HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: j.jacc.2006.03.057v1 48/5/973    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Wu, T. Articles by Rimm, E. B. Search for Related Content PubMed PubMed Citation Articles by Wu, T. Articles by Rimm, E. B.

CLINICAL RESEARCH: ATHEROSCLEROSIS

Is Plasma Oxidized Low-Density Lipoprotein, Measured With the Widely Used Antibody 4E6, an Independent Predictor of Coronary Heart Disease Among U.S. Men and Women?

Tianying Wu, MD, PhD^_*,_*, Walter C. Willett, MD, DrPh^_*,,, Nader Rifai, PhD^||, Iris Shai, PhD^_*, JoAnn E. Manson, MD, DrPh^,, and Eric B. Rimm, ScD^_*,,

^_* Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
Channing Laboratory, Harvard Medical School and Brigham & Women’s Hospital, Boston, Massachusetts
Division of Preventive Medicine, Department of Medicine, Harvard Medical School and Brigham & Women’s Hospital, Boston, Massachusetts
^|| Department of Laboratory Medicine, Children’s Hospital and Harvard Medical School, Boston, Massachusetts

Manuscript received January 6, 2006; revised manuscript received March 17, 2006, accepted March 20, 2006.

^_* Reprint requests and correspondence: Dr. Tianying Wu, Department of Nutrition, Harvard School of Public Health, 655 Huntington Avenue, Boston, Massachusetts 02115. (Email: tianying{at}hsph.harvard.edu).

	Abstract

Top Abstract Methods Results Discussion References

 
OBJECTIVES: Our aim was to examine whether circulating oxidized low-density lipoprotein (oxLDL) is a predictor of coronary heart disease (CHD) independent of lipid markers and to compare oxLDL, apolipoprotein B100 (apoB), and total cholesterol (TC)/high-density lipoprotein-cholesterol (HDL-C) ratio as predictors of CHD.

BACKGROUND: Measurement of circulating oxLDL with antibody 4E6, has been widely used in many studies; however, few large prospective studies have examined whether this marker is a predictor of CHD independent of lipids and compared oxLDL with other important lipid predictors.

METHODS: After 6 years of follow-up among 18,140 men from the HPFS (Health Professionals Follow-up Study) and 8 years among 32,826 women from the Nurses’ Health Study who provided blood samples at baseline, we identified incident nonfatal myocardial infarction or fatal CHD in 266 men and 235 women. Each case was matched with two control subjects by age, smoking, and time of blood draw. The oxLDL was measured via enzyme-linked immunosorbent assay with antibody 4E6 against oxidized apoB.

RESULTS: Among both men and women, oxLDL was significantly related to risk of CHD in multivariate analysis before adjustment for any lipid markers. However, when oxLDL, LDL cholesterol, HDL-C, and triglycerides were mutually adjusted, oxLDL was no longer predictive. When oxLDL and apoB were mutually adjusted, only apoB was predictive of CHD. Similar results were found when oxLDL and TC/HDL-C ratio were mutually adjusted.

CONCLUSIONS: Our results suggest that circulating oxLDL, measured with antibody 4E6, is not an independent overall predictor of CHD after adjustment of lipid markers and is less predictive in development of CHD than apoB and TC/HDL-C ratio.

Abbreviations and Acronyms   ApoB = apolipoprotein B100   CHD = coronary heart disease   CI = confidence interval   ELISA = enzyme-linked immunosorbent assay   HDL-C = high-density lipoprotein-cholesterol   LRT = likelihood ratio test   MI = myocardial infarction   oxLDL = oxidized low-density lipoprotein   OR = odds ratio   RR = relative risk   TC = total cholesterol

Reliable markers of oxLDL for epidemiologic studies are limited. Biopsy samples from atherosclerotic lesions for measuring oxLDL are difficult to obtain and commonly used in vitro measurements of oxLDL (6,7) are time consuming and not practical for large studies with stored samples. Recently, direct measurement of circulating oxLDL in plasma by either an in-house enzyme-linked immunosorbent assay (ELISA) or a commercial ELISA kit provided by Mercodia (Winston-Salem, North Carolina) with the monoclonal antibody 4E6 have been used in many case-control, cross-sectional (8–17) and some prospective studies (18–21). These studies suggest that oxLDL is positively associated with coronary heart disease (CHD) and related risk factors. However, large prospective studies including men and women designed to evaluate this marker as an independent predictor of CHD are lacking.

