Plasma Phospholipid Trans Fatty Acids, Fatal Ischemic Heart Disease, and Sudden Cardiac Death in Older Adults
The Cardiovascular Health Study
Background— Intake of trans fatty acids is associated with increased risk of coronary heart disease. Whether different classes of trans fatty acids show similar associations is unclear. We previously reported an association of sudden cardiac death with red cell membrane trans-18:2 but not trans-18:1 fatty acids. To extend these findings, we investigated the associations of plasma phospholipid trans fatty acids with fatal ischemic heart disease (IHD) and sudden cardiac death.
Methods and Results— We conducted a case-control study nested in the Cardiovascular Health Study. We identified 214 cases of fatal IHD (fatal myocardial infarction and coronary heart disease death) between 1992 and 1998. We randomly selected 214 controls, matched to cases on demographics, prevalent cardiovascular disease, and timing of blood draw. Plasma phospholipid fatty acids were assessed in blood samples collected earlier. Higher levels of plasma phospholipid trans-18:2 fatty acids were associated with higher risk of fatal IHD (odds ratio [OR] for interquintile range 1.68, 95% confidence interval [CI] 1.21 to 2.33) after adjustment for risk factors and trans-18:1 levels. Trans-18:1 levels above the 20th percentile were associated with lower risk (OR 0.34, 95% CI 0.18 to 0.63). In analyses limited to cases of sudden cardiac death (n=95), higher levels of trans-18:2 fatty acids were associated with higher risk (OR 2.34, 95% CI 1.27 to 4.31) and higher trans-18:1 with lower risk (OR 0.18, 95% CI 0.06 to 0.54).
Conclusions— Higher levels of trans-18:2 and lower levels of trans-18:1 fatty acids are associated with higher risks of fatal IHD and sudden cardiac death. If confirmed, these findings suggest that current efforts at decreasing trans fatty acid intake in foods should take into consideration the trans-18:2 content.
Received February 10, 2006; revision received April 26, 2006; accepted May 10, 2006.
The use of partially hydrogenated oils by the food industry has made trans fatty acids (TFAs) ubiquitous in the Western diet. Unfortunately, TFA consumption may be detrimental to the health of the heart. In 4 large cohort studies, higher dietary consumption of TFAs was associated with higher risk of coronary heart disease.1–4 In short-term feeding trials, consumption of moderate to high levels of TFAs resulted in higher low-density lipoprotein (LDL) cholesterol when substituted for polyunsaturated fatty acids (PUFAs) or carbohydrate and lower levels of high-density lipoprotein (HDL) cholesterol when substituted for unsaturated or saturated fatty acids.5 On the basis of these studies, the Food and Drug Administration (FDA) required food labels to indicate the TFA content starting January 2006.6
Most studies have assessed consumption of total TFA. However, several types of TFAs are produced during the partial hydrogenation of vegetable and seed oils, including trans-isomers of oleic acid (trans-18:1) and trans-isomers of linoleic acid (trans-18:2). Bacteria in ruminants also produce small amounts of trans-isomers of palmitoleic acid (trans-16:1). In a previous study of primary cardiac arrest (sudden cardiac death) as a first clinical manifestation of heart disease,7 we found that higher levels of trans-18:2 in red blood cell membranes, a biomarker of intake, were associated with higher risk. However, levels of trans-18:1, the most abundant TFA in partially hydrogenated oils, and trans-16:1 were not associated with risk.
Clinical Perspective p 215
We used data from the Cardiovascular Health Study (CHS),8 a prospective study of cardiovascular disease risk factors among older men and women, to investigate the association of plasma phospholipid trans-18:2 and trans-18:1 fatty acids, a biomarker of intake, with fatal ischemic heart disease (IHD) and sudden cardiac death.
Study Design and Participants
We conducted a case-control study nested in the CHS.8 The CHS cohort consists of 5888 noninstitutionalized men and women aged ≥65 years at baseline, recruited from 4 US communities (Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Allegheny County, Pennsylvania). Initially 5201 participants were recruited between June 1989 and June 1990. An additional 687 blacks were recruited between June 1992 and June 1993. The study was approved by each center’s institutional review committee, and the subjects gave informed consent.
