Abstract
Background
Total intake of trans fat is associated with coronary heart disease (CHD) and recent reports in primarily male populations suggest that blood levels of specific trans isomers may have different effects on risk, particularly risk of sudden cardiac death (SCD).
Methods
We prospectively examined the association between dietary intake of trans fat and SCD among 86,762 women from the Nurses’ Health Study. CHD risk factors, including diet and lifestyle factors were updated via questionnaires every 2–4 years, beginning in 1980.
Results
Over 26 years, we documented 317 SCD events. In the primary analysis, we found no significant association between intake of total trans fat, trans-18:1 or trans-18:2 isomers and risk of SCD. Compared to the lowest quintile of intake, the relative risk (RR) (95% CI) of SCD in the highest quintile was 1.28 (0.82, 2.00) for total trans, 1.08 (0.64, 1.83) for trans-18:1 and 1.19 (0.76, 1.88) for trans-18:2. In a secondary pre-specified analysis, total trans fat was significantly related to SCD among women who reported a diagnosis of CHD prior to SCD (RR: 3.24; 95% CI: 1.42, 7.40 for the highest versus lowest quintile, P trend=0.01); however, the test for interaction was not significant (P=0.11)
Conclusions
In this large prospective cohort of women, neither dietary intake of trans fat, nor the individual trans isomers, trans-18:1 and trans-18:2, were significantly associated with risk of SCD. However, trans fat intake may be associated with SCD risk among women with CHD, suggesting that trans fat intake may play a greater role in SCD risk among those with clinically manifest atherosclerosis.
Introduction
Sudden cardiac death (SCD) accounts for approximately half of all CHD deaths, with over 50% of the cases occurring without any previously diagnosed CHD1. The majority of SCD are due to lethal ventricular arrhythmias2,3, thus factors that influence myocardial electrical stability may influence SCD risk4. Fatty acids have varying effects on the propensity for arrhythmias, influenced by their structural properties, like chain length and saturation5. Omega-3 fatty acids, which have anti-arrhythmic properties6, are associated with lower risk of SCD7.
Intake of trans fat, mainly from hydrogenated vegetable oils, is associated with higher risk of CHD8–10. Trans fatty acids have pro-arrhythmic properties11, which may increase risk of SCD, although this relationship is not well-established. In two recent studies, composed primarily of men, blood levels of trans-18:2 isomers, but not trans-18:1, were positively associated with risk of SCD12,13. Because trans fat may have different effects on SCD risk in women, we prospectively investigated the relationship between intake of total trans fat and the individual trans-18:1 and trans-18:2 isomers and risk of SCD in women.
Methods
The Nurses’ Health Study Cohort
The Nurses’ Health study is a prospective cohort of 121,700 registered female nurses, aged 30 to 55 y at baseline in 197614. We assess information on medical history, CHD risk factors, lifestyle factors and newly diagnosed disease through self-administered questionnaires biennially. Beginning in 1980, and approximately every 4 years, participants completed a food frequency questionnaire (FFQ). For this analysis, we excluded women who did not complete the 1980 FFQ, left ≥10 food items blank or had implausible energy intake (<600 or >3500 kcal/day). We also excluded women who reported a history of stroke or cancer prior to 1980. The Institutional Review Board of Brigham and Women’s Hospital approved the study protocol.
Dietary assessment
We collected information on usual diet using a FFQ administered approximately every 4 years. For each food item, a portion size was specified and participants were asked how often, on average, she had consumed that quantity over the past year. Average intake of trans fat and other nutrients was calculated by multiplying the frequency of consumption of each food by its nutrient content and then summing across all foods. Nutrient values were obtained from the Harvard University Food Composition Database15, which accounts for types of margarine and fats used in cooking and baking. Intake of trans fat estimated from the FFQ is significantly correlated with trans fat concentrations in adipose tissue (r=0.51; p<0.001)16 and RBC (r=0.43; p<0.01)17.
Assessment of Medical History, Anthropometric Data, and Lifestyle Factors
On the baseline questionnaire, we collected information on weight, height, smoking status, parental history of MI, menopausal status, use of medications (aspirin and hormone therapy), dietary supplements, physical activity and personal history of CHD and other diseases. This information, with the exception of height and parental history, has been updated on biennial follow-up questionnaires. Details on the validity of the questionnaire has been reported elsewhere18–20.