Measurement of LDL-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), and triglycerides are traditionally recommended lipid screening tests for CHD; therefore, it is important to examine whether oxLDL can predict CHD independent of these lipid markers. Several prospective studies have suggested that apolipoprotein B100 (apoB), a marker of the number of pro-atherogenic particles (22,23), was the strongest predictor of CHD. Because the antibody 4E6 is specific for oxidized apoB (8), it is important to determine whether this marker of oxidation is independent of and adds prognostic information beyond apoB itself. None of the previous studies using the same antibody has evaluated this issue. Furthermore, several studies do suggest that total cholesterol (TC)/HDL-C ratio, a major lipid index, is better than TC, LDL-C, HDL-C, or triglycerides alone; it is easily obtained and one of the most powerful important risk factors for CHD (24,25). Therefore, we also compared oxLDL and TC/HDL-C ratio.

	Methods

Top Abstract Methods Results Discussion References

 
Study population and collection of blood samples.   HPFS (Health Professionals Follow-Up Study)
The HPFS is a prospective cohort study of diet, CHD, and cancer conducted among 51,529 U.S. male health professionals who were 40 to 75 years old at baseline in 1986. Health information, including reports of diagnosed heart disease, was obtained at baseline and assessed biennially by follow-up questionnaires. In 1993 and 1994 we sent venipuncture kits to participants, and 18,140 men returned specimens on ice with an overnight courier. Multiple aliquots of plasma were stored in liquid nitrogen freezers for future nested case-control analyses. The men who returned blood samples were not substantially different from the remaining men in the cohort except that the prevalence of current smoking was slightly lower among those who returned blood samples. We identified 16,453 men who were free of cardiovascular diseases and cancer for future nested case-control studies.

The Nurses’ Health Study I
The Nurses’ Health Study I cohort, established in 1976, consists of 121,700 female registered nurses 30 to 55 years of age who provided information on medical history and lifestyle factors at baseline and on subsequent biennial questionnaires. In 1989 and 1990, we collected blood samples from 32,826 cohort members who were then 43 to 69 years of age. Whole blood was shipped, processed, and stored by the methods described previously. The women who returned blood samples were not substantially different from the remaining women in the cohort. We identified 28,601 women among those who returned samples who were free of cardiovascular disease and cancer for our nested case-control study. The study was approved by the institutional review board of Brigham and Women’s Hospital, Boston.

Ascertainment of cases and selection of control subjects.   The assessment of nonfatal myocardial infarction (MI) and fatal CHD and selection of control subjects are described in detail elsewhere (26,27). Briefly, when an MI was reported on a biennial follow-up questionnaire, we sought permission to review medical records. For confirmation of cases of MI, we used World Health Organization criteria, which require symptoms plus either diagnostic electrocardiographic changes or elevated cardiac enzymes. The MIs of undetermined date were not included in this analysis.

The end point for this study comprised incident cases of nonfatal MI and fatal CHD that occurred before February 2000 for men and before June 1998 for women. We confirmed 266 cases in men and 235 cases in women among the "at risk" participants. Each case was matched by year of age, month of blood draw, and smoking status (never, past, current) to 2 control subjects who were free of CHD at the time of the case diagnosis. All women were also matched for fasting status (lower/higher than 8 h) before blood draw. All assays were conducted without knowledge of the case/control status. Matched case-control triplets were handled identically and together and assayed in the same analytical run.

