was checked for completion by a dietitian in the same manner as for the controls. Controls were usually recruited and matched to cases 3–6 mo after the case was biopsied. Nutrient intakes were calculated by Diaryan (25), a computer database of foods in which nutrient composition was based on McCance and Widdowson’s The Composition of Foods (26) modified to include Australian foods from published sources, commercial sources and in the case of margarines, from direct food analysis previously undertaken at CSIRO. The TFA composition of margarines was derived from the locally analyzed data of TFA content of commonly used domestic margarines. The TFA content of beef, dairy foods, and combined dishes was derived from locally analyzed milk and beef, and a values of 4 g TFA/100g dairy fat and 5 g TFA/100g beef fat was used for the dietary analysis (24).

    Statistics. Statistical analysis was performed using SPSS for Windows version 9.01. Data are means ± SD. Procedures used included general linear model ANOVA, logistic regression, Pearson’s correlations, and cross-tabulation. Variables included in the logistic regression were dietary intake, energy, percentage of energy as fat, protein, carbohydrate, saturated fat, polyunsaturated fat and TFAs, BMI, age, sex, blood pressure, lipids, smoking, and job classification. In the logistic regression relating adipose tissue fatty acids to myocardial infarction, all measured fatty acids were included in the regression equation. Differences were considered to be significant at P < 0.05.

Approximately half-way through the study (January and March 1996), TFAs were unexpectedly withdrawn from two major margarine brands requiring analysis of the data by time of biopsy. The data for adipose tissue and for dietary intake were analyzed separately before and after June 1996 when trans-enriched margarines were no longer available in the supermarket. In the logistic regression relating adipose tissue levels to rates of myocardial infarction, the biopsy week (from 1 to 152) was used as an obligatory covariate.

Although awareness of high lipids was an initial exclusion criteria, a minority of cases and controls subsequently indicated in the detailed questionnaires that at some stage in the past, they had been told their lipids were abnormal. This awareness was entered as a factor in the analyses.

We could not recruit matching controls for 38 cases, particularly in the male manual laborer group. Four cases had two controls. Analysis was conducted separately in the completely matched group only and in the whole group.

	RESULTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Subjects and controls. Recruitment of 209 cases of first MI and 174 controls occurred over the years 1995–1997 from 4 major hospitals in Adelaide. The cases had a higher plasma total cholesterol concentration than the controls and a slightly lower triglyceride concentration (Table 1). Unfortunately, HDL cholesterol was not available for over half of the cases, so this was not evaluated. The BMI did not differ between cases and controls. As expected, cases had a higher prevalence of elevated blood pressure (P < 0.001) and twice as many cases were smokers (P < 0.001) (Table 1).

After withdrawal of TFAs from margarines, adipose tissue 18:1(n-9) and (n-10) levels fell continuously from March 1996 with a total fall of 23% in both cases and controls; however, margarine intake did not change (controls only shown in Fig. 1).

View larger version (16K): [in this window] [in a new window]   FIGURE 1 Change in adipose tissue concentration of total TFAs and TFA intake from margarine in controls with time of biopsy. Data are means ± SD, n = 167 by year of biopsy since the study commenced.

    Dietary intake and adipose tissue fatty acid. There was an association between apparent intake of TFAs from margarines and adipose tissue trans 18:1(n-9) in cases and controls pooled in 1995 (r = 0.66, P < 0.01) (Fig. 2) and 1996 (r = 0.19, P < 0.05) but not in 1997 when TFAs disappeared from both adipose tissue and the food supply. Apparent TFA intake from margarines was similarly related to adipose tissue 18:1(n-10) in 1995 (r = 0.66, P < 0.01) and 1996 (r = 0.22, P < 0.05).

View larger version (10K): [in this window] [in a new window]   FIGURE 2 Relation between intake of TFAs from margarines and the amount of 18:1t(n- 9) in adipose tissue biopsies in 1995 in cases of first MI (n = 25).

	DISCUSSION

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

Baylin et al. (21) found a positive association between MI and TFAs in a Central American population; however, the association was attributed mainly to 18:2 TFA, which is abundant in partially hydrogenated soybean oil and not widely used in the Australian food supply. Pedersen et al.(22), in a study similar to ours, also reported that adipose tissue levels of 18:1 TFAs, 20:1 TFAs, and total TFAs were higher in cases of MI than controls, but animal and vegetable sources were not distinguished. In contrast, the Euramic study (19) found no association between adipose tissue TFAs and MI.

Unfortunately, there are no North American data on adipose tissue levels of TFAs in case control studies, although both prospective cohort studies and case control studies showed a link between dietary intake of hydrogenated vegetable oils and coronary artery disease but not TFAs from animal sources (10,13,14). In one American study, Siguel and Lerman (27) showed in a case control study that plasma TFAs were higher in 47 patients with angiographically demonstrated coronary artery disease compared with 56 controls.