Ascertainment of sudden death
Details for the classification of SCD have been described elsewhere3. Briefly, cardiac deaths were considered sudden if the death or cardiac arrest occurred within 1 hour of symptom onset as documented by medical records or through reports from next of kin. We included unwitnessed deaths that could have occurred within 1 hour of symptom onset and that had autopsy findings consistent with SCD in our analysis (n=36). To increase the specificity for an “arrhythmic death”, we excluded women with evidence of circulatory collapse (hypotension, exacerbation of congestive heart failure or neurologic dysfunction) before disappearance of the pulse, based on the definition of Hinkle and Thaler2. This rigorous definition of SCD is highly specific for arrhythmic death and systematically excludes most unwitnessed deaths and deaths during sleep. In a secondary analysis, we included unwitnessed deaths and deaths that occurred during sleep where the participant was documented to be symptom free when last observed within the preceding 24 hours and where circumstances suggested that the death could have been sudden (n=104).
Statistical analysis
For each woman, person-months of follow-up were calculated from the date of return of the 1980 questionnaire until date of death or June 1, 2006, whichever came first. We postulated that if dietary trans fat influenced the risk of SCD, the mechanism of action would most likely be through pro-arrhythmic effects, thus most recent diet most likely influences risk. In primary analysis, we used the most recent diet prior to event21, where 1980 diet was used for the 1980–1984 follow-up period, and 1984 diet was used for the 1984–1986 follow-up period, and so on. Because dietary trans fat may influence SCD risk through more long-term mechanisms related to atherogenesis, in secondary analysis we used the cumulative average of the diet to represent long-term effects and reduce random measurement error21. Because participants may change their diet after diagnosis of intermediate conditions, we stopped updating dietary information in the cumulative average estimate after new diagnoses of nonfatal MI, nonfatal stroke, coronary revascularization, angina, diabetes, hypertension, hypercholesterolemia or transient ischemic attack.
We used Cox proportional hazards models to estimate the relative risk across quintiles of trans fat intake. Models were adjusted for age (in months) and calendar year and adjusted for calories (continuous), smoking (5 categories), BMI (<25, 25–29.9, 30+ kg/m2), family history of CHD (no, prior to 60 years, 60 years or older), menopausal status, use of postmenopausal hormones (current, past, never), aspirin use (<1, 1–6, 7+/week), multivitamin and vitamin E supplements, moderate to vigorous activity (hours/week), alcohol intake (0, 0.1–4.9, 5–14.9 and 15+ g/day), intake of fatty acids (long-chain omega-3, alpha-linolenic and ratio of polyunsaturated to saturated) (in quintiles) and diagnosis of CHD, stroke, diabetes, hypertension and hypercholesterolemia. All variables were included as time-varying covariates. We conducted tests for linear trend by assigning the median value to each quintile and modeling this variable as a continuous variable.
To estimate the impact of substituting a specific percentage of energy from trans fat for the same percentage of energy from carbohydrates, we modeled intake of trans fat, protein and all major types of fat (saturated, monounsaturated, and omega-6 and omega-3 polyunsaturated fats) as continuous variables simultaneously in the model. To estimate the relative risk of substituting energy from trans fat for another fatty acid, we used the difference between the regression coefficients from the same model and calculated the 95% CIs by using the covariance of the regression coefficients22.
In pre-specified secondary analysis, we explored whether the relation between trans fat and SCD differed according to presence or absence of CHD (angina, MI, or coronary revascularization), age (<60, ≥60 y) and intake of alpha-linolenic acid. To test formally for interaction, we modeled the cross-product term between trans fat and the variable of interest (CHD, age or alpha-linolenic acid) and used a likelihood ratio test, comparing models with and without the interaction term. For all stratified analyses, we used the most recent dietary intake. All statistical analysis was performed using SAS software, version 9.1.3 (SAS Institute Inc, Cary NC). This work was funded by grants from the NIH and American Heart Association. The authors are solely responsible for the design, conduct and analyses of the study and the drafting and editing of the manuscript, and its final contents.
Results
The median intake of trans-18:1 isomers was 1.1% of energy [interquartile range (IQR): 0.8%, 1.7%] while the median intake of trans-18:2 isomers was 0.20% of energy (IQR: 0.15%, 0.26%). The median intake (IQR) of trans fat during the first half of follow-up (1980–1994) was 1.7% (1.3%, 2.3%) of total energy, but only 1.2% (0.9%, 1.5%) during the second half of follow-up (1994–2006).
Women who consumed higher amounts of trans fat tended to consume greater amounts of all other types of fat, with the exception of the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) (table 1). Women with higher trans fat intake were less likely to report a diagnosis of hypercholesterolemia, take vitamin supplements and exercise and more likely to smoke.
Table I.