We identified participants (cases) who experienced a fatal IHD event between June 1992 and June 1998. IHD deaths were defined as fatal myocardial infarction or fatal events that did not meet the criteria for definite myocardial infarction in which participants had chest pain within 72 hours of death or had a history of chronic IHD. Myocardial infarction was defined on the basis of cardiac enzyme levels, chest pain, and serial ECG changes. All IHD events were classified by a morbidity and mortality committee. One of the authors (N.S., a cardiologist) reviewed all fatal IHD records, including hospital records; interviews with physicians, next-of-kin, and/or witnesses; death certificates; and autopsy reports to identify sudden cardiac deaths. Operationally, sudden cardiac death was defined as a sudden pulseless condition of cardiac origin in a previously stable individual that occurred out of the hospital or in the emergency department. By definition, sudden cardiac death cases could not have a life-threatening noncardiac comorbidity or be under hospice or nursing home care. A blinded second review by another author (T.R) of a random sample of 70 of these death records showed an 88% interreviewer agreement and κ=0.74 for sudden cardiac death.
We excluded participants who died in nursing homes and those who used fish oil supplements at the time of the blood draw (fish oil use would change fatty acid membrane composition). These analyses included 214 fatal IHD cases. Of those, 95 were identified as sudden cardiac deaths.
For each case, 1 control subject was randomly selected from the CHS participants who did not experience a fatal IHD event and did not use fish oil supplements, individually matched to the case subject on the basis of gender, clinic site, entry cohort, age (±5 years), time of blood draw (±90 days), presence or absence of cardiovascular disease at the time of the blood draw, and a follow-up duration ≥ that of the case subject.
Measurement of Plasma Phospholipid Fatty Acids
Fasting blood samples were obtained during the 1992 to 1993 clinic visit, the baseline for the present analysis. The blood samples were collected on average 3.0±1.6 years before the events.
Plasma samples were stored at −70°C until they were analyzed. Total lipids were extracted by the method of Folch et al.9 Phospholipids were separated from neutral lipids by 1-dimensional thin-layer chromatography with 250-μm Silica Gel G plates (Analtech Inc, Newark, Del) and a 67.5:15:0.75 hexane/diethyl ether/acetic acid development solvent with 0.005% butylated hydroxytoluene. The phospholipid fractions were then directly transesterified to prepare fatty acid methyl esters (FAMEs) by the method of Lepage and Roy.10 FAMEs of individual fatty acids were separated by gas chromatography. The FAMEs were injected in a split mode (1:50) into a gas chromatography system (model 6890, Agilent Technologies Inc, Palo Alto, Calif). The gas chromatograph was equipped with a flame ionization detector, electronic pressure control, automatic sampler, and Chemstation software (Agilent Technologies Inc, Palo Alto, Calif). The FAMEs were separated on a 100-m×0.25-mm internal-diameter capillary silica column with a 0.2-μm coating (SP2560, Supelco, Bellefonte, Pa). The carrier gas was helium at 1.3 mL/min; makeup gas was nitrogen at 35.1 mL/min. Column linear velocity was set at 20.0 cm/s at an oven temperature of 200°C. The injector and detector port temperatures were both set at 250°C. The oven temperature (160°C at the start) and electronic pressure (50 psi at the start) were controlled by a set program for a total run of 60 minutes to optimize the separation of TFAs. We measured 10 TFAs in the plasma phospholipids: 5 trans-18:1 fatty acids (12 trans-18:1, 11 trans-18:1, 10 trans-18:1, 9 trans-18:1, and a mixture of 6 to 9 trans-18:1); 3 trans-18:2 fatty acids (9 cis, 12 trans-18:2; 9 trans, 12 cis-18:2; and 9 trans, 12 trans-18:2); and 2 trans-16:1 (7 trans-16:1 and 9 trans-16:1). The method was not optimized for the measurement of conjugated linoleic acid isomers, which were not assessed. Fatty acid concentrations are expressed as percentages of total fatty acids by weight.