Assessment of medical history, lifestyle, and dietary factors.   Questions related to disease and lifestyle factors were sent out every 2 years, and a semiquantitative food frequency questionnaire was sent out every 4 years. For nutrients and other lifestyle characteristics, such as body mass index (BMI) and physical activity, we used the information from the time when subjects’ blood was collected (1994 for men and 1990 for women). The validity and reproducibility of self-reported lifestyle characteristics and semiquantitative food frequency questionnaire have been previously reported (28–32).

Measurement of oxLDL, apoB, other lipids, and inflammatory markers.   The oxLDL was measured by a sandwich ELISA kit with the monoclonal antibody 4E6 (Mercodia). The antibody 4E6 is especially against an epitope in the apoB-100 moiety of oxLDL that is formed from substitution of lysine residues of apoB-100 with aldehydes (18). The coefficient variations of the intra- and inter-assay for measurement of oxLDL were <8%. Total apoB was measured by an immunoturbidimetric technique on the Hitachi 911 analyzer (Roche Diagnostics, Indianapolis, Indiana). Total cholesterol, HDL-C, LDL-C, and triglycerides were measured by standard method with reagent from Roche Diagnostics and Genzyme (Cambridge, Massachusetts). Soluble tumor necrosis factor (TNF)-alpha receptors types 1 and 2 (sTNF-R1 and sTNF-R2) and C-reactive protein was measured by latex-enhanced immunoturbidimetric assay from Denka Seiken (Tokyo, Japan) on the Hitachi 911 system. Interleukin-6 was measured by ELISA (R&D Systems, Minneapolis, Minnesota). The coefficient variations for apoB, other lipids, and inflammatory markers were <4% to 9%. The laboratory used for analysis is certified by the Centers for Disease Control and Prevention/National Heart, Lung, and Blood Institute Lipid Standardization Program.

Stability of oxLDL in whole blood stored on ice up to 36 h.   As described earlier, participants sent whole blood shipped on ice via overnight courier from across the country. To assess the stability of oxLDL, we conducted a pilot study that mimicked these conditions and found that there was no degradation or increase in the measurement of oxLDL when assessed at baseline, 24 h, and 36 h after whole blood remained on ice (33).

Statistical analysis.   Baseline characteristics
For baseline variables, we calculated means, medians, or proportions for cases and control subjects. We assessed statistical significance by chi-square tests for categorical variables. We used Wilcoxon signed-rank tests for non-normally distributed variables and 2 sample t tests for normally distributed variables and the age-adjusted, partial Spearman rank-correlation coefficient to assess the associations between oxLDL and other variables.

Association of oxLDL with risk of CHD
We categorized participants into quintiles according to the distribution of plasma levels of oxLDL in the control participants. We used conditional logistic regression analyses with and without adjustment for traditional cardiovascular risk factors, including family history of MI, alcohol intake, BMI, physical activity, and history of hypertension or high cholesterol. Tests for trends were performed by entering a single continuous variable assigned as the median value for each quintile.

Comparison of oxLDL with apoB and other lipids
To examine whether oxLDL captures information beyond apoB or TC/HDL-C ratio, we compared the full model that included oxLDL and either apoB or TC/HDL-C ratio to the reduced model without oxLDL with a likelihood ratio test with 4 df. Oxidized LDL and other lipid markers (apoB and TC/HDL-C ratio) were included as quintiles with 4 dummy variables. With a similar approach, we examined whether apoB or TC/HDL-C ratio adds additional information beyond oxLDL. To pool the relative risk (RR) estimates for men and women, we used the weighted average of estimates with the DerSimonian and Laird random effects model (34).

Because of the linear relationship of the oxLDL, apoB, and TC/HDL-C with risk of CHD, to reduce residual confounding, we also fit the aforementioned models with oxLDL, apoB, and TC/HDL-C ratio as continuous, linear variables.

	Results

Top Abstract Methods Results Discussion References

 
Baseline characteristics.   We compared characteristics at blood draw between cases and control subjects (Table 1). Levels of oxLDL at baseline were significantly higher among cases than control subjects and also significantly correlated with all lipid parameters. The correlation between oxLDL and apoB was 0.59 in men and 0.44 in women; for TC/HDL-C ratio, the correlations were 0.40 in men and 0.65 in women (Table 2). The oxLDL was modestly correlated with inflammatory markers in women but not in men.