Selected characteristics* across quintiles of trans fatty acid intake among women in the Nurses’ Health Study in 1994
| Quintiles of total trans fat (% energy) | |||||
|---|---|---|---|---|---|
| Q1 | Q2 | Q3 | Q4 | Q5 | |
| Range, (%energy) | <0.97 | 0.97–1.27 | 1.28–1.61 | 1.62–2.12 | >2.12 |
| Median, (% energy) | 0.77 | 1.12 | 1.43 | 1.83 | 2.55 |
| Age, mean (SD), y | 61 (7) | 61 (7) | 60 (7) | 60 (7) | 60 (7) |
| Current smokers (%) | 10 | 13 | 14 | 15 | 15 |
| Reported diagnosis of | |||||
| Hypertension (%) | 36 | 37 | 37 | 38 | 37 |
| Diabetes (%) | 6.0 | 6.5 | 6.7 | 6.4 | 7.2 |
| High cholesterol (%) | 51 | 49 | 47 | 46 | 45 |
| Prior CHD (%) | 9 | 8 | 8 | 8 | 8 |
| BMI (kg/m2) | 25.6 | 26.4 | 26.8 | 26.9 | 27.0 |
| Family history of MI before age 60 (%) | 14 | 14 | 13 | 13 | 11 |
| Post-menopausal (%) | 83 | 83 | 82 | 82 | 80 |
| Aspirin use, ≥ 7 times/week (%) | 12 | 11 | 11 | 10 | 9 |
| Vitamin supplement use | |||||
| Vitamin E (%) | 36 | 28 | 23 | 19 | 14 |
| Multivitamin (%) | 49 | 43 | 39 | 33 | 26 |
| Moderate to vigorous physical activity (hours/week) | 4.5 | 3.6 | 3.2 | 2.9 | 2.6 |
| Nutrient intake | |||||
| Alcohol (g/day) | 6.0 | 5.6 | 4.9 | 4.3 | 3.7 |
| Total fat (% energy) | 23.9 | 28.7 | 31.3 | 33.6 | 36.9 |
| Saturated fat (% energy) | 7.6 | 9.7 | 10.8 | 11.7 | 12.9 |
| Monounsaturated fat (% energy) | 9.4 | 11.2 | 12.2 | 13.1 | 14.8 |
| Polyunsaturated fat (% energy) | 4.5 | 5.1 | 5.4 | 5.7 | 6.2 |
| Omega-3 fat (% energy) | 0.16 | 0.12 | 0.11 | 0.09 | 0.07 |
| Alpha-linolenic acid (% energy) | 0.44 | 0.48 | 0.50 | 0.51 | 0.53 |
| Trans fat (% energy) | |||||
| trans-18:1 isomer | 0.55 | 0.87 | 1.13 | 1.49 | 2.25 |
| trans-18:2 isomer | 0.12 | 0.18 | 0.22 | 0.26 | 0.31 |
All characteristics are age-standardized with the exception of age
Over 26 years of follow up, we documented 317 cases of sudden cardiac death. Using the simple update method, trans fat intake was positively associated with risk of SCD after adjusting for age and total energy (P-trend=0.01) but this association was attenuated and no longer significant after adjustment for CHD risk factors (table 2). Findings were similar when we used the cumulative average of trans fat intake (multivariate RR: 1.23; 95%CI: 0.81, 1.87). These results were not materially altered when deaths that occurred during sleep or otherwise were unwitnessed and symptom free within 24 hours of death were included (multivariate RR: 1.00; 95%CI: 0.67, 1.48).
Table II.
Relative risks (95% confidence intervals) of sudden cardiac death according to total trans fatty acid intake
| Quintiles of total trans fat (% energy) | P - trend | |||||
|---|---|---|---|---|---|---|
| Total trans (median intake, % energy) | 0.77 | 1.12 | 1.43 | 1.83 | 2.55 | |
| Cases | 69 | 77 | 59 | 61 | 51 | |
| Person-years | 443,754 | 443,149 | 444,421 | 446,960 | 450,507 | |
| Age and calorie adjusted | 1.0 (ref) | 1.33 (0.96–1.85) | 1.15 (0.81–1.63) | 1.48 (1.03–2.12) | 1.65 (1.11–2.45) | 0.01 |
| Multivariate adjusted 1 | 1.0 (ref) | 1.15 (0.83–1.60) | 0.90 (0.63–1.28) | 1.02 (0.71–1.48) | 0.95 (0.63–1.43) | 0.95 |
| Multivariate adjusted 2 | 1.0 (ref) | 1.27 (0.91–1.79) | 1.02 (0.70–1.48) | 1.18 (0.80–1.74) | 1.18 (0.76–1.83) | 0.64 |
| Multivariate adjusted 3 | 1.0 (ref) | 1.27 (0.90–1.79) | 1.04 (0.72–1.52) | 1.26 (0.85–1.87) | 1.28 (0.82–2.00) | 0.36 |
Multivariate adjusted 1: Adjusted for age, calories, smoking, BMI, parental history of MI, menopausal status, use of postmenopausal hormones, aspirin use, multivitamin and vitamin E supplements, physical activity and alcohol intake.
