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High-dose [alpha]-tocopherol therapy does not affect HDL subfractions in patients with coronary artery disease on statin therapy.

Numerous clinical and epidemiological studies have demonstrated an inverse relationship between HDL-cholesterol (HDL-C) and the risk of coronary artery disease (CAD) (1, 2). The small HDL subclasses (HDL3) contribute to increased risk, whereas large HDL subclasses (HDL2) are associated with decreased risk for CAD (3, 4). Inflammation and oxidative stress are pivotal in atherosclerosis; dietary micronutrients with antioxidant and antiinflammatory activities may play a critical role in the prevention of CAD (5). Although [alpha]-tocopherol (AT) has several beneficial effects on lipid peroxidation and inflammation, the results of randomized clinical trials have been equivocal and have been essentially negative (6). HDL Atherosclerosis Treatment Study (HATS) investigators (7-9) have reported that the combination of an antioxidant (AOX) cocktail [800 N/day of 2R,4'R,8'R-(RRR)-AT + 1 g vitamin C, 25 mg [beta]-carotene, and 100 [micro]g selenium] or individual AOX vitamin therapies (vitamins A, E + C, and [beta]-carotene) attenuated the HDL2-C response that was obtained by simvastatin-niacin (S-N) therapy. Few data are available, however, on the effect of AT therapy alone on HDL subfractions or on LDL and VLDL subfractions. Therefore, we investigated whether RRR-AT supplementation has any effect on lipoprotein subclasses in patients with stable CAD on Statin therapy. We recruited and randomized 127 patients in a double-blind manner to placebo or RRR-AT (1200 N/day) supplementation for 2 years. Selection criteria were nonsmokers, no high-intensity exercisers, not on antioxidant supplementation, no other chronic disease or gastrointestinal problems, no recent infection/trauma/surgery, no pregnancy/lactation, no bleeding diathesis, normal complete blood cell count, normal renal and liver function, alcohol intake <1 ounce/day, and not on thyroid drugs, nonsteroidal antiinflammatory drugs, oral contraceptives, or anticoagulants. The study was performed at University of Texas Southwestern Medical Center, Dallas, Texas, and University of California Davis Medical Center, Sacramento, California, and was approved by both the Institutional Review Boards. All patients gave informed consent. Fasting blood was collected at 5 different time points: baseline and 6, 12, 18, and 24 months. This study was a substudy of the primary trial designed to examine the effect of AT supplementation on carotid atherosclerosis, biomarkers of oxidative stress, and inflammation in patients with CAD on Statin therapy. A total of 90 patients (71%) completed the study. Reasons for dropping out included the long study duration, movement of participants to different geographic locations, and 3 deaths (2 in placebo and 1 in AT group). We had 85 samples for analysis of lipoprotein subfractions in the current report.

We analyzed lipids (total cholesterol, triglycerides, LDL, and HDL) (10) and apolipoprotein A1 (apoA1) concentrations. Plasma AT concentrations were measured by reversed-phase HPLC (11) and lipid standardized as described previously (11). Lipoprotein subfractions were measured by nuclear magnetic resonance spectroscopy at Liposcience (12). HDL subfraction measurement included total particles and small (7.3-8.2 nm; HDL3 b and c), medium (8.2-8.8 nm; HDL3 a), and large (8.8-13.0 nm; HDL2 a and b) particles. We also measured VLDL and LDL fractions as total, small, and large particles (12). ApoA1 concentrations were measured by an immunoassay (Beckman Lx 20) at baseline and at 2 years in the sera of patients in the AT group. The infra- and interassay CVs for lipoprotein subclasses and apoA1 were <10%. Data were analyzed using SPSS statistical software. Repeated measures ANOVA were conducted to determine time and dose-response effects followed by appropriate post hoc analyses of parametric and nonparametric data. The level of significance was set at P <0.05. With n = 40 patients per group, the study had a power of 0.9 to detect significant difference in HDL subfractions at the 0.05 significance level.

