A dietary pattern that lowers oxidative stress increases antibodies to oxidized LDL: Results from a randomized controlled feeding study

doi:10.1016/j.atherosclerosis.2005.04.001

Atherosclerosis

Volume 183, Issue 1, November 2005, Pages 175-182

https://doi.org/10.1016/j.atherosclerosis.2005.04.001 Get rights and content

Abstract

Background:

Oxidation of LDL (oxLDL) is thought to have an important role in early stages of atherogenesis. Antibody to oxLDL (Ab-oxLDL) has been proposed as a biomarker which might be directly associated with oxidative stress. Yet studies designed to test this hypothesis are lacking. We tested the hypothesis that consumption of a healthy diet rich in fruits and vegetables and reduced in saturated fat, total fat, and cholesterol will concomitantly reduce oxidative stress and Ab-oxLDL.

Methods:

One hundred and three healthy individuals were randomly assigned to consume a typical American (control) diet or the DASH diet rich in fruits, vegetables and low-fat dairy products and reduced in fat (27%), saturated fat (7%), and cholesterol (150 mg/day) for 3 months. Outcomes were urinary isoprostanes (in vivo marker of oxidative stress), oxygen radical absorbing capacity (ORAC, an in vitro assay measuring antioxidant activity in serum), and Ab-oxLDL measured at baseline, 1–3 months of feeding.

Results:

Compared to the control diet, consumption of the DASH diet significantly lowered urinary isoprostane (−226 pg/ml, 95% CI: −420 to −32, P = 0.023). Compared with the control group, change in ORAC was higher in the DASH group, 143 trolox units/ml (95% CI: −23 to 308, P = 0.091). In comparison with the control diet, increased titers of Ab-oxLDL (37 mU/ml [95% CI: 16–57, P = 0.006]) were seen after consumption of the DASH diet. Higher titers of Ab-oxLDL occurred at month 2 (56 mU/ml, 95% CI: 20–90, P = 0.004) and month 3 (41 mU/ml, 95% CI: −6 to 88, P = 0.082), after initially small increases at month 1 (20 mU/ml, 95% CI: −10 to 51, P = 0.176). End-of-study increases in AB-oxLDL were highly correlated with increased ORAC (Spearman's ρ = 0.46, P < 0.0001), but not with changes in specific carotenoids, tocopherols or with change in LDL cholesterol (each: P > 0.10).

Conclusion:

Consumption of a healthy diet replete in antioxidants reduced oxidative stress (urinary isoprostanes) yet increased Ab-oxLDL. This indirect association of Ab-oxLDL with urinary isoprostanes hinders use of Ab-oxLDL as a marker of oxidative damage.

Introduction

The direct relationship between LDL cholesterol (LDL-c) and risk of atherosclerosis is well established. Oxidation of LDL-c appears to accelerate this process [1], [2], [3]. Hence, measurement of oxidized LDL-c (oxLDL) has been proposed as a biomarker of cardiovascular disease risk beyond that which is predicted by LDL-c. While this is an appealing hypothesis, measurement of oxidation of LDL (oxLDL) has methodological barriers, which limit its use in epidemiological studies. Instead, non-specific markers of oxidative stress, including assays to determine the susceptibility of lipids to oxidation (i.e., lag time, thiobarbituric acid substances, malondialdehyde, oxygen radical absorbing capacity (ORAC) or assays that measure, in vivo, end-product of oxidative damage to lipids (e.g., breath ethane or urinary isoprostanes)), are commonly used. However, because these assays may not reflect oxLDL directly, their interpretation is limited. As an alternative, the antibody titer to oxLDL-c (Ab-oxLDL) has been proposed as a more direct estimate of oxLDL antigen in vivo [4], [5]. This assay has greater appeal in part because of its wide commercial availability and better measurement standardization.