Multivariate adjusted 2: Adjusted for multivariate 1 plus intake of omega-3 fatty acid, alpha-linolenic fatty acids and ratio of polyunsaturated to saturated fatty acids
Multivariate adjusted 3: Adjusted for multivariate 2 plus diagnosis of CHD, stroke, diabetes, high blood pressure or high cholesterol
When modeled as a continuous variable, the replacement of 2% of energy of carbohydrates with trans fat was not significantly associated with risk of SCD after adjustment for CHD risk factors (Table 3). Results were similar for the isocaloric substitution of most major fat subtypes for trans fat. A nonsignificant trend toward higher risk of SCD was seen with the substitution of omega-3 fatty acids (ALA, EPA and DHA) with trans fat; for each 1% energy, the relative risk of SCD with trans fat was 1.74 (95%CI: 0.83, 3.67). The results were similar in the first and last halves of the study follow-up period. The relative risk of SCD for the substitution of 2% of energy of carbohydrates with trans fat was 1.35 (95%CI: 0.65, 2.79) from 1980–1994 and 0.97 (95%CI: 0.50–1.90) from 1994–2006.
Table III.
Relative risks (95% CI) of sudden cardiac death associated with the isocaloric substitution of energy of major types of fat with trans fat intake
| RR (95% CI)* | |
|---|---|
| Intake of trans fat for: | |
| Carbohydrates (2%)† | 1.20 (0.75–1.91) |
| Saturated fat (2%)† | 1.22 (0.74–2.00) |
| Monounsaturated fat (2%)† | 1.20 (0.72–2.01) |
| Total polyunsaturated fat (2%)† | 1.37 (0.83–2.28) |
| omega-3 fat (1%)‡ | 1.74 (0.83–3.67) |
| omega-6 fat (1%)‡ | 1.11 (0.84–1.46) |
Model adjusted for age, calories, smoking, BMI, parental history of MI, menopausal status, use of postmenopausal hormones, aspirin use, multivitamin and vitamin E supplements, physical activity, alcohol intake and diagnosis of stroke, diabetes, high blood pressure or high cholesterol
From a single model including linear terms for all types of fat (saturated, monounsaturated, polyunsaturated, and trans), protein, and total energy intake. The relative risk is for a substitution of 2% of total energy.
From a single model including linear terms for all types of fat (saturated, monounsaturated, omega-3 polyunsaturated, omega-6 polyunsaturated, and trans), protein, and total energy intake. The relative risk is for a substitution of 1% of total energy.
One potential explanation for the lack of a significant association may be the reduction in trans fat in the food supply throughout follow-up. Therefore we estimated the relative risk comparing more extreme intakes of trans fat. Compared to women with <1% of energy from trans fat, the risk of SCD among women with ≥3% of energy from trans fat (4% of the population) was higher, although not statistically significant (multivariate RR: 1.55; 95%CI: 0.80, 3.01).
We found a significant positive association between dietary intake of the trans-18:1 isomer and risk of SCD after adjustment for age and total energy (P-trend=0.01), which was attenuated after adjustment for CHD risk factors (table 4). Dietary intake of the trans-18:2 isomer was not associated with risk of SCD. For each 0.25% of total energy increment, intake of trans-18:1 fat was associated with an adjusted relative risk of 1.00 (95%CI: 0.94, 1.07) while intake of trans-18:2 fat was associated with an adjusted relative risk of 1.28 (95%CI: 0.89, 1.83).
Table IV.