We performed similar analyses to compare oxLDL versus TC/HDL-C ratio and found similar patterns. The risk of oxLDL between extreme quintiles after adjustment for TC/HDL-C ratio was reduced to 1.70 (95% CI 0.93 to 3.13) in men and 1.17 (95% CI 0.51 to 2.68) in women (Tables 3 and 4). However, the RR of TC/HDL-C ratio between extreme quintiles was 2.82 (95% CI 1.48 to 5.38) in men and 4.30 (95% CI 1.76 to 10.52) in women after adjustment for oxLDL (Table 4). With the likelihood ratio test, we also found that oxLDL did not add any information beyond TC/HDL-C ratio, but TC/HDL-C ratio added significant information beyond oxLDL (Table 4).

Similarly, we entered oxLDL and TC/HDL-C ratio as continuous variables simultaneously in the model and found similar results. In men, the OR/1 SD increase was 1.25 (95% CI 1.04 to 1.50; p = 0.02) for oxLDL and 1.44 (95% CI 1.19 to 1.75; p = 0.0002) for TC/HDL-C ratio. In women, the OR/1 SD increase was 1.16 (95% CI 0.85 to 1.47; p = 0.4) for oxLDL and 1.36 (95% CI 1.13 to 1.62; p = 0.0009) for TC/HDL-C ratio.

In both men and women, additional adjustment for inflammatory markers in multivariate models did not appreciably alter the RRs for oxLDL.

When we combined the results for the men and women with a random effects model, the RR for oxLDL was marginally significant in the multivariate analysis after adjustment for apoB or TC/HDL-C ratio. The RR for the highest versus the lowest quintile was 1.47 (95% CI 0.87 to 2.48), p for trend = 0.06 after adjustment for apoB; and the RR was 1.49 (95% CI 0.71 to 2.07), p for trend = 0.02 after adjustment for TC/HDL-C ratio.

	Discussion

Top Abstract Methods Results Discussion References

 
We found that the measurement of circulating oxLDL with the 4E6 antibody, the most widely used antibody for this assay, predicted the risk of CHD in a large prospective setting including men and women. However, this association was not independent of standard lipid variables. Most importantly, this association was not independent of two powerful predictors, apoB and TC/HDL-C ratio. Conversely, apoB or the TC/HDL-C ratio predicted CHD independent of oxLDL. Even in the pooled analysis, the independent association between oxLDL and CHD was weak after accounting for lipid variables. These comparisons were not done in previous studies using the same antibody via ELISA.

The strong positive association found in multivariate analyses for oxLDL predicting CHD without adjustment for lipid markers was similar to that from several previous studies that have used antibody 4E6 via either the in-house ELISA or the commercially available ELISA kit provided by Mercodia. In several case-control and cross-sectional studies, oxLDL was associated with CHD (9) or stable CHD (17), higher CHD risk on the basis of the Framingham score (12), metabolic syndrome and a greater disposition to atherothrombotic coronary disease (13), glucose tolerance (15), or greater intima thickness and presence of plaque (14). At least 3 cohort studies and 1 nested-case control study, which used antibody 4E6, have found that oxLDL was associated with number and the size of plaques (20), with MI cases among men (19), with cardio-transplanted vasculopathy in men and women (18), and acute CHD events in men (21). However, many of these studies were small and lacked the power to control for all potential confounders and, especially, did not finely adjust for lipid markers. Most importantly, none of them determined whether oxLDL was independent of apoB, and only 1 study (21) adjusted for TC/HDL-C ratio, but their analysis included only men and adjusted for physical activity and obesity only as dichotomized variables, leaving the possibility of residual confounding.

Inflammatory processes produce oxidative products. However, oxLDL can also induce production of monocyte chemotactic protein-1 and monocyte-colony stimulating factor and lead to inflammatory response in vascular cells (35–37). Inflammation, reflected by circulating inflammatory markers such as C-reactive protein, are associated with incidence of CHD in large prospective studies (27,38). However, on the basis of our data, the association for oxLDL is not explained by inflammation, because the risk of oxLDL did not change after adjustment of any inflammatory markers.