We found that men and women presenting with a first MI apparently consumed 0.5 g/d (or 16%) more TFAs than age-, sex-, and occupation-matched control subjects free of clinical coronary artery disease. Adjustment for total energy intake removed any significant differences between the groups. The small increase in absolute TFA consumption appears to be of biological importance because cases biopsied before June 1996 had higher levels of 18:1 TFAs in adipose tissue than controls, and adjustment for saturated fat intake did not alter this difference. Before June 1996, levels of total 18:1 TFAs were 22% higher in the cases with increases in both the 18:1t(n-9) and (n-11) isomers. Dietary data in this group showed that intake of total TFAs was also 24% higher in the cases compared with the controls. The major source in Australia of the trans 18:1(n-11) isomer, or trans vaccenic acid, is beef and dairy fat, whereas the major source of the trans 18:1(n-9) isomer, or elaidic acid, is margarine. It is suggested by the strong correlation between estimates of margarine intake from the dietary questionnaire and the level of elaidic acid in adipose tissue that margarines play a role in this increase in adipose tissue TFAs. Although BMI did not differ between cases and controls, cases in this study seemed to be a distinctive group with higher consumption of energy, total and saturated fat, beef and dairy fat, and TFAs from all sources. This suggests that they may have been more physically active, e.g., manual laborers. Although their energy intake was appropriate for such work, their saturated fat and TFA intakes were detrimental to their health.

In parallel with our results, Ascherio et al. (10) demonstrated a risk ratio between the highest and lowest quintile of absolute intakes of TFAs of 2.14 after age and sex adjustment. However significance was lost in our study after adjustment for either energy or SFA intake, whereas it was strengthened in the Boston study (15). The Boston case control study also found that both total vegetable sources of TFAs and TFAs from margarine were associated with a first MI and that animal sources of TFAs were not related to heart disease. In contrast, we found that animal sources of TFAs were also important. The reason for this may be that in the United States, hydrogenated vegetable fats are more widespread in manufactured goods, constituting >70% of the total TFA intake, whereas in Australia, beef tallow is frequently used in baked products, and margarines are the major vegetable source constituting 36–64% of the total TFA intake (28). In Australia, animal sources of TFA are now the major contributor to the dietary intake of TFAs because margarines in Australia are nearly all free of TFAs. However, dietary advice to minimize SFA will also reduce TFAs.

The validity of the dietary intake methodology used in the current study is demonstrated by the correlations found between the adipose tissue and the dietary fatty acid data. The FFQ dietary methodology is a well-established technique, which has been used in landmark studies of dietary patterns and risk of heart disease (29). Lemaitre et al. (30) and Baylin et al. (31) validated a FFQ methodology similar to the one used in our study with adipose tissue levels of TFAs.

Although TFAs clearly elevate LDL cholesterol and lower HDL cholesterol, there appear to be other mechanisms for their association with heart disease because the adipose tissue level of trans 18:1(n-11) is still a predictor for heart disease after adjustment for total cholesterol. This result is similar to that of the Boston study in which adjustment for LDL and HDL cholesterol concentrations had little effect on the risk ratios; thus, it would appear that only a minor part of the negative effects of TFAs is via plasma lipoproteins.

The current study also provided unique information on the disappearance rate of trans 18:1(n-9) and (n-10) from adipose tissue with a loss of 15% of total TFA/y with declining dietary intake from margarines. All TFAs began to disappear from adipose tissue after mid-1996 when margarine became TFA free, but the fall in intake of dairy TFAs explains the fall in trans 18:1(n-11).

Although both beef and dairy consumption have been strongly linked with coronary artery disease (32), it has been difficult to link TFAs in adipose tissue from these sources to coronary disease. No prospective adipose tissue fatty acid data are available, and the usual case control design is prone to bias. Some of the cases may have had high cholesterol and a family history of coronary artery disease and decreased (consciously or unconsciously) their intake of beef and dairy fat in the recent past; this would then be reflected in a lower total 18:1 TFA level. Biochemical measures, even those of adipose tissue, reflect only recent intake and not the 40–60 y of atherosclerosis development. Nevertheless, in this study in which we reduced bias considerably by careful selection of cases, we showed a relation between both the dietary intake of TFAs from margarines, beef, and dairy fat and their levels in adipose tissue and presentation with a first heart attack.

In conclusion, we showed that TFAs in adipose tissue are associated with an increased risk of MI and that when a major vegetable source of TFAs is removed from the food supply, TFAs rapidly disappear from adipose tissue.

	FOOTNOTES

 
¹ Presented in part in Abstract form at the Scientific Sessions of the American Heart Association Meeting November 1999 [Clifton, P. M. & Noakes, M. (1999) Adipose tissue trans fatty acid levels and first myocardial infarction. Circulation 100 (suppl.): 601 (abs.)].

² Supported in part by Meadow Lea Foods Australia.

⁴ Abbreviations used: CSIRO, Commonwealth Scientific and Industrial Research Organization; MI, myocardial infarction; OR, odds ratio; TFA, trans fatty acid.

Manuscript received 30 October 2003. Initial review completed 7 December 2003. Revision accepted 15 January 2004.

	LITERATURE CITED

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

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