Relative risks (95% confidence intervals) of sudden cardiac death according to intake of 18:1 and 18:2-trans fat isomers
| Quintiles of intake of trans fat isomers (% energy) | ||||||
|---|---|---|---|---|---|---|
| Q1 | Q2 | Q3 | Q4 | Q5 | P - trend | |
| 18:1 trans (median intake, % energy) | 0.58 | 0.87 | 1.13 | 1.52 | 2.24 | |
| Cases | 72 | 68 | 68 | 57 | 52 | |
| Person-years | 443,498 | 443,143 | 444,225 | 446,820 | 451,108 | |
| Age and calorie adjusted | 1.0 (ref) | 1.12 (0.80–1.56) | 1.24 (0.88–1.74) | 1.34 (0.93–1.93) | 1.70 (1.14–2.53) | 0.01 |
| Multivariate adjusted* | 1.0 (ref) | 1.05 (0.74–1.48) | 1.13 (0.79–1.61) | 1.11 (0.75–1.65) | 1.22 (0.78–1.90) | 0.38 |
| Multivariate adjusted* + 18:2 trans | 1.0 (ref) | 0.97 (0.66–1.41) | 1.03 (0.68–1.55) | 1.00 (0.63–1.58) | 1.08 (0.64–1.83) | 0.71 |
| 18:2 trans (median intake, % energy) | 0.11 | 0.16 | 0.20 | 0.24 | 0.33 | |
| Cases | 65 | 60 | 68 | 59 | 65 | |
| Person-years | 446,631 | 445,697 | 445,314 | 444,973 | 446,179 | |
| Age and calorie adjusted | 1.0 (ref) | 0.95 (0.67–1.35) | 1.10 (0.78–1.55) | 1.00 (0.70–1.42) | 1.10 (0.78–1.56) | 0.53 |
| Multivariate adjusted* | 1.0 (ref) | 1.03 (0.72–1.48) | 1.23 (0.86–1.76) | 1.16 (0.79–1.70) | 1.22 (0.84–1.79) | 0.27 |
| Multivariate adjusted* + 18:1 trans | 1.0 (ref) | 1.03 (0.72–1.49) | 1.23 (0.83–1.82) | 1.15 (0.75–1.76) | 1.19 (0.76–1.88) | 0.45 |
Model adjusted for age, calories, smoking, BMI, parental history of MI, menopausal status, use of postmenopausal hormones, aspirin use, multivitamin and vitamin E supplements, physical activity, alcohol intake, intake of omega-3 fatty acid, alpha-linolenic fatty acids and ratio of polyunsaturated to saturated fatty acids and diagnosis of stroke, diabetes, high blood pressure or high cholesterol
In secondary analyses, total trans fat intake was significantly associated with risk of SCD even after adjustment for CHD risk factors among the sub-group of women with clinically diagnosed CHD (Table 5). In this subgroup, women in the highest quintile of trans fat intake had a relative risk of SCD of 3.24 (95% CI, 1.42, 7.40) compared to women in the lowest quintile of intake. The relative risk for the substitution of 1% of energy from omega-3 fat for trans fat was 5.70 (95%CI: 1.30, 25.0). In contrast, trans fat intake was not associated with risk of SCD among women without a history CHD (Table 5). The statistical power to detect an interaction by history of CHD was limited, with only 100 cases among women with prior CHD (P-interaction=0.11). We found no evidence for interactions between trans fat intake and age (P-interaction=0.31) or intake of alpha-linolenic acid (P-interaction=0.45).
Table V.
Relative risks (95% confidence intervals) of sudden cardiac death according to trans fat intake stratified by history of nonfatal CHD before event
| Quintiles of total trans fat (% energy) | P - trend | |||||
|---|---|---|---|---|---|---|
| Total trans (median intake, % energy) | 0.77 | 1.12 | 1.43 | 1.83 | 2.55 | |
| Prior history of CHD | ||||||
| Cases | 23 | 27 | 18 | 15 | 17 | |
| Person-years | 46,732 | 38,520 | 32,875 | 26,127 | 19,251 | |
| Age and calorie adjusted | 1.0 (ref) | 1.38 (0.78–2.45) | 1.31 (0.70–2.47) | 1.59 (0.80–3.15) | 3.07 (1.52–6.23) | 0.004 |
| Multivariate adjusted* | 1.0 (ref) | 1.78 (0.96–3.31) | 1.53 (0.76–3.08) | 1.90 (0.87–4.15) | 3.24 (1.42–7.40) | 0.01 |
| No prior history of CHD | ||||||
| Cases | 46 | 50 | 41 | 46 | 34 | |
| Person-years | 397,022 | 404,630 | 411,546 | 420,833 | 431,256 | |
| Age and calorie adjusted | 1.0 (ref) | 1.25 (0.83–1.87) | 1.12 (0.73–1.71) | 1.51 (0.98–2.31) | 1.41 (0.87–2.30) | 0.12 |
| Multivariate adjusted* | 1.0 (ref) | 1.04 (0.69–1.58) | 0.84 (0.53–1.32) | 1.01 (0.64–1.61) | 0.86 (0.50–1.47) | 0.60 |
Multivariate adjusted: Model adjusted for age, calories, smoking, BMI, parental history of MI, menopausal status, use of postmenopausal hormones, aspirin use, multivitamin and vitamin E supplements, moderate to vigorous activity, alcohol intake, intake of omega-3 fatty acid, alpha-linolenic fatty acids and ratio of polyunsaturated to saturated fatty acids and diagnosis of stroke, diabetes, high blood pressure or high cholesterol
Discussion
In this large prospective cohort of women, neither intake of trans fat, nor the individual trans isomers, trans-18:1 and trans-18:2, were significantly associated with risk of SCD. Total trans fat intake was associated with a three-fold elevated SCD risk among women with a prior history of CHD, after adjustment for classic CHD risk factors and other important dietary variables; however, the interaction was not significant and this analysis is limited by the small numbers of women with a prior history of CHD in this generally healthy cohort.