Identification, precision, and accuracy were evaluated with model mixtures of known FAMEs and an established in-house quality-control pool. The identification of plasma phospholipid fatty acids has been confirmed by gas chromatography coupled to mass spectroscopy at the US Department of Agriculture Lipid Laboratory in Peoria, Ill. In addition, TFA identification has been verified by silver ion thin-layer chromatography.11 Interassay coefficients of variation in the quality-control pool samples for TFAs were as follows: trans-16:1, 13%; trans-18:1, 8%; and trans-18:2, 11%. Laboratory analyses were conducted by technicians blinded to case and control status.
Assessment of Other Risk Factors
At the time of the blood draw, participants completed standardized questionnaires on medical history, health status, and personal habits and underwent a clinic examination that included blood pressure and anthropometric measurements.8 Dietary intake, assessed from a picture-sort food-frequency questionnaire, was assessed &3 years before the blood draws on a subset of participants included in the present report (150 matched pairs). Prevalent clinical cardiovascular disease was defined as a history of myocardial infarction, angina, congestive heart failure, stroke, coronary artery bypass, and angioplasty.
We compared the distribution of risk factors and means of plasma phospholipid TFA among cases and their matched controls using paired t tests. Categorical variables with >2 levels were compared with χ2 tests. We compared risk factor distributions across quintiles of TFA among controls using χ2 tests (categorical variables) and ANOVA. Correlations between plasma phospholipid fatty acids were determined as Pearson correlations adjusted for age.
We used conditional logistic regression to obtain odds ratios (ORs; estimates of relative risks) of fatal IHD and sudden cardiac death associated with increasing levels of plasma phospholipid TFA. Statistical significance was assessed with the likelihood ratio test. Using the lowest quintile of TFA distribution as the reference, we assessed the risk of fatal IHD associated with each upper quintile of TFA. These categorical analyses were consistent with a linear association with risk of trans-18:2. We used linear models to estimate risk associated with trans-18:2 in the main analyses, and we present ORs for trans-18:2 levels corresponding to the 80th percentile of the distribution of these fatty acids compared with trans-18:2 levels corresponding to the 20th percentile (ie, ORs for the interquin-tile range). Categorical analyses with quintiles of trans-18:1 were most compatible with a threshold higher risk in the lowest quintile. In the main analyses, we estimated risk for trans-18:1 levels above versus below the 20th percentile of the trans-18:1 distribution. Sensitivity analyses with alternate cut points corresponding to the 15th and 25th percentiles gave similar results. Interaction between trans-18:2 and trans-18:1 fatty acids was evaluated by testing whether addition of cross-products between trans-18:1 and trans-18:2 improved the model.
The covariates used in the analyses were from the examination of the blood collection. The analyses were based on the updated CHS databases, which incorporated minor corrections up to March 2002. Statistical analyses were performed with STATA 8.2 (StataCorp LP, College Station, Tex).
The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.
Given the matching, age and sex distribution and prevalence of prior clinical coronary heart disease were similar in cases and controls (Table 1). As expected, other traditional risk factors for IHD, such as current smoking and diabetes mellitus, were more prevalent in cases than in controls. In addition, cases were more likely to report lower education, lower income, and poor health. In univariate analyses, mean levels of TFA did not differ significantly between cases and controls (Table 1).
There were few differences in clinical characteristics between participants with high and low levels of membrane trans-18:2 and trans-18:1 fatty acids; no apparent differences in lifestyle characteristics; and among the participants with dietary data, no differences in nutritional characteristics assessed 3 years earlier (data not shown). Participants with high levels of trans-18:2 were more likely to be female (53% in the highest quintile [Q5] and 28% in the lowest quintile [Q1]) and had lower mean body weight (Q5 73.6 kg; Q1 75.4 kg). Participants with high levels of trans-18:1 had lower mean levels of insulin (Q5 9.9 μ/mL; Q1 17.7 μ/mL). Plasma phospholipids levels of trans-18:2 were positively associated with trans-18:1 levels (r=0.42, P<0.001), and levels of trans-18:2 and trans-18:1 fatty acids were negatively associated with docosahexaenoic acid plus eicosapentaenoic acid levels (r=−0.17, P=0.01 and r=−0.15, P=0.03, respectively).
