© 1997 American Heart Association, Inc.
Articles |
Association of Serum Vitamin Levels, LDL Susceptibility to Oxidation, and Autoantibodies Against MDA-LDL With Carotid Atherosclerosis
A Case-Control Study
From the Division of Epidemiology, School of Public Health (C.I., A.R.F., D.R.J., M.D.G., J.D.B.), and the Department of Laboratory Medicine and Pathology, School of Medicine (J.H.E.), University of Minnesota, Minneapolis.
Correspondence to Dr Aaron R. Folsom, Division of Epidemiology, School of Public Health, University of Minnesota, 1300 S Second St, Suite 300, Minneapolis, MN 55454-1015.
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Abstract |
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Abstract Oxidative modification of LDL is believed to be a crucial step in atherosclerosis. Thus, antioxidant vitamins may have a role in the prevention of coronary disease. We examined the cross-sectional association of serum vitamin levels, the susceptibility of LDL to hemin-induced oxidation (lag phase to conjugated diene formation), and the malondialdehyde-LDL (MDA-LDL) to native LDL radioactivity binding ratio with carotid intima-media thickness (IMT), a measure of asymptomatic early atherosclerosis. The participants in this observational study were 231 asymptomatic age-, sex-, race-, and field center–matched case-control pairs selected from the Atherosclerosis Risk in Communities (ARIC) study cohort on the basis of B-mode carotid artery ultrasonograms obtained from 1986 through 1989. Cases exceeded the 90th percentile of IMT, and control subjects were below the 75th percentile of IMT for all arterial segments. Biochemical analyses were performed on fasting frozen (-70°C) serum specimens collected from 1990 through 1992. In conditional logistic regression adjusting for age, blood storage time, total cholesterol, and log-triglyceride concentrations, serum ß-cryptoxanthin and lutein plus zeaxanthin levels were inversely related to the extent of atherosclerosis (odds ratio [OR] per 1-SD increase: 0.75, 95% confidence interval [CI]: 0.59-0.94; and OR per 1-SD increase: 0.76, 95% CI: 0.59-0.95, respectively). Increases in
-carotene and lycopene were associated with nonsignificantly lower odds of being a case, whereas ß-carotene, retinol, and -tocopherol were unrelated to IMT. Although not reaching statistical significance, the lag phase and autoantibodies against MDA-LDL were positively associated with asymptomatic atherosclerosis. After adjustment for potential confounders, only the inverse association of lutein plus zeaxanthin with asymptomatic atherosclerosis was maintained. This study supports a modest inverse association between circulating levels of some carotenoids, particularly lutein plus zeaxanthin, and carotid IMT. These findings suggest that these carotenoid compounds (regarded as biomarkers of fruit and vegetable intake) may be important in early stages of atherosclerosis.
Key Words: cardiovascular disease • atherosclerosis • autoantibodies • LDL oxidation
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Introduction |
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Both in vitro and in vivo systems suggest that free radical–mediated injury may play an important role in the development of chronic degenerative diseases.1 2 3 For instance, laboratory investigations4 and animal models5 have shown that the oxidative modification of LDL is a crucial step in the initiation of atherosclerosis, the pathological process responsible for most coronary and cerebrovascular diseases. The mechanisms by which modified LDL may accelerate early events in atherogenesis include cytotoxic and chemotactic actions that promote the formation of foam cells,6 an increase in the adhesion of monocytes to the arterial endothelium,7 and the release of inflammatory cytokines and growth factors.8
Ecological correlational studies have shown inverse associations between consumption of antioxidant vitamins and mortality from coronary heart disease in different countries.9 10 11 Further, some epidemiological studies within populations have provided an indication that high dietary intake,12 13 high blood levels,14 15 16 or high adipose tissue levels17 of vitamins C, E, ß-carotene, and selenium are associated with decreased cardiovascular disease risk. In addition, several studies have demonstrated that patients with either progression of carotid atherosclerosis,18 severe carotid atherosclerosis,19 or unstable atherosclerotic cardiovascular disease20 develop autoimmune antibodies to epitopes of oxidatively modified LDL. In contrast, other epidemiological studies have found no association between plasma levels or dietary intake of antioxidant vitamins and cardiovascular disease.21 22 23 Moreover, the limited published data from human supplementation trials are conflicting.24 25 26 27 28
In an earlier report based on the baseline examination from the ARIC study, carotid artery IMT was inversely related to vitamin C intake among men and women >55 years old and inversely related to -tocopherol intake in women.29 The aim of the present study was to estimate the cross-sectional associations of serum vitamin levels, the susceptibility of LDL to oxidation, and autoantibodies against MDA-LDL with IMT in a case-control subsample of the ARIC cohort. The specific hypotheses of the study were that the serum level of carotenoids and -tocopherol would be lower in cases than control subjects.