The oxLDL is thought to be a mixture of heterogeneously modified particles. Many components in LDL can be oxidized, including apoB, phospholipids, LDL-cholesterol, and unsaturated fatty acids. Therefore, several antibodies against different epitopes on LDL have been generated, including the most widely used antibody 4E6 against oxidized apoB (as used in this report), antibody FOH1a/DLH3 (39), and antibody E06 (40,41) against oxidized phospholipids. Circulating oxLDL measured via the antibodies, FOH1a/DLH3, or E06 was not associated with apoB (40–42), and oxLDL measured via the antibody E06 was found to be significantly associated with lipoprotein(a) (Lp[a]) (41). However, we and several others (14–17) found that oxLDL measured via the antibody 4E6 is significantly associated with apoB but not with Lp(a). These data do highlight the importance of antibody selection, because different antibodies might reflect different components of oxLDL.

Two cross-sectional studies (41,42), with the antibody FOH1a/DLH3 and the antibody E06 to detect oxLDL, found that oxLDL was significantly associated with CHD after adjustment for apoB. Because there is 1 apoB particle/LDL particle, it is important to adjust apoB even if antibodies FOH1a/DLH3 and E06 are not specifically against apoB. These two studies indirectly support our contention that antibodies other than the most widely used antibody 4E6 could be alternative choices. Alternatively, a combination of antibodies should be evaluated simultaneously in future prospective studies.

We think our data have clinical implications for several reasons. Our study is the largest prospective study including men and women, and we compared oxLDL with other lipid markers after finely controlling multiple CHD risk factors. Given that so many studies that had used this 4E6 antibody found a strong relationship between this marker and CHD without finely controlling lipid variables in their analyses, our results for the first time raise the questions of whether we should add additional costs to measure oxLDL with this antibody for screening and to justify the potential improvement in risk prediction over the currently available lipid risk factors. Total cholesterol and HDL-C are standard lipid measures, and TC/HDL-C ratio can be directly calculated at no incremental cost beyond usual lipid evaluation. Measurement of apoB is also easier and less expensive than measurement of oxLDL via ELISA with this 4E6 antibody. Both TC/HDL-C ratio and apoB are more powerful predictors of CHD than oxLDL. Taken together, measurement of oxLDL via ELISA with different antibodies should be further evaluated before this marker is applied in clinical practice.

Our study has several strengths and limitations. We had a large sample size, included both men and women, and we accounted for several well-measured confounders in our analyses, including multiple markers of lipids and inflammation. Additionally, we collected plasma samples before the diagnosis of disease, which should reduce the impact of CHD on level of oxLDL at baseline. However, other antibodies for measuring oxLDL were not available from these studies at the time of this analysis. We recognize that the risk of CHD in our cohorts might be lower than in other populations. However, major cohort studies, such as the Framingham Heart Study, have also not relied on national samples. The advantages of our cohorts are that our participants had a high level of education and can provide high-quality and valid information on self-administrated forms. Data validity is the chief prerequisite for generalizing results. The range of lifestyle and biochemical variables in our cohorts is quite broad. In previous analyses we observed that the associations for CHD and other diseases are very similar to those found in other broad-based U.S. populations.

In conclusion, we found that circulating oxLDL, measured by the most widely used antibody 4E6, can predict the risk of CHD but not independent of the two strongest risk factors, apoB and TC/HDL-C ratio, or other conventional lipid markers, including LDL-C, HDL-C, and triglycerides. Apolipoprotein B100 and TC/HDL-C ratio are more predictive in development of CHD than oxLDL. Measurement of oxLDL with multiple antibodies is needed in future large-scale, prospective studies to address the long-desired question of whether oxLDL is an independent risk factor of CHD.

	Footnotes

 
This work was supported by National Institutes of Health grants CA87969, HL34594, CA55075, and HL35464 and American Heart Association grant 0430202N.