Our nonsignificant results for dietary intake appear at odds with the previously published literature on biomarkers of trans fat and SCD risk. In a population-based case-control study, RBC concentration of trans-18:2 isomers, but not trans-18:1, was positively associated with risk of SCD (odds ratio for IQR = 3.1; 95%CI: 1.7, 5.4)13. In the Cardiovascular Health Study, higher plasma levels of trans-18:2 isomers were associated with a doubling in risk (odds ratio for IQR = 2.3; 95%CI: 1.3, 4.3) while plasma trans-18:1 was inversely associated with risk of SCD12. Finally, in an autopsy study, adipose levels of trans-18:1 isomers were inversely associated with SCD while adipose levels of trans-18:2 isomer were not associated with SCD risk; however, the number of cases was small (n=66)23.
There are several potential explanations for our apparent disparate results regarding dietary intake compared to previous studies using biomarkers. First, the trans-18:2 isomer, which was associated with SCD in previous studies, comprises a minority of trans fat in diet, and many of the same food sources contain both trans isomers. Our ability to discriminate fully between intake of trans-18:1 and 18:2 isomers from our dietary questionnaire may be limited. Additionally, the level of trans fats in the cell membranes, such as RBC, is determined by many factors including dietary intake, absorption and metabolism. Biomarkers may approximate better the true biologic effect of trans fat, thus dietary assessment of intake may underestimate the true association.
Secondly, prior studies of trans fat and risk of SCD were conducted in primarily male populations13 or in older populations where the majority of participants had a history of CHD12. Therefore, the underlying disease process in the majority of these cases is most likely CHD, which may not be the case in this younger population of women, where the prevalence of underlying CHD is typically lower3, 24–26. The association between trans fat and SCD was statistically significant in secondary analyses among women with prior CHD, which supports the possibility that trans fat intake plays a greater role in SCD risk in the setting of CHD.
A third potential explanation for the null association may be the lower level of trans fat intake in this population. When we looked at a more extreme comparison of trans fat intake (≥3% v. <1% of energy), the risk of SCD was higher than in the quintile analysis. After a reduction of trans fat in the food supply of Costa Rica, the relationship between trans fat and nonfatal MI was no longer significant27. The effect of trans fat may be even greater in countries like Iran, where average trans fat intake was estimated at 4.2% of energy28. Future research is needed on the association between trans fat and SCD in countries where intake remains high.
Additional limitations of this study warrant discussion. Although we attempted to control for potential confounding variables, the possibility of residual confounding remains. We had more cases of SCD than prior studies, however, the numbers of SCD in this study were lower than the number of CHD events in studies reporting positive associations between trans fat and total CHD8–10, and therefore our power to detect modest associations and examine interactions was limited. However, the association between trans fat and SCD for a substitution of 2% of energy from trans fat (RR=1.20; 95%CI: 0.52, 1.91) was similar to the association with risk of CHD (RR=1.23, 95%CI: 1.11 to 1.37)29. The selective nature of this cohort, US female registered nurses, may limit the generalizability of these findings, although the high level of education and health interest of these participants, and the accuracy of reported dietary information has been well documented30. Another strength is the repeated assessment of diet, which captured the changes in trans fat in the food supply over time.
Conclusion
In conclusion, we found no significant association between trans fatty acid intake and risk of SCD among a large-prospective cohort of women. However, higher dietary intake of trans fat may be associated with an increased risk of SCD among women with established coronary heart disease. Future research is needed to determine whether differences in study results are due to gender differences, other clinical characteristics of participants, or differences in exposure level or endogenous trans-fat metabolism.
Acknowledgments
This study was supported by NIH grants CA-87969 and HL-34594, a Lerner Research Young Investigator Award and an Established Investigator Award from the American Heart Association (Dr. Albert).