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Case and Control Subject Definitions
The ARIC study is investigating the risk factors and clinical sequelae of clinical and subclinical atherosclerotic disease in four US communities.30 The baseline survey, conducted between December 1986 and December 1989, included real-time high-resolution B-mode ultrasound examination of 1-cm segments of the common and internal extracranial carotid arteries and their bifurcations bilaterally.31
B-mode scans were read by standardized techniques, and the IMT was measured as an indication of atherosclerosis.32 Quality control procedures and reproducibility of measures can be found elsewhere.33 Case-control pairs were defined as previously described.34 Cases exceeded approximately the 90th percentile of IMT for the cohort, and control subjects were below the 75th percentile of IMT for all artery segments. Exclusion criteria for both cases and control subjects included baseline exertion angina or claudication by the Rose questionnaire, or self-reported physician-diagnosed myocardial infarction, transient ischemic attack, or stroke. Case-control pairs were matched one to one on the basis of study center, race (black, white), sex, 10-year age groups, and 6-month baseline examination period.
Measurements
Serum Antioxidant Vitamins
Antioxidant vitamins were measured on fasting serum specimens obtained and frozen at -70°C in 1990 and 1992 (during ARIC visit 2) until analysis. Serum samples were analyzed for carotenoids, retinol, and -tocopherol by high-performance liquid chromatography–based assays. Detection and quantitation of carotenoids and retinol was performed by a modification of the method of Bieri et al35 with calibration as described by Craft et al.36 The modifications of the assay included the addition of N,N-diisopropylethylamine (0.015%) in the high-performance liquid chromatography solvent, as an aid to analyte recovery and detection of retinol by use of a second absorbance channel set at 325 nm. Retinol acetate was the internal standard for retinol, and the retention time of retinol was 2.3 minutes. Carotenoids quantified by the analysis included lycopene, -carotene, ß-carotene, ß-cryptoxanthin, and lutein plus zeaxanthin. -Tocopherol was quantitated by the method of Craft et al36 with a minor modification that the internal standard was tocol rather than tocopherol acetate. Calibration for both assays was done with crystalline standards (Hoffman-LaRoche, Sigma Chemical Co). Quality control procedures included routine analysis of plasma and serum control pools containing high and low concentrations of each analyte. In addition, our laboratory routinely analyzed National Institutes of Standards and Technology reference sera and was a participant in its Fat-Soluble Vitamin Quality Assurance Group. To determine the test-retest reliability of the measurement of serum vitamins and LDL susceptibility to oxidation, as well as the short-term stability of levels of antioxidants in frozen samples (after 4, 8, and 20 weeks), we conducted a concurrent pilot study in our laboratory on 24 healthy subjects recruited at the University of Minnesota (Myron D. Gross, unpublished data, 1996). The intraclass correlation coefficient (ratio of between-person variance to between-plus within-person variance) was .93 for -carotene, .99 for ß-carotene, .73 for lutein plus zeaxanthin, .97 for ß-cryptoxanthin, .73 for lycopene, .98 for retinol, and .93 for -tocopherol. These results indicate adequate laboratory reproducibility and minimal decay of vitamin levels in frozen serum samples due to passage of time. Sample collection and storage did not allow determination of vitamin C, because the protocol did not include the use of metaphosphoric acid and dithiothreitol for the stabilization of ascorbic acid.
