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Originally published In Press as doi:10.1194/jlr.M600361-JLR200 on November 8, 2006

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Journal of Lipid Research, Vol. 48, 425-433, February 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Relationship of IgG and IgM autoantibodies to oxidized low density lipoprotein with coronary artery disease and cardiovascular events

Sotirios Tsimikas1,*, Emmanouil S. Brilakis{dagger}, Ryan J. Lennon§, Elizabeth R. Miller**, Joseph L. Witztum**, Joseph P. McConnell{dagger}{dagger}, Kenneth S. Kornman§§ and Peter B. Berger***

* Division of Cardiovascular Diseases, University of California, San Diego, CA
** Division of Endocrinology and Metabolism, University of California, San Diego, CA
{dagger} University of Texas Southwestern Medical Center and North Texas Veterans Affairs Medical Center, Dallas, TX
§ Division of Cardiovascular Diseases and Biostatistics, Mayo Clinic, Rochester, MN
{dagger}{dagger} Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
§§ Interleukin Genetics, Waltham, MA
*** Division of Cardiovascular Medicine, Geisinger Center for Health Research, Danville, PA

Published, JLR Papers in Press, November 8, 2006.

1 To whom correspondence should be addressed. e-mail: stsimikas{at}ucsd.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The relationship between autoantibodies to oxidized low density lipoprotein (OxLDL) and coronary artery disease (CAD) remains controversial. IgM and IgG OxLDL autoantibodies to malondialdehyde (MDA)-modified LDL, copper oxidized low density lipoprotein (CuOxLDL), and oxidized cholesterol linoleate (OxCL), as well as apolipoprotein B-100 immune complexes (apoB-ICs), were measured in 504 patients undergoing clinically indicated coronary angiography. Patients were followed for cardiovascular events for a median of 4 years. In univariate analysis, IgM OxLDL autoantibodies and IgM apoB-ICs were inversely associated with the presence of angiographically determined CAD, whereas IgG OxLDL autoantibodies and IgG apoB-ICs were positively associated. In logistic regression analysis, compared with the first quartile, patients in the fourth quartile of IgM OxLDL autoantibodies and apoB-ICs showed a lower probability of angiographically determined CAD (>50% diameter stenosis). Odds ratios and (95% confidence intervals) were as follows: MDA-LDL, 0.51 (0.32–0.82; P = 0.005); CuOxLDL, 0.63 (0.39–1.01; P = 0.05); OxCL, 0.63 (0.39–1.01; P = 0.05); and apoB-IC, 0.55 (0.34–0.88; P = 0.013). These relationships were accentuated in the setting of hypercholesterolemia, with the highest IgM levels showing the lowest risk of CAD for the same level of hypercholesterolemia. Multivariable analysis revealed that neither IgM or IgG OxLDL autoantibodies nor apoB-ICs were independently associated with angiographically determined CAD or cardiovascular events. In conclusion, IgG and IgM OxLDL biomarkers have divergent associations with CAD in univariate analysis but are not independent predictors of CAD or clinical events.

Supplementary key words angiography • atherosclerosis • antibodies • lipoproteins • oxidation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Oxidative modification of LDL is postulated to be one of the earliest events in the initiation of atherogenesis (1, 2). Oxidized low density lipoprotein (OxLDL) is present in aortas of human fetuses of hypercholesterolemic mothers (3) even before macrophage foam cell formation, in progressing atherosclerotic lesions of animal models (4), and within human vulnerable plaques (5, 6). Conceptually, OxLDL is not a single defined chemical entity but represents a variety of modifications of both the lipid and protein components of LDL after the initiation of lipid peroxidation. The resulting oxidized lipid and oxidized lipid-protein adducts are not only proinflammatory (7) but also are recognized as foreign by the immune system and therefore are highly immunogenic (8).

Although autoantibodies to OxLDL epitopes correlate well with atherosclerosis in animal models (9–11), an ongoing controversy exists regarding whether OxLDL autoantibodies are markers of cardiovascular disease and/or have a causative role in either the progression of or protection against the development of atherosclerosis in humans (12). Much of this controversy is fueled by many factors, including measurement of different OxLDL epitopes, underpowered studies and incomplete assessment of different OxLDL autoantibodies, differences among patient cohorts, comparison of different vascular areas, and lack of standardization of antigens and assays. In this large cross-sectional study of 504 patients, we evaluated a comprehensive panel of both IgG and IgM OxLDL autoantibodies to a wide array of OxLDL epitopes, including malondialdehyde (MDA)-LDL, copper oxidized low density lipoprotein (Cu-OxLDL), and oxidized cholesterol linoleate (OxCL), as well as apolipoprotein B-100 immune complexes (apoB-ICs), and their relationship to angiographically determined coronary artery disease (CAD).


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study design
The patient cohort included 504 patients (>97% Caucasian), age 26–75 years, undergoing clinically indicated coronary angiography at the Mayo Clinic from June 1998 to January 1999 and has been described previously (13). The initial study was designed to assess genetic polymorphisms in cardiovascular risk assessment. Therefore, patients with well-established risk factors or risk equivalents, such as diabetes mellitus and smoking history of >50 pack years, as well as prior revascularization procedures, were excluded. This study was approved by the Mayo Clinic Institutional Review Board, and all subjects provided written informed consent. Aliquots of blood in EDTA-containing tubes were collected before coronary angiography and frozen at –70°C until analyses were performed.

Four hundred sixty-six patients (92.5%) were contacted by a follow-up questionnaire or by telephone in September 2002 [median follow-up of 4.0 years (interquartile range, 3.9–4.2 years)]. The remaining 38 patients either refused to participate in the follow-up (n = 18) or could not be contacted (n = 20). The medical records of the patients who had an event were obtained and reviewed to ascertain the type of event or the cause of death. The follow-up events of these patients were described previously (14) and consisted of 20 deaths (6 cardiac), 14 myocardial infarctions, 26 coronary revascularizations (15 percutaneous intervention only, 9 coronary artery bypass surgery only, and 2 with both), and 10 strokes.

Angiographic analysis
Coronary angiograms were analyzed as described previously (13) and divided into those revealing normal coronary arteries [smooth arteries with either no stenosis or with diameter stenosis (DS) <= 10%], mild disease (DS 10–50% in one or more coronary arteries), one-vessel (>=50% DS in a single coronary artery or its major branches), two-vessel, and three-vessel disease.

Laboratory analyses
Total cholesterol, HDL cholesterol (HDL-C), and triglycerides were determined on a COBAS MIRA system. LDL cholesterol (LDL-C) was estimated from the Friedewald formula. High-sensitivity C-reactive protein (hsCRP) was measured as described previously (15). Hypercholesterolemia was defined as total cholesterol >= 250 mg/dl or LDL >= 150 mg/dl, or ongoing treatment with lipid-lowering agents in patients