Footnotes
Disclosures: The authors report no conflict of interest
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References
- 1.Kannel WB, McGee DL. Epidemiology of sudden death: insights from the Framingham Study. Cardiovasc Clin. 1985;15(3):93–105. [PubMed] [Google Scholar]
- 2.Hinkle LE, Thaler HT. Clinical classification of cardiac deaths. Circulation. 1982;65:457–464. doi: 10.1161/01.cir.65.3.457. [DOI] [PubMed] [Google Scholar]
- 3.Albert CM, Chae CU, Grodstein F, Rose LM, Rexrode KM, Ruskin JN, et al. Prospective study of sudden cardiac death among women in the United States. Circulation. 2003;107(16):2096–101. doi: 10.1161/01.CIR.0000065223.21530.11. [DOI] [PubMed] [Google Scholar]
- 4.Siscovick DS, Lemaitre RN, Mozaffarian D. The fish story: a diet-heart hypothesis with clinical implications: n-3 polyunsaturated fatty acids, myocardial vulnerability, and sudden death. Circulation. 2003;107(21):2632–4. doi: 10.1161/01.CIR.0000074779.11379.62. [DOI] [PubMed] [Google Scholar]
- 5.Katz AM. Trans-fatty acids and sudden cardiac death. Circulation. 2002;105(6):669–71. [PubMed] [Google Scholar]
- 6.Billman GE, Kang JX, Leaf A. Prevention of sudden cardiac death by dietary pure ω-3 polyunsaturated fatty acids in dogs. Circulation. 1999;99:2452–2457. doi: 10.1161/01.cir.99.18.2452. [DOI] [PubMed] [Google Scholar]
- 7.Siscovick DS, Raghunathan TE, King I, Weinman S, Wicklund KG, Albright J, et al. Dietary intake and cell membrane levels of long-chain N-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. JAMA. 1995;274:1363–1367. doi: 10.1001/jama.1995.03530170043030. [DOI] [PubMed] [Google Scholar]
- 8.Oh K, Hu FB, Manson JE, Stampfer MJ, Willett WC. Dietary fat intake and risk of coronary heart disease in women: 20 years of follow-up of the nurses' health study. Am J Epidemiol. 2005;161(7):672–9. doi: 10.1093/aje/kwi085. [DOI] [PubMed] [Google Scholar]
- 9.Pietinen P, Ascherio A, Korhonen P, Hartman AM, Willett WC, Albanes D, et al. Intake of fatty acids and risk of coronary heart disease in a cohort of Finnish men. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Am J Epidemiol. 1997;145(10):876–87. doi: 10.1093/oxfordjournals.aje.a009047. [DOI] [PubMed] [Google Scholar]
- 10.Oomen CM, Ocke MC, Feskens EJ, van Erp-Baart MA, Kok FJ, Kromhout D. Association between trans fatty acid intake and 10-year risk of coronary heart disease in the Zutphen Elderly Study: a prospective population-based study. Lancet. 2001;357(9258):746–51. doi: 10.1016/s0140-6736(00)04166-0. [DOI] [PubMed] [Google Scholar]
- 11.Wenzel DG, Kleoppel JW. Incorporation of saturated and cis- and trans-unsaturated long chain fatty acids in rat myocytes and increased susceptibility to arrhythmias. Toxicology. 1980;18(1):27–36. doi: 10.1016/0300-483x(80)90035-9. [DOI] [PubMed] [Google Scholar]
- 12.Lemaitre RN, King IB, Mozaffarian D, Sotoodehnia N, Rea TD, Kuller LH, et al. Plasma phospholipid trans fatty acids, fatal ischemic heart disease, and sudden cardiac death in older adults: the Cardiovascular Health Study. Circulation. 2006;114(3):209–15. doi: 10.1161/CIRCULATIONAHA.106.620336. [DOI] [PubMed] [Google Scholar]
- 13.Lemaitre RN, King IB, Raghunathan TE, Pearce RM, Weinmann S, Knopp RH, et al. Cell membrane trans-fatty acids and the risk of primary cardiac arrest. Circulation. 2002;105(6):697–701. doi: 10.1161/hc0602.103583. [DOI] [PubMed] [Google Scholar]
- 14.Willett WC, Green A, Stampfer MJ, Speizer FE, Colditz GA, Rosner B, et al. Relative and absolute excess risks of coronary heart disease among women who smoke cigarettes. N Engl J Med. 1987;317:1303–1309. doi: 10.1056/NEJM198711193172102. [DOI] [PubMed] [Google Scholar]
- 15.U. S. Department of Agriculture. Agricultural Handbook No. 8. Washington, DC: U.S. Gov't Printing Offices; 1963. Composition of foods--raw, processed, and prepared. [Google Scholar]