LDL Susceptibility to Hemin-Induced Oxidation
LDL was isolated using the micro method from serum specimens collected and frozen (-70°C) in 1990 through 1992. Freshly thawed serum (0.5 mL, 4°C) was gently mixed for 10 minutes with 250 mg of anhydrous KBr to raise the plasma density to 1.30 g/mL. The tubes were centrifuged at 100 000 rpm for 45 minutes at 4°C. This method cleanly separated LDL from VLDL, as shown by agarose gel electrophoresis. The oxidation of LDL was monitored by measuring the decreasing absorbance of hemin at 405 nm as previously described.37 The decrease in hemin absorbance at 405 nm exactly parallels the increase in thiobarbituric acid–reactive substances and conjugated dienes. The susceptibility of LDL to oxidation is given by the duration of the lag phase, which is the time in minutes between the start of the assay and the time when the propagation phase reaches maximum velocity. The propagation phase is characterized by a sudden rapid decrease in hemin absorbance. All chemicals and reagents were purchased at Sigma Chemical Co. Quality control for LDL isolation and measurement of LDL susceptibility to oxidation was monitored with aliquots of serum and LDL stored frozen at -70°C. The intraclass correlation coefficient for the lag phase in the 24 participants in the pilot study was .57, indicating poor reproducibility of this measure (ie, large within-person and/or laboratory variance).
Autoantibodies to Modified LDL
Autoantibody titers to modified LDL were measured by solid-phase radioimmunoassay.38 Each well of a 96-well polyvinyl plastic plate (Dynatech Lab) was coated with 50 µL of a target antigen (5 µg/mL) in PBS for 2 hours at 37°C. One target antigen was native LDL (protected from oxidation by PBS containing 0.27 mmol/L EDTA and 20 µmol/L BHT) prepared from the pooled plasma of 10 donors, and the remaining binding sites were postcoated (the term "postcoated" represents the addition of another nonspecific protein to block remaining adsorptive sites on the plastic well) by incubation with 2% BSA for 2 hours at room temperature. A second target antigen was MDA-LDL, a prominent epitope of MDA-lysine that is one of the epitopes formed in oxidized LDL and found in human atheroscleromatous tissue.39 The second antigen was also postcoated with BSA. Then 1:48 and 1:96 dilutions of the participant's serum were added for incubation at 4°C overnight. The wells were then aspirated and washed, and iodinated monoclonal antibody specific for human IgG was added (Zymed Laboratories). The amount of bound radioactivity was measured in a gamma counter (model 1282, LKB). We used binding to native LDL as the nonspecific control and defined our quantitative measure of autoantibodies to modified LDL as the ratio of radioactivity binding to MDA-modified LDL to radioactivity binding to native LDL (MDA-LDL/native LDL). The correlation between the ratios at 1:48 and 1:96 dilutions was high (r=.94). Therefore, only the 1:96 dilution was used in the analysis. For quality control purposes, every analysis was run in duplicate, and the intra-assay coefficient of variation was 8%.
Dietary Intake of Vitamins
Usual dietary intake over the past year was estimated by a 66-item semiquantitative food-frequency questionnaire, which was a modified version of the 61-item questionnaire originally developed and validated by Willett et al.40 The questionnaire was administered by trained interviewers to a 10% random subsample of the ARIC cohort in 1990 through 1992, including a subset of the cases and control subjects. Daily nutrient intakes were calculated by multiplying the nutrient content of the specified portion of each food item by the frequency of its daily consumption and summing over all items. Total calories and content of vitamins A and C were obtained from US Department of Agriculture sources.41 Values for total carotenes were imputed from the vitamin A content.42 -Tocopherol values were derived from the USDA Handbook No. 8-4 and from values reported by McLaughlin et al.43
Dietary supplement use was ascertained in all participants by a survey of medication use. Participants were asked to bring to the field center all the medications and supplements that they had taken in the preceding 2 weeks, and the names of all medications and supplements were coded.
Other Risk Factors
Total cholesterol and triglyceride concentrations were measured by enzymatic methods.44 The lipid laboratory participated in the NHLBI/CDC (National Heart, Lung, and Blood Institute/Centers for Disease Control and Prevention) Lipid Standardization Program. Weight was measured with subjects wearing only scrub suits. Body mass index was computed as weight (in kilograms) divided by height (in meters squared). Sitting systolic and fifth-phase diastolic blood pressures were taken three times in the right arm with a random zero sphygmomanometer. The average of the last two measurements was used in the analysis. Prevalent hypertension was defined as systolic blood pressure 
140 mm Hg or diastolic blood pressure 90 mm Hg or self-reported use of antihypertensive medication in the preceding 2 weeks. Prevalent diabetes mellitus was defined as fasting glucose 7.8 mmol/L (140 mg/dL) and/or a self-reported history of or treatment for diabetes.