	References

Top Abstract Methods Results Discussion References

 

1. Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D. Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids Proc Natl Acad Sci U S A 1984;81:3883-3887.[Abstract/Free Full Text]
2. Heinecke JW. Oxidants and antioxidants in the pathogenesis of atherosclerosisimplications for the oxidized low density lipoprotein hypothesis. Atherosclerosis 1998;141:1-15.[ISI][Medline]
3. Leeuwenburgh C, Rasmussen JE, Hsu FF, Mueller DM, Pennathur S, Heinecke JW. Mass spectrometric quantification of markers for protein oxidation by tyrosyl radical, copper, and hydroxyl radical in low density lipoprotein isolated from human atherosclerotic plaques J Biol Chem 1997;272:3520-3526.[Abstract/Free Full Text]
4. Leeuwenburgh C, Hardy MM, Hazen SL, et al. Reactive nitrogen intermediates promote low density lipoprotein oxidation in human atherosclerotic intima J Biol Chem 1997;272:1433-1436.[Abstract/Free Full Text]
5. Rosenfeld ME, Palinski W, Yla-Herttuala S, Butler S, Witztum JL. Distribution of oxidation specific lipid-protein adducts and apolipoprotein B in atherosclerotic lesions of varying severity from WHHL rabbits Arteriosclerosis 1990;10:336-349.[Abstract/Free Full Text]
6. Esterbauer H, Striegl G, Puhl H, Rotheneder M. Continuous monitoring of in vitro oxidation of human low density lipoprotein Free Radic Res Commun 1989;6:67-75.[ISI][Medline]
7. Wu T, Geigerman C, Lee YS, Wander RC. Enrichment of LDL with EPA and DHA decreased oxidized LDL-induced apoptosis in U937 cells Lipids 2002;37:789-796.[ISI][Medline]
8. Holvoet P, Donck J, Landeloos M, et al. Correlation between oxidized low density lipoproteins and von Willebrand factor in chronic renal failure Thromb Haemost 1996;76:663-669.[ISI][Medline]
9. Holvoet P, Vanhaecke J, Janssens S, Van de Werf F, Collen D. Oxidized LDL and malondialdehyde-modified LDL in patients with acute coronary syndromes and stable coronary artery disease Circulation 1998;98:1487-1494.[Abstract/Free Full Text]
10. Holvoet P, Stassen JM, Van Cleemput J, Collen D, Vanhaecke J. Oxidized low density lipoproteins in patients with transplant-associated coronary artery disease Arterioscler Thromb Vasc Biol 1998;18:100-107.[Abstract/Free Full Text]
11. Holvoet P, Mertens A, Verhamme P, et al. Circulating oxidized LDL is a useful marker for identifying patients with coronary artery disease Arterioscler Thromb Vasc Biol 2001;21:844-848.[Abstract/Free Full Text]
12. Holvoet P, Harris TB, Tracy RP, et al. Association of high coronary heart disease risk status with circulating oxidized LDL in the well-functioning elderlyfindings from the Health, Aging, and Body Composition study. Arterioscler Thromb Vasc Biol 2003;23:1444-1448.[Abstract/Free Full Text]
13. Holvoet P, Kritchevsky SB, Tracy RP, et al. The metabolic syndrome, circulating oxidized LDL, and risk of myocardial infarction in well-functioning elderly people in the health, aging, and body composition cohort Diabetes 2004;53:1068-1073.[Abstract/Free Full Text]
14. Hulthe J, Fagerberg B. Circulating oxidized LDL is associated with subclinical atherosclerosis development and inflammatory cytokines (AIR Study) Arterioscler Thromb Vasc Biol 2002;22:1162-1167.[Abstract/Free Full Text]
15. Kopprasch S, Pietzsch J, Kuhlisch E, et al. In vivo evidence for increased oxidation of circulating LDL in impaired glucose tolerance Diabetes 2002;51:3102-3106.[Abstract/Free Full Text]
16. Sigurdardottir V, Fagerberg B, Hulthe J. Circulating oxidized low-density lipoprotein (LDL) is associated with risk factors of the metabolic syndrome and LDL size in clinically healthy 58-year-old men (AIR study) J Intern Med 2002;252:440-447.[CrossRef][ISI][Medline]
17. Weinbrenner T, Cladellas M, Covas M-I, et al. High oxidative stress in patients with stable coronary heart disease Atherosclerosis 2003;168:99-106.[CrossRef][ISI][Medline]
18. Holvoet P, Van Cleemput J, Collen D, Vanhaecke J. Oxidized low density lipoprotein is a prognostic marker of transplant-associated coronary artery disease Arterioscler Thromb Vasc Biol 2000;20:698-702.[Abstract/Free Full Text]
19. Nordin Fredrikson G, Hedblad B, Berglund G, Nilsson J. Plasma oxidized LDLa predictor for acute myocardial infarction?. J Intern Med 2003;253:425-429.[CrossRef][ISI][Medline]