Demographic variables and baseline laboratory measurements are presented in Table 1 in the Data Supplement that accompanies the online version of this technical brief at http://www.clinchem.org/content/vol53/issue3. Patients were well-matched for age, body mass index, presence of diabetes/hypertension, and statin therapy. No significant difference in lipid concentrations as either a time or a treatment effect was observed in the 2 patient groups (Table 1A). Compared with baseline concentrations and concentrations in the placebo group, AT concentrations in patients receiving AT therapy significantly increased (P <0.01) as early as 6 months and up to 24 months after therapy (Fig. 1). Similar results were obtained for lipid-standardized AT concentrations. Concentrations of different HDL subclasses or total HDL particles were not significantly (all P >0.5) different from baseline after 2 years of AT therapy (Table 1B). Also, no differences were seen between treatment groups at any time point. Furthermore, the measurement of mean (SD) apoA1 concentrations in sera at baseline [134.6 (23.1) mg/L] and after AT therapy for 2 years [132.9 (17.6) mg/L] did not reveal any significant change (P = 0.73). The subclasses of VLDL and LDL also did not significantly differ as either a time or treatment effect (see Table 2 in the online Data Supplement). Thus we observed no change from baseline or difference from placebo in any of the lipoprotein subclasses after 2 years of AT therapy.

Although the consensus has been that HDL2 renders a protective effect, HDL3 leads to increased risk of CAD. Several lines of evidence in epidemiological studies support a relationship between low AT concentrations and the development of atherosclerosis (5), but the results of prospective and randomized clinical trials have been equivocal (6). HATS investigators (7) tested the effect of an AOX supplement in combination with S-N on coronary stenosis quantitated by angiography. In a 3-year, double-blind trial, 160 patients with CAD, low HDL-C, and LDL-C concentrations within the reference interval were randomly assigned to receive 1 of 4 regimens: S-N, AOX cocktail, S-N plus AOX (S-n + A), or placebos. These authors reported that the mean concentrations of LDL and HDL-C were unaltered in the AOX (n = 39) and the placebo (n = 34) groups; these concentrations changed substantially (by -34% and +25%, respectively) in the S-N group (n = 38). Furthermore, these concentrations changed by -31% and +18%, respectively, in the S-n + A group (n = 40). However, the protective increase in HDL2-C with S-N (42%; measured by nondenaturing polyacrylamide gradient gel electrophoresis) was attenuated by concurrent therapy with antioxidants (S-n + A). The compliance reported for S-N and AOX in this study was [greater than or equal to]89%. Subsequently, these authors (8) demonstrated that the increase in HDL-C seen with niacin therapy can result from a reduction in catabolism, an increase in the expression of ABC1 transporter, or an enhancement in the conversion of HDL3 to HDL2C by the phospholipids transfer proteins lecithin: cholesterol acyltransferase and lipoprotein lipase (4,13). An additional substudy (9) was conducted by the same investigators in a total of 44 patients given S-N for 3 months and randomly assigned to receive 1 of 6 AOX options: 800 IU vitamin E + vitamin C, 25 mg [beta]-carotene, 50 000 N vitamin A, 100 [micro]g selenium, the original AOX cocktail, or placebo. The 3 individual vitamin therapies, vitamin A, vitamins E + C, and [beta]-carotene, were as effective as the cocktail in blunting the HDL2-C response to S-N therapy. The number of patients in each subgroup from the total of 44 was not specified in this study, however. The authors acknowledged the limitation of sample size, with a caution for confirmation of the study. Importantly, none of these patients received supplementation with AT alone, thus prompting us to investigate whether AT therapy alone attenuates HDL2 subfraction compared with placebo in CAD patients on statin therapy. We provide here the evidence that there was no significant difference in lipoprotein subclasses as either a time or a treatment effect. Also, ApoA1 concentrations after AT therapy were not affected. A strength of our study is the greater sample size of patients (n = 85) with CAD followed for 2 years at 5 different time points compared with an earlier study of a small number of patients (n = 44) subdivided into 6 subgroups in which one of the subgroup received vitamins E + C and was studied at only 2 different time points, baseline and 3 months (9). The larger sample size in our study was appropriate not only to measure HDL subfractions but to confirm or refute the notion put forward by HATS Investigators that AOX vitamins, especially AT, have a negative effect on HDL subfractions in CAD patients on statin therapy. Importantly, ~90% of our patients were on statin therapy, similar to the percentage in the HATS study ([greater than or equal to]89% reported compliance for S-N and AOX cocktail). Thus, we conclude that high-dose RRR-AT therapy for 2 years, in patients with CAD on concomitant statin therapy, does not negatively affect HDL subclasses, especially the protective and large HDL subclass HDL2-, although we did not examine the functional characteristics of HDL from the 2 groups. In addition, we report no significant differences in LDL and VLDL subfractions.