While many observational studies have shown direct associations between Ab-oxLDL and established atherosclerosis [6], [7], [8], [9], [10], [11], [12], [13], [14], others have not [15], [16], [17]. Uncertainties about the interpretation of Ab-oxLDL, are based in part, on the finding that titer of Ab-oxLDL is highly dependent on the balance between free radical activity and antioxidant activity. For example, diabetes is a state of high oxidative stress and is associated with high Ab-oxLDL [18], [19]. However, there is an inverse association between diabetes control (hemoglobin A–1C) and Ab-oxLDL titer, suggesting that Ab-oxLDL is more rapidly removed from circulation under conditions of high oxidative stress resulting in lower serum levels. In addition, a low titer of Ab-oxLDL with poor diabetes control is associated with high levels of circulating immune complex (oxLDL/Ab-oxLDL) [18], [20]. Hence, simultaneous measurement of oxidative stress and Ab-oxLDL may be critical in the interpretation of titers of Ab-oxLDL [21].

We previously documented, in the setting of a randomized controlled feeding study, that consumption of a healthy diet rich in fruits and vegetables and reduced in saturated fat, total fat, and cholesterol reduces oxidative stress (i.e., reduces in vivo oxidation of lipids) and increases antioxidant activity [22]. The objective of this study is to examine effects of this diet on the response of Ab-oxLDL titers in the setting of a randomized, controlled feeding trial.

Section snippets

Methods

This research was conducted as an ancillary study at the Johns Hopkins clinical center within the Dietary Approaches to Stop Hypertension-Sodium (DASH-sodium) trial, a National Heart Lung and Blood Institute sponsored trial that assessed the effects of dietary patterns and sodium intake on blood pressure. As an ancillary study, this study was designed and analyzed only by the coauthors. Details of the DASH-sodium trial and its main results have been published elsewhere [23]. The protocol was

Participants

Study participants consisted of 103 healthy adults (age ≥22 years) who were not taking antihypertensive medications and who had a systolic blood pressure of 120–159 mmHg and diastolic blood pressure of 80–95 mmHg (average of three screening visits). Major exclusion criteria for entry into the trial were poorly controlled diabetes, hypercholesterolemia (total cholesterol >260 mg/dl, use of cholestyramine or cholesterol binders, or unstable doses of a statin), cardiovascular event, chronic disease

Study design and diets

Participants were randomly assigned to either the DASH diet or control diet using a parallel group design, and were fed each of three sodium levels using a randomized crossover design. The two dietary patterns were used in the original DASH study [24]. The control diet is typical of what many Americans eat. In contrast, the DASH diet is rich in fruits, vegetables and low-fat dairy products; includes whole grains, poultry, fish, and nuts; and is reduced in red meat, sweets, sugar-containing

Data collection

After attending a series of three screening visits, participants began a 2-week run-in feeding period on the control diet at the higher sodium level. Participants were then randomized to diet and sodium sequence. Following randomization, there were three, 30-day feeding periods, one at each of the three sodium levels. Three periods were separated by 0–5 days, during which the participants ate their own food. Sampling of blood and urine occurred at baseline (prior to randomization) and at the

Outcome variables

The primary outcome variable of this ancillary study was serum autoantibodies to oxidized LDL (Ab-oxLDL). Other outcomes were urine isoprostanes (an in vivo marker of oxidative stress), serum antioxidants (tocopherols, carotenoids and retinol) and oxygen radical absorbing capacity of serum (ORAC).

The antibodies to oxidized LDL-c (Ab-oxLDL) in serum was determined by enzyme immunoassay. In this ELISA kit assay (Alpco Corporation, Windham, NH), copper oxidized LDL is coated onto microtiter strips

Other measurements

Serum lipids were obtained as part of the DASH-sodium protocol and were measured centrally at the Core Laboratories of the Washington University Medical School. Low-density lipoprotein (LDL) cholesterol concentration was calculated by the Friedwald equation [28]: LDL-cholesterol = total cholesterol − HDL-cholesterol − triglyceride/5, for triglyceride levels less than 400 mg/dl. Serum albumin was determined spectrophotometrically by Sigma Diagnostics (St Louis, MO) albumin assay with a reported CV

Power calculations

The designated recruitment goal for the Hopkins Center was 100 participants. The a priori minimum detectable effect size (expressed in absolute terms and as a percent of the estimated population mean) calculated at a power of 80%, α = 0.05 (two-tailed), were 46% for Ab-oxLDL, 6% for urinary isoprostanes, and 5% for ORAC.