20. Wallenfeldt K, Fagerberg B, Wikstrand J, Hulthe J. Oxidized low-density lipoprotein in plasma is a prognostic marker of subclinical atherosclerosis development in clinically healthy men J Intern Med 2004;256:413-420.[CrossRef][ISI][Medline]
21. Meisinger C, Baumert J, Khuseyinova N, Loewel H, Koenig W. Plasma oxidized low-density lipoprotein, a strong predictor for acute coronary heart disease events in apparently healthy, middle-aged men from the general population Circulation 2005;112:651-657.[Abstract/Free Full Text]
22. Walldius G, Jungner I, Holme I, Aastveit AH, Kolar W, Steiner E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study)a prospective study. Lancet 2001;358:2026-2033.[CrossRef][ISI][Medline]
23. Pischon T, Girman CJ, Sacks FM, Rifai N, Stampfer MJ, Rimm EB. Non-high-density lipoprotein cholesterol and apolipoprotein B in the prediction of coronary heart disease in men Circulation 2005;112:3375-3383.[Abstract/Free Full Text]
24. Ridker PM, Rifai N, Cook NR, Bradwin G, Buring JE. Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women JAMA 2005;294:326-333.[Abstract/Free Full Text]
25. Shai I, Rimm EB, Hankinson SE, et al. Multivariate assessment of lipid parameters as predictors of coronary heart disease among postmenopausal womenpotential implications for clinical guidelines. Circulation 2004;110:2824-2830.[Abstract/Free Full Text]
26. Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB. Plasma adiponectin levels and risk of myocardial infarction in men JAMA 2004;291:1730-1737.[Abstract/Free Full Text]
27. Pai JK, Pischon T, Ma J, et al. Inflammatory markers and the risk of coronary heart disease in men and women N Engl J Med 2004;351:2599-2610.[Abstract/Free Full Text]
28. Feskanich D, Rimm EB, Giovannucci EL, et al. Reproducibility and validity of food intake measurements from a semiquantitative food frequency questionnaire J Am Diet Assoc 1993;93:790-796.[CrossRef][ISI][Medline]
29. Willett W. Nutritional EpidemiologyNew York, NY: Oxford University Press; 1998.
30. Willett WC, Sampson L, Stampfer MJ, et al. Reproducibility and validity of a semiquantitative food frequency questionnaire Am J Epidemiol 1985;122:51-65.[Abstract/Free Full Text]
31. 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.[Medline]
32. Wolf AM, Hunter DJ, Colditz GA, et al. Reproducibility and validity of a self-administered physical activity questionnaire Int J Epidemiol 1994;23:991-999.[Abstract/Free Full Text]
33. Pai JK, Curhan GC, Cannuscio CC, Rifai N, Ridker PM, Rimm EB. Stability of novel plasma markers associated with cardiovascular diseaseprocessing within 36 hours of specimen collection. Clin Chem 2002;48:1781-1784.[Free Full Text]
34. Takkouche B, Cadarso-Suarez C, Spiegelman D. Evaluation of old and new tests of heterogeneity in epidemiologic meta-analysis Am J Epidemiol 1999;150:206-215.[Abstract/Free Full Text]
35. Cushing SD, Berliner JA, Valente AJ, et al. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells Proc Natl Acad Sci U S A 1990;87:5134-5138.[Abstract/Free Full Text]
36. Li D, Liu L, Chen H, Sawamura T, Mehta JL. LOX-1, an oxidized LDL endothelial receptor, induces CD40/CD40L signaling in human coronary artery endothelial cells Arterioscler Thromb Vasc Biol 2003;23:816-821.[Abstract/Free Full Text]
37. Ross R. Cell biology of atherosclerosis Annu Rev Physiol 1995;57:791-804.[CrossRef][ISI][Medline]
38. Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease N Engl J Med 2004;350:1387-1397.[Abstract/Free Full Text]
39. Itabe H, Yamamoto H, Suzuki M, et al. Oxidized phosphatidylcholines that modify proteins. Analysis by monoclonal antibody against oxidized low density lipoprotein J Biol Chem 1996;271:33208-33217.[Abstract/Free Full Text]
40. Tsimikas S, Witztum JL, Miller ER, et al. High-dose atorvastatin reduces total plasma levels of oxidized phospholipids and immune complexes present on apolipoprotein B-100 in patients with acute coronary syndromes in the MIRACL trial Circulation 2004;110:1406-1412.[Abstract/Free Full Text]
41. Tsimikas S, Brilakis ES, Miller ER, et al. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease N Engl J Med 2005;353:46-57.[Abstract/Free Full Text]
42. Toshima S, Hasegawa A, Kurabayashi M, et al. Circulating oxidized low density lipoprotein levels. A biochemical risk marker for coronary heart disease Arterioscler Thromb Vasc Biol 2000;20:2243-2247.[Abstract/Free Full Text]