In multivariate analyses, total TFA and trans-16:1 fatty acids were not associated with risk of fatal IHD (Table 2). However, higher levels of trans-18:2 fatty acids were associated with higher risk. An increase in trans-18:2 from 0.22% to 0.35% of total fatty acids, corresponding to the interquintile range, was associated with 30% higher risk (OR 1.31; 95% confidence interval [CI] 0.99 to 1.72) in analyses that accounted for the matching factors and further adjusted for diabetes, congestive heart failure, stroke, smoking status, education, and levels of docosahexaenoic acid plus eicosapentaenoic acid. With further adjustment for trans-18:1, trans-18:2 fatty acids were associated with a 68% higher risk (OR 1.68; 95% CI 1.21 to 2.33). Risk estimates in increasing quintiles of trans-18:2 were 1.0 (reference), 0.87 (95% CI 0.41 to 1.84), 1.08 (95% CI 0.52 to 2.28), 3.20 (95% 1.42 to 7.20), and 4.52 (95% CI 1.83 to 11.20) with adjustment for risk factors and trans-18:1.
Higher levels of trans-18:1 were associated with lower risk of fatal IHD. After adjustment for risk factors and levels of trans-18:2, risk estimates in increasing quintiles of trans-18:1 fatty acids were 1.0 (reference), 0.29 (95% CI 0.14 to 0.61), 0.32 (95% CI 0.15 to 0.70), 0.45 (95% CI 0.21 to 0.97), and 0.38 (95% CI 0.17 to 0.86), consistent with a threshold in risk at the 20th percentile. Compared with lower levels, trans-18:1 levels above the 20th percentile were associated with a 66% lower risk (OR 0.34; 95% CI 0.18 to 0.63; Table 2).
We found no evidence of interaction between trans-18:2 and trans-18:1 (P=0.42). Further adjustment for the covariates listed in Table 1 did not change the results appreciably. Similar results were obtained in analyses restricted to participants in good-to-excellent health at the time of the blood draw.
In analyses restricted to the 95 cases with sudden cardiac death and their matched controls, higher trans-18:2 fatty acids that corresponded to the interquintile range were associated with >2-fold higher risk of sudden cardiac death (OR 2.34; 95% CI 1.27 to 4.31) after adjustment for trans-18:1 fatty acids and the covariates listed in Table 2. Higher trans-18:1 was associated with lower risk of sudden cardiac death (OR for levels above the 20th percentile, 0.18; 95% CI 0.06 to 0.54). ORs among cases whose events were not believed to be sudden cardiac deaths were 1.54 (95% CI 1.01 to 2.37) for higher trans-18:2 corresponding to the interquintile range and 0.47 (95% CI 0.20 to 1.12) for levels of trans-18:1 above the 20th percentile.
In this study, higher plasma phospholipid levels of trans-isomers of linoleic acid (trans-18:2) in blood samples collected on average 3 years before the event were associated with higher risk of fatal IHD and sudden cardiac death among older adults. In contrast, higher levels of trans-isomers of oleic acid (trans-18:1) were associated with lower risk. These associations were independent of demographics, clinical and lifestyle risk factors, and plasma phospholipid levels of n-3 PUFAs from seafood.
The study results are consistent with our findings from a population-based case-control study of sudden cardiac death conducted in the greater Seattle area.7 In the prior investigation, higher levels of trans-18:2 in red blood cell membranes were associated with increased risk of sudden cardiac death (OR corresponding to the interquintile range 3.1, 95% CI 1.7 to 5.4). Of note, the prior study differed from the present one with regard to the study population age (58 versus 77 years old in the present study) and preexisting conditions (no prior clinically diagnosed heart disease in the prior study versus subjects with and without heart disease in the present study), the exposure assessment (red cell membrane fatty acids in blood samples collected by paramedics at the time of the event versus plasma phospholipid fatty acid in blood collected on average 3 years before the events), and the main outcome (sudden cardiac death versus fatal IHD). Perhaps due to the study differences, the OR of fatal IHD corresponding to the interquintile range of plasma phospholipid trans-18:2 was somewhat lower in the present study, 1.7 (95% CI 1.2 to 2.3). However, the associations appeared similar in analyses that compared upper with lowest quintiles, although the CIs were large: Participants in the upper quintile of trans-18:2 appeared to be at 4-fold higher risk of fatal IHD in the present study (OR 4.5, 95% CI 1.8 to 11.2) and at 4-fold higher risk of sudden cardiac death in the prior study (OR 4.3, 95% CI 1.4 to 13.3, unpublished data).