Analytic approach

For continuous variables with a normal distribution, mean (±standard deviation) are presented. For variables with skewed distributions, median (±95% confidence intervals) are presented for baseline levels and change from baseline. Between group differences were tested by regression analysis for normally distributed data and median regression analyses for skewed variables. In each regression model, the dependent variable was change from baseline. Co-variates in each model were the baseline level

Results

Baseline characteristics of participants are presented in Table 1, Table 2. Participants tended to be middle aged (mean age 52 years), 75% were African American, and 56% were women. Baseline levels of Ab-oxLDL, urinary isoprostanes and ORAC were similar in the two randomized diet groups (P > 0.20).

Results of the effects of diet on lipid and oxidative stress markers are presented in Table 2. Compared with the control diet, the DASH dietary pattern significantly increased Ab-oxLDL by a median of 37

Discussion

Formation of oxLDL is dependent on free radical activity (i.e., metabolic rate), substrate concentration (i.e., lipids), and antioxidant activity (both endogenous and dietary). This study demonstrated that consumption of a diet high in fruits, vegetables and low-fat dairy products and reduced in total fat, saturated fat, and cholesterol (the DASH diet) lowered LDL, reduced oxidative stress, increased serum antioxidants, and resulted in higher Ab-oxLDL. Overall, our data are consistent with the

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This diet may also improve small artery elasticity and the aortic augmentation index (two indices of vascular function) in SS subjects [13]. However, a study by Miller et al. observed no significant impact of the DASH diet on biomarkers of oxidative stress in healthy individuals [15]. According to our knowledge, there is no published meta-analysis evaluating the effects of the DASH diet on oxidative stress parameters.
Oxidative stress (OS) is one of the main risk factors for several chronic diseases. The Dietary Approaches to Stop Hypertension (DASH) contain many antioxidants and may contribute to managing OS.
To perform a systematic review and meta-analysis to examine the impacts of the DASH diet on OS parameters.
A comprehensive electronic search in MEDLINE, Scopus, EMBASE, and the Cochrane Central Register of Controlled Trials was performed through September 2020 to find related studies evaluating the impact of the DASH diet on OS parameters. Standardized mean differences were pooled using random-effects meta-analysis.
Eight studies with a total of 317 subjects met our inclusion criteria. Four studies included in meta-analysis model with 200 participants (100 in treatment and 100 in control group). The DASH diet was associated with a statistically significant decrease in malondialdehyde (MDA) (SMD: −0.53; 95% CI: −0.89, −0.16; I² = 42.1%), and a significant increase in glutathione (GSH) (SMD: 0.83; 95% CI: 0.36, 1.03; I² = 42.1%). Meta-analysis found no statistically significant effect of DASH diet on nitric oxide (NO) (SMD: −1.40; 95% CI: −0.12, 1.93; I² = 92.6%) or total antioxidant capacity (TAC) levels (SMD: 0.95; 95% CI: −0.10, 1.99; I² = 87.6%).
Our results demonstrated that a DASH diet could significantly increase GSH and decrease MDA levels. Furthermore, there is a trend to improve TAC, NO, and f2-isoprostanes by the adherence to the DASH diet. However, long-term, large sample size and well-designed randomized clinical trials are still needed to draw concrete conclusions about DASH diet’s effects on OS parameters.
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^☆: Presented in part at the Scientific Sessions of the American Heart Association, New Orleans, LA, November 12–15, 2000 and previously published in abstract form (Circulation 2000;102:II-82).

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A dietary pattern that lowers oxidative stress increases antibodies to oxidized LDL: Results from a randomized controlled feeding study☆

Abstract

Background:

Methods:

Results:

Conclusion:

Introduction

Section snippets

Methods

Participants

Study design and diets

Data collection

Outcome variables

Other measurements

Power calculations

Analytic approach

Results

Discussion

Lancet

Free Radic Biol Med

Clin Lab Med

Atherosclerosis

J Am Coll Cardiol

Atherosclerosis

Am J Cardiol

Atherosclerosis

Clin Immun

Clin Chim Acta

J Am Diet Assoc

Free Radic Biol Med

Am J Clin Nutr

Free Radic Biol Med

Clin Chim Acta

Am J Clin Nutr

J Nutr

J Nutr.

Lancet

Am J Clin Nutr

J Am Diet Assoc

J Am Diet Assoc

Beyond cholesterol: modifications of low-density lipoprotein that increase atherogenicity

N Eng J Med