Statistical Analysis
Case-control differences were assessed using paired t tests for continuous variables and the McNemar's paired test for categorical variables. The association of IMT with plasma vitamin levels, lag phase, and the autoantibodies against MDA-LDL was examined by conditional logistic regression in the 231 matched case-control pairs who fasted for at least 8 hours before venipuncture and had complete data on all study variables at the second ARIC study visit in 1990 through 1992.45 We estimated the ORs and associated 95% CIs per 1-SD increase in each predictor variable. The SD was determined among all study participants. For each serum vitamin, the lag phase, and autoantibodies against MDA-LDL, three sequential models were considered. Model 1 included only age and visit 2 date, the latter as a surrogate of blood storage time. Then, in recognition of the dependency of serum vitamin concentrations on lipid levels, total cholesterol and log-triglyceride levels were entered as covariates (model 2). To further adjust for potential confounding by other risk factors for atherosclerotic disease, model 3 provided ORs standardized for education level (less than or equal to high school education versus higher education), body mass index (kg/m2), smoking status (current and former smoking, relative to never smoking), ethanol intake (g/wk), hypertension (yes/no), diabetes mellitus (yes/no), and vitamin supplement use (yes/no). For descriptive purposes, the energy-adjusted dietary intake of total carotenoids, vitamin C, and vitamin E (-tocopherol) among cases and control subjects was estimated using the residual method.46 All statistical analyses were performed using the SAS package.47
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Overall, 60% of participants were male and 10% were black (Table 1
). Cases were slightly older than control subjects and had lower educational attainment. The average carotid IMT (±SD) was twice as large in cases (1.2±0.3 mm) as in control subjects (0.6±0.1 mm) (Table 1). Cases were on average heavier and more likely to be current smokers than control subjects. Cases had higher concentrations of total cholesterol and triglycerides, higher prevalences of hypertension and diabetes mellitus, and reported greater use of cholesterol-lowering medication and antihypertensive drugs than control subjects. In a subset of 132 matched pairs, dietary intake of total carotenoids and vitamin E was lower and vitamin C higher in cases than in control subjects, but none of these differences in dietary vitamin intake were statistically significant. The proportion of individuals reporting use of vitamin E supplements was slightly higher in cases, but the proportion using any vitamin supplements was similar in both groups.
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Cases had significantly lower serum levels of ß-cryptoxanthin and lutein plus zeaxanthin and nonsignificantly lower -carotene, ß-carotene, and lycopene (Table 2). Contrary to expectation but without achieving statistical significance, retinol and -tocopherol levels were higher and the lag phase longer in cases than in control subjects. Autoantibodies against MDA-LDL were nonsignificantly higher in cases than in control subjects. Bivariate Pearson correlations among serum vitamins were high for -carotene and ß-carotene (r=.67) and moderate for all other vitamins (ranging from .17 to .44). By contrast, the correlations of retinol levels with the other vitamins were low, ranging from .02 to .10.
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After controlling for case-control status in a multiple linear regression model, the lag phase was independently correlated with age (r=-.14), male sex (r=.12), retinol (r=20), I-tocopherol (r=.27), and autoantibodies against MDA-LDL (r=.17). These variables combined explained about 19% of the variation in the lag phase. Non–statistically significant bivariate correlation was found between current (r=.07) or former smoking (r=.06) and the length of the lag phase. In another multiple regression model, autoantibodies against MDA-LDL were weakly correlated with age (r=-.09), retinol (r=.11), and -tocopherol (r=-.09). These three predictors accounted for only 4% of the variance of the auto-antibodies measured.