In the prior study, we reported no association of trans-18:1 levels with risk of sudden death (OR for interquintile range 0.8, 95% CI 0.5 to 1.2). However, when we reanalyzed the data, we found a 60% lower risk of sudden death associated with red cell membrane trans-18:1 levels above the 20th percentile (OR 0.4, 95% CI 0.2 to 0.9), in good agreement with the finding from the present study (OR of fatal IHD associated with plasma phospholipid levels of trans-18:1 above the 20th percentile 0.3, 95% CI 0.2 to 0.9). Taken together, these 2 observational studies suggest that dietary intake of trans-18:2 may increase the risk of fatal IHD and sudden cardiac death and that different types of trans-isomers in the diet may influence risks differently.
The association of trans-18:2 with the risk of fatal IHD might be due to an effect on atherosclerosis. In support of this possibility, higher levels of trans-18:2 in adipose tissue, but not high levels of trans-18:1, were associated with higher risk of nonfatal myocardial infarction in a case-control study among Costa Ricans12; however, the trans-isomer composition of adipose tissue in the Costa Rican population is unusual. Whether the association of trans-18:2 with nonfatal myocardial infarction can be generalized to other populations needs to be investigated. In other epidemiological studies of TFA and coronary heart disease, trans-18:2 was not assessed.1–4,13 Additionally, documented adverse effects of TFAs on blood lipids,5 and possibly on inflammation14–16 and endothelial function,17 do not explain different associations of trans-18:1 and trans-18:2 with IHD death and sudden death.
The association of trans-18:2 with fatal IHD and sudden cardiac death might also be due to proarrhythmic effects. Dietary fatty acids, particularly n-3 PUFAs, can influence myocardial vulnerability to triggers of arrhythmia in experimental settings,18,19 and in vitro studies with cardiac myocytes suggest an effect of n-3 PUFAs on action potential and on sodium and calcium ion channel function.20 Possible effects of trans-18:2 and other trans-isomers on ventricular fibrillation and cardiac ion channels need to be investigated.
The association of higher levels of trans-18:1 with lower risk of fatal IHD and sudden cardiac death is new and needs to be confirmed by further studies. It has been suggested that the metabolic effects of trans-vaccenic acid, one of the trans-18:1 isomers, might have beneficial metabolic effects in part because it can be desaturated to conjugated linoleic acid.21 Of note, trans-vaccenic acid was highly correlated to the other trans-18:1 isomers in the present study (correlation coefficients between 0.8 and 0.9), which precludes an investigation of the associations of the separate trans-18:1 isomers.
We have now observed in 2 different studies that trans-18:1 and trans-18:2 fatty acids differ in their association with risk. Although further studies are needed to investigate differences in effects of these 2 subclasses of TFA, in vitro studies suggest fundamental biological differences. In particular, trans-18:2 fatty acids are preferentially incorporated in the sn-2 (middle) position of phospholipids, where PUFAs are typically found. In contrast, trans-18:1 fatty acids are incorporated equally in the sn-1 position, where saturated fatty acids are usually found. Furthermore, the fatty acid composition of phospholipids can affect membrane properties. For example, changes in membrane phospholipid composition within the range of normal variation have been shown to influence the activity of the sodium ion channel in red blood cells.22
Trans-18:2 fatty acids are found in small amounts in partially hydrogenated oils, nonhydrogenated refined oils, and dairy products. In nonhydrogenated oils, trans-18:2 fatty acids are formed by isomerization of linoleic acid during the process of deodorization due to the heat treatment.23 Consequently, trans-18:2 fatty acids are present in refined soybean, sunflower, corn, peanut, and canola oils, although trans-18:1 levels are very low or undetectable.24 Furthermore, trans-18:2 fatty acids can be produced during the frying of foods, which raises the possibility that food preparation, both by the food industry and by consumers, might affect food levels of trans-18:2 fatty acids.25 The relative contribution of the different sources of dietary trans-18:2 fatty acids is unknown and likely varies with study populations and trends in food manufacturing. Consequently, there are currently no good data on the different food sources of trans-18:2 and trans-18:1 fatty acids. In addition, the relationship of dietary trans-18:2 fatty acids to plasma levels has not been studied. However, estimates of dietary trans-18:2 fatty acids correlate with levels of trans-18:2 fatty acids in adipose tissue, another biomarker of intake.26
In the present study, the correlation of plasma phospholipid trans-18:2 and trans-18:1 fatty acids was only 0.4. Although measurement error might lower the correlation, the modest correlation of trans-18:2 and trans-18:1 fatty acids suggests the presence of both subclasses in some but not all foods with TFA. Because the food content of trans-18:2 fatty acids may be largely unknown to the food industry, the labeling of TFA in foods might not include these potentially harmful isomers.