In conclusion, the negative interaction previously proposed between AOX cocktail and statin therapy cannot be ascribed to AT. Based on the totality of evidence, we do not recommend high-dose AT supplementation in patients with CAD. In other populations at increased risk, however, vitamin E may still be beneficial, and its use is being tested in randomized clinical trials such as the PiVENS and TONIC trials of patients with nonalcoholic steatohepatitis who also have low HDL and the metabolic syndrome.

[FIGURE 1 OMITTED]

This work was supported by National Institutes of Health grants R01 AT 00005 and K24 AT 00596 (LJ.). We thank Beverley Huet for statistical analyses.

Previously published online at D01: 10.1373/clinchem.2006.078865

References

(1.) Genest J, Marcil M, Denis M, Yu L. High density lipoproteins in health and in disease [Review]. J Investig Med 1999;47:31-42.

(2.) Berneis K, Jeanneret C, Muser J, Felix B, Miserez AR. Low-density lipoprotein size and subclasses are markers of clinically apparent and non-apparent atherosclerosis in type 2 diabetes. Metabolism 2005;54:227-34.

(3.) Atger V, Giral P, Simon A, Cambillau M, Levenson J, Gariepy J, et al. High-density lipoprotein subfractions as markers of early atherosclerosis. Am J Cardiol 1995;75:127-31.

(4.) Tall AR. Plasma high-density lipoproteins: metabolism and relationship to atherogenesis. J Clin Invest 1990;86:379-84.

(5.) Singh U, Devaraj S, Jialal I. Vitamin E, oxidative stress, and inflammation. Annu Rev Nutr 2005;25:151-74.

(6.) Jialal I, Devaraj S. Antioxidants and atherosclerosis: don't throw out the baby with the bath water. Circulation 2003;107:926-8.

(7.) Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583-92.

(8.) Cheung MC, Zhao ZQ, Chait A, Albers JJ, Brown BG. Antioxidant supplements block the response of HDL to simvastatin-niacin therapy in patients with coronary artery disease and low HDL. Arterioscler Thromb Vasc Biol 2001; 21:1320-6.

(9.) Brown BG, Cheung MC, Lee AC, Zhao XQ, Chait A. Antioxidant vitamins and lipid therapy: end of along romance. Arterioscler Thromb Vasc Biol 2002; 22:1535-46.

(10.) Jialal I, Fuller CJ, Huet BA. The effect of [alpha]-tocopherol supplementation on LDL oxidation: a dose-response study, Arterioscler Thromb Vasc Biol 1995; 15:190-8.

(11.) Devaraj S, Adams-Huet B, Fuller CJ, Jialal I. Dose-response comparison of RRR-AT and all-racemic AT on LDL oxidation. Arterioscler Thromb Vasc Biol 1997;10:2273-9.

(12.) Kuller L, Arnold A, Tracy R, Otvos J, Burke G, Psaty B, et al. Nuclear magnetic resonance spectroscopy of lipoproteins and risk of coronary heart disease in the cardiovascular health study. Arterioscler Thromb Vasc Biol 2002;22: 1175-80.

(13.) Albers JJ, Tu A-Y, Wolfbauer G, Cheung MC, Marcovina SM. Molecular biology of phospholipid transfer protein. Curr Opin Lipidol 1996;7:88-93.