The ORs of being above the 90th percentile of IMT, corresponding to 1-SD increase in serum vitamin levels, lag phase, and autoantibodies against MDA-LDL, are provided in Table 3. After adjusting for age and blood storage time (model 1), higher ß-cryptoxanthin and lutein plus zeaxanthin were both associated with significantly lower odds of asymptomatic atherosclerosis. Associations were in the hypothesized direction (OR<1) for -carotene, ß-carotene, and lycopene. However, contrary to the study hypothesis, greater levels of retinol and -tocopherol and a longer lag phase were associated with nonsignificant higher odds of being a case. There was a weak positive (but not statistically significant) association between autoantibodies against MDA-LDL and IMT. Adjustment for total cholesterol and log-triglyceride concentrations (model 2) did not materially change the outcome of the associations of carotenoids but eliminated the positive associations of retinol and -tocopherol and attenuated the OR corresponding to a 1-SD longer lag phase. Further standardization for additional risk factors for atherosclerotic disease (model 3) altered the direction and magnitude of some of the associations. For example, the ORs for increases in -carotene and ß-carotene became weakly positive, the association with ß-cryptoxanthin was somewhat attenuated and lost its statistical significance, and the ORs corresponding to higher -tocopherol and lag time became more positive. After adjusting for the influence of covariates, the inverse association of serum lutein plus zeaxanthin was virtually unchanged but became only borderline significant. Contrary to the other serum carotenoids, the OR for a 1-SD increase in serum lycopene was somewhat reduced after the adjustment, indicating a steeper inverse independent relationship. Supplementary stepwise analysis including one additional risk factor at a time revealed that these effects of multivariate adjustment were largely due to the control for smoking status.
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To rule out bias as a result of vitamin supplement use, a subset unconditional logistic regression analysis was performed after excluding vitamin supplement users. In the remaining 177 cases and 180 control subjects, the pattern of associations was largely maintained, with the exception of a sharper and significant inverse relationship between a 1-SD increase in -carotene and IMT (OR, 0.75; 95% CI, 0.58-0.97). Although this study was not designed to evaluate interactions among serum vitamins and was underpowered, no synergistic or antagonistic effects were observed between lutein plus zeaxanthin and retinol, or between lutein and ß-carotene.
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Discussion |
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The main finding of this study was that cases with increased carotid IMT had lower levels of all carotenoids (statistically significantly so for ß-cryptoxanthin and lutein plus zeaxanthin) than did control subjects. Findings of higher prevalence of risk factors as well as use of cholesterol-lowering medication in the cases were expected. On the other hand, and counter to expectation, levels of retinol and
-tocopherol were higher among cases than control subjects, although not significantly so. This observation is perhaps due to a conscious shift in diet after diagnosis of cardiac risk factors. The fact that the exclusion of supplement users altered the relation between ß-carotene and IMT from a risk factor to a protective factor reiterates the potential confounding effects of drug and supplement use. Low circulating levels of carotenoids have been presumed to play a role in atherogenesis.48 Naturally occurring carotenoid pigments have been shown to be efficient quenchers of singlet oxygen generated in solution, a biological effect attributed to their system of conjugated double bonds.49 Further, these nutrients have been found to interact during intestinal absorption, metabolism, and serum clearance.50 Lower levels of lutein plus zeaxanthin may represent lower intake of fruit and vegetables (particularly carrots, tomatoes, and dark-green vegetables like spinach), which has been shown to be a risk factor for cardiovascular diseases and various forms of human cancers in epidemiological studies.51
We found that an increment in the lag phase, both before and after adjusting for additional risk factors, was positively but not significantly related to greater IMT. Previous research has suggested that the susceptibility to LDL oxidation depends on the severity of atherosclerosis52 and that individuals with LDL enriched in triglycerides are at particular risk.53 Nevertheless, the relatively low intraclass correlation for the lag phase (due to the large within-individual variance and method variance of this laboratory measure) renders this association difficult to interpret.
Serum -tocopherol and retinol concentrations were positively associated with the lag phase of conjugate diene formation. The correlation of -tocopherol with the lag phase has been documented in cell-culture experiments54 and epidemiological data55 56 and suggests that heavy modification of LDL does not occur unless the LDL particle is depleted of its endogenous vitamin E.57 However, although -tocopherol plays a crucial role, other parameters such as oleic acid58 and ubiquinol-1059 (not measured in this study) may also be important in determining susceptibility to oxidative modification of LDL.