The present study has several strengths. Selection of controls within a prospectively enrolled cohort provides control subjects representative of the noncases. Blood samples were collected prospectively. The matching design and the wealth of information on risk factors in the CHS minimize the possibility of confounding. The use of a biomarker of dietary TFA allowed us to assess different trans-isomers.
The study also has limitations. Because of the observational nature of the study, we cannot eliminate the possibility of residual confounding by imprecisely measured risk factors or unmeasured risk factors. In particular, we had incomplete dietary information, which was assessed 3 years before the blood draws. The higher risk associated with lower trans-18:1 fatty acids was confined to the lowest quintile, and residual confounding in the lowest quintile cannot be eliminated. However, when we reanalyzed data from our Seattle study using quintiles, we observed a similarly higher risk with lower levels of trans-18:1 fatty acids, as described above. The number of study subjects was modest, and we had limited power to investigate effect modification. The levels of TFAs in plasma phospholipids may be subject to laboratory and biological variation; however, we measured fatty acid levels in cases and their matched controls in the same chromatography runs to minimize differential laboratory variation between cases and controls. Nondifferential error in measurement, as expected from moderately high coefficients of variation, would bias the results toward the null.
Higher levels of plasma phospholipid trans-18:2 fatty acids are associated with higher risk of fatal IHD and sudden cardiac death among older adults. In contrast, low levels of trans-18:1 fatty acids are associated with higher risks. If confirmed, these findings suggest that current efforts at decreasing trans fatty acid intake in foods should take into consideration the trans-18:2 fatty acid content.
Sources of Funding
The research reported in this article was supported by contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, and U01 HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of participating CHS investigators and institutions can be found at http://www.chs-nhlbi.org.
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As mandated by the Food and Drug Administration, nutritional labels on food products now indicate the total content of trans fatty acids. However, the present study suggests that not all trans fatty acids carry the same risk. We studied the association of trans fatty acids in plasma phospholipids, a marker of dietary intake, with fatal ischemic heart disease (fatal myocardial infarction and coronary heart disease death) and sudden cardiac death in a case-control study nested in a cohort study, the Cardiovascular Health Study. In multivariate analyses, elevated levels of a specific type of trans fatty acid (trans-18:2) were associated with increased risk of fatal ischemic heart disease and sudden cardiac death. Trans-18:2 are minor trans fatty acids that derive from linoleic acid, the major polyunsaturate in commercial oils, and are produced by heat treatment of the oils. Although higher intake of these minor trans fatty acids appeared to increase risk, higher levels of the trans fatty acids commonly produced during partial hydrogenation (“trans-18:1”) were associated with lower risks. A reanalysis of data from a previous population-based case-control study showed nearly identical associations of red blood cell membrane trans-18:2 fatty acids with higher risk and trans-18:1 fatty acids with lower risk of sudden cardiac arrest. Future studies need to distinguish between trans-18:2 and trans-18:1 fatty acids to reassess the risks and possible benefits of different trans fatty acids.
Guest Editor for this article was Gregg C. Fonarow, MD.