This article has been cited by other articles:

				B. Ky, A. Burke, S. Tsimikas, M. L. Wolfe, M. G. Tadesse, P. O. Szapary, J. L. Witztum, G. A. FitzGerald, and D. J. Rader The Influence of Pravastatin and Atorvastatin on Markers of Oxidative Stress in Hypercholesterolemic Humans J. Am. Coll. Cardiol., April 29, 2008; 51(17): 1653 - 1662. [Abstract] [Full Text] [PDF]

				P. Castilla, A. Davalos, J. L. Teruel, F. Cerrato, M. Fernandez-Lucas, J. L. Merino, C. C. Sanchez-Martin, J. Ortuno, and M. A Lasuncion Comparative effects of dietary supplementation with red grape juice and vitamin E on production of superoxide by circulating neutrophil NADPH oxidase in hemodialysis patients Am. J. Clinical Nutrition, April 1, 2008; 87(4): 1053 - 1061. [Abstract] [Full Text] [PDF]

				T. Wu, N. Rifai, W. C. Willett, and E. B. Rimm Plasma Fluorescent Oxidation Products: Independent Predictors of Coronary Heart Disease in Men Am. J. Epidemiol., September 1, 2007; 166(5): 544 - 551. [Abstract] [Full Text] [PDF]

				R. K. Schindhelm, M. Alssema, P. G. Scheffer, M. Diamant, J. M. Dekker, R. Barto, G. Nijpels, P. J. Kostense, R. J. Heine, C. G. Schalkwijk, et al. Fasting and Postprandial Glycoxidative and Lipoxidative Stress Are Increased in Women With Type 2 Diabetes Diabetes Care, July 1, 2007; 30(7): 1789 - 1794. [Abstract] [Full Text] [PDF]

				J. L. Mehta Oxidized or Native Low-Density Lipoprotein Cholesterol: Which Is More Important in Atherogenesis? J. Am. Coll. Cardiol., September 5, 2006; 48(5): 980 - 982. [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: j.jacc.2006.03.057v1 48/5/973    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Wu, T. Articles by Rimm, E. B. Search for Related Content PubMed PubMed Citation Articles by Wu, T. Articles by Rimm, E. B.