In our study, no significant cross-sectional relation was observed between autoantibodies against MDA-LDL and IMT. The association of autoantibodies against oxidatively modified LDL with manifestations of atherosclerotic disease is not entirely consistent.18 19 20 60 61 Autoantibodies against oxidized LDL were associated with the 2-year progression of carotid atherosclerosis,18 clinical manifestations of advanced atherosclerotic disease,19 and early-onset peripheral vascular disease.60 However, a recent study does not support an association between autoantibody titers to oxidized LDL and the extent of coronary stenosis.61 It has been proposed that the autoantibodies are an indicator for an active atherogenic process and that a lack of an association may thus reflect a "stable state" of atherosclerosis.61
Taken together, epidemiological investigations on the association between serum or adipose tissue antioxidant levels and cardiovascular disease have yielded mixed results. Whereas some ecological9 and case-control studies15 17 suggest a protective relation, several other studies found no relation between antioxidants and various aspects of coronary disease.21 22 23 62 63 64 In addition, the results of human intervention trials have been, with one exception,28 essentially negative.
There are some reasons that blood levels of antioxidants may appear unrelated to atherosclerotic disease. First, it has been argued that what happens subendothelially is important and that there is no evidence that what we measure in the blood reflects the arterial subendothelium. Second, a number of other factors besides the antioxidant defense may determine the susceptibility of LDL to oxidation. These include the types of circulating fatty acids, the free radical content of the LDL particles,65 and the LDL particle size.66
We recognize that there are some sources of potential bias in the design of this study. First, ambiguity may have been introduced by the delay of 3 years between the carotid examination and the measurement of serum antioxidants and susceptibility to oxidation. Second, various interventions (suggested by the high prevalence of treatment with lipid-lowering and antihypertensive drugs) could have impacted the differences between groups. Finally, misclassification of outcome (that is, control subjects developing carotid intima thickening between the first and second visits) might have occurred. We noted that three control subjects had developed carotid intima-media thickening (90th percentile) between the first and second ARIC visits. However, exclusion of these three case-control pairs did not materially alter the results of the study.
In conclusion, this study provides evidence for a modest inverse association between serum levels of carotenoids, particularly lutein plus zeaxanthin, and early carotid artery IMT. These findings suggest that serum levels of certain carotenoids (presumably biomarkers of fruit- and vegetable-rich food intake) may be important in early stages of atherogenesis.
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The members of the ARIC staff are listed below:
Phyllis Johnson, Marilyn Knowles, and Catherine Paton (University of North Carolina, Chapel Hill); Shirley Cothern, Amy Haire, Kim Jones, and Delilah Posey (University of North Carolina, Forsyth County); Agnes Hayes, Jane Johnson, Penney Lowery, and Patricia Martin (University of Mississippi Medical Center, Jackson); Chris Hunkins, Ellie Justiniano, Laura Kemmis, and Irene Keske (University of Minnesota, Minneapolis); Patricia Hawbaker, Joel Hill, and Joan Nelling (Johns Hopkins University, Baltimore, Md); Valerie Stinson, Pam Pfile, Hoagn Pham, and Teri Trevino (University of Texas Medical School, Houston); Wanda Alexander, Doris Harper, Charlie Rhodes, and Selma Soyal (The Methodist Hospital, Atherosclerosis Clinical Laboratory, Houston, Tex); Charlene Kearny-Cash, Kelli Collins, Deliah Cook, and Melanie Eller (Bowman-Gray School of Medicine, Ultrasound Reading Center, Winston-Salem, NC); and Myra Carpenter, Limin Clegg, Chris Coffey, and John Crouch (University of North Carolina, Chapel Hill, Coordinating Center).
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Acknowledgments |
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This study was supported by contracts NO1-HC-55015, NO1-HC-55016, NO1-HC-55018, NO1-HC-55019, NO1-HC-55020, NO1-HC-55021, and NO1-HC-55022 from the National Heart, Lung, and Blood Institute. The authors are grateful to Joseph L. Witztum, MD (Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego), for the measurement of the autoantibodies to MDA-LDL and to F. Javier Nieto, MD, PhD, for his insightful comments.
Received May 2, 1996; accepted August 21, 1996.
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References |
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