Uma Singh, [1] James Otvos, [2] Amitava Dasgupta, [3] James A. de Lemos, [4] Sridevi Devaraj, [1] and Ishwarlal Jialal [1] *

[1] University of California Davis Medical Center, Sacramento, California;

[2] Liposcience, Raleigh, North Carolina;

[3] University of Texas-Houston Medical School, Houston, Texas;

[4] University of Texas Southwestern Medical Center, Dallas, Texas;

* address correspondence to this author at: Laboratory for Atherosclerosis and Metabolic Research, Department of Medical Pathology & Laboratory Medicine, University of California Davis Medical Center, 4635 Second Avenue, Research Bldg. 1, Rm. 3000, Sacramento, CA 95817; fax: 916-734-6593, e-mail ishwarlal.jialal@ucdmc.ucdavis.edu
Table 1. Effects of Therapy.

A. Effect of AT therapy on lipid analysis in patients with CAD
in placebo and AT group. (a)

 Time, months

 0 6 12

Total cholesterol
 Placebo 4.3 (0.6) 4.3 (0.7) 4.3 (0.9)
 AT 4.2 (0.9) 4.2 (0.6) 4.2 (0.7)
Triglyceride
 Placebo 1.6 (0.9) 1.7 (0.8) 1.72 (0.5)
 AT 1.5 (0.7) 1.7 (0.8) 1.5 (0.8)
LDL-C
 Placebo 2.5 (0.6) 2.5 (0.7) 2.5 (0.8)
 AT 2.6 (0.7) 2.6 (0.6) 2.6 (0.6)
HDL-C
 Placebo 1.1 (0.3) 1.0 (0.2) 1.1 (0.2)
 AT 0.9 (0.2) 0.9 (0.2) 0.9 (0.2)

 Time, months

 18 24

Total cholesterol
 Placebo 4.1 (0.6) 4.2 (0.8)
 AT 4.3 (0.9) 4.2 (0.6)
Triglyceride
 Placebo 1.6 (1.1) 1.5 (1.1)
 AT 1.7 (0.9) 1.4 (0.8)
LDL-C
 Placebo 2.4 (0.7) 2.6 (1.0)
 AT 2.6 (0.9) 2.8 (1.6)
HDL-C
 Placebo 1.0 (0.2) 1.1 (0.2)
 AT 1.0 (0.2) 0.9 (0.2)

B. Effect of RRR-AT therapy on different HDL particles compared
with placebo (treatment and time interaction). (b)

 Time, months

 0 6 12

HDL-P
 Placebo 32.6 31.4 31.2
 AT 28.4 30.1 31.2
HDL-L
 Placebo 4.2 3.71 4.15
 AT 2.5 2.44 2.65
HDL-M
 Placebo 1.80 0.81 1.65
 AT 1.40 0.62 1.18
HDL-S
 Placebo 24.4 25.3 25.8
 AT 24.3 25.0 25.0

 Time, months Interaction,
 P value
 18 24

HDL-P
 Placebo 29.7 29.4
 AT 29.7 29.4 0.47
HDL-L
 Placebo 3.98 5.0
 AT 2.4 3.2 0.18
HDL-M
 Placebo 1.56 1.15
 AT 0.83 0.40 0.41
HDL-S
 Placebo 24.3 25.3
 AT 24.2 24.7 0.10

(a) All values are mean (SD) in mmol/L.

(b) The values for different HDL particles are given as median
values in terms of [micro]mol/L. HDL-P, total HDL particles;
HDL-L, large-sized HDL; HDL-M, medium-sized HDL; HDL-S,
small-sized HDL.
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Title Annotation:Technical Briefs
Author:Singh, Uma; Otvos, James; Dasgupta, Amitava; de Lemos, James A.; Devaraj, Sridevi; Jialal, Ishwarlal
Publication:Clinical Chemistry
Article Type:Clinical report
Date:Mar 1, 2007
Words:2455
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