- 16.London SJ, Sacks FM, Caesar J, Stampfer MJ, Siguel E, Willett WC. Fatty acid composition of subcutaneous adipose tissue and diet in post-menopausal US women. Am J Clin Nutr. 1991;54:340–345. doi: 10.1093/ajcn/54.2.340. [DOI] [PubMed] [Google Scholar]
- 17.Sun Q, Ma J, Campos H, Hankinson SE, Manson JE, Stampfer MJ, et al. A prospective study of trans fatty acids in erythrocytes and risk of coronary heart disease. Circulation. 2007;115(14):1858–65. doi: 10.1161/CIRCULATIONAHA.106.679985. [DOI] [PubMed] [Google Scholar]
- 18.Willett WC, Sampson L, Stampfer MJ, Rosner B, Bain C, Witschi J, et al. Reproducibility and validity of a semiquantitative food frequency questionnaire. Am J Epidemiol. 1985;122:51–65. doi: 10.1093/oxfordjournals.aje.a114086. [DOI] [PubMed] [Google Scholar]
- 19.Rimm EB, Stampfer MJ, Colditz GA, Chute CG, Litin LB, Willett WC. Validity of self-reported waist and hip circumferences in men and women. Epidemiology. 1990;1:466–473. doi: 10.1097/00001648-199011000-00009. [DOI] [PubMed] [Google Scholar]
- 20.Chasan-Taber S, Rimm EB, Stampfer MJ, Spiegelman D, Colditz GA, Giovannucci E, et al. Reproducibility and validity of a self-administered physical activity questionnaire for male health professionals. Epidemiology. 1996;7:81–86. doi: 10.1097/00001648-199601000-00014. [DOI] [PubMed] [Google Scholar]
- 21.Hu FB, Stampfer MJ, Rimm E, Ascherio A, Rosner BA, Spiegelman D, et al. Dietary fat and coronary heart disease: a comparison of approaches for adjusting total energy intake and modeling repeated dietary measurements. Am J Epidemiol. 1999;149:531–540. doi: 10.1093/oxfordjournals.aje.a009849. [DOI] [PubMed] [Google Scholar]
- 22.Willett WC. Implications of total energy intake for epidemiologic analyses. In: Willett WC, editor. Nutritional Epidemiology. Chapter 10. New York: Oxford University Press; 1990. [Google Scholar]
- 23.Roberts TL, Wood DA, Riemersma RA, Gallagher PJ, Lampe FC. trans isomers of oleic and linoleic acids in adipose tissue and sudden cardiac death. Lancet. 1995;345(8945):278–82. doi: 10.1016/s0140-6736(95)90274-0. [DOI] [PubMed] [Google Scholar]
- 24.Spain DM, Bradess VA, Mohr C. Coronary atherosclerosis as a cause of unexpected and unexplained death. An autopsy study from 1949–1959. JAMA. 1960;174:384–8. doi: 10.1001/jama.1960.03030040038010. [DOI] [PubMed] [Google Scholar]
- 25.Chugh SS, Chung K, Zheng ZJ, John B, Titus JL. Cardiac pathologic findings reveal a high rate of sudden cardiac death of undetermined etiology in younger women. Am Heart J. 2003;146(4):635–9. doi: 10.1016/S0002-8703(03)00323-5. [DOI] [PubMed] [Google Scholar]
- 26.Albert CM, McGovern BA, Newell JB, Ruskin JN. Sex differences in cardiac arrest survivors. Circulation. 1996;93:1170–1176. doi: 10.1161/01.cir.93.6.1170. [DOI] [PubMed] [Google Scholar]
- 27.Colon-Ramos U, Baylin A, Campos H. The relation between trans fatty acid levels and increased risk of myocardial infarction does not hold at lower levels of trans fatty acids in the Costa Rican food supply. J Nutr. 2006;136(11):2887–92. doi: 10.1093/jn/136.11.2887. [DOI] [PubMed] [Google Scholar]
- 28.Mozaffarian D, Abdollahi M, Campos H, Houshiarrad A, Willett WC. Consumption of trans fats and estimated effects on coronary heart disease in Iran. Eur J Clin Nutr. 2007;61(8):1004–10. doi: 10.1038/sj.ejcn.1602608. [DOI] [PubMed] [Google Scholar]
- 29.Mozaffarian D, Katan MB, Ascherio A, Stampfer MJ, Willett WC. Trans fatty acids and cardiovascular disease. N Engl J Med. 2006;354(15):1601–13. doi: 10.1056/NEJMra054035. [DOI] [PubMed] [Google Scholar]
- 30.Feskanich D, Rimm EB, Giovannucci EL, Colditz GA, Stampfer MJ, Litin LB, et al. Reproducibility and validity of food intake measurements from a semiquantitative food frequency questionnaire. J Am Diet Assoc. 1993;93:790–796. doi: 10.1016/0002-8223(93)91754-e. [DOI] [PubMed] [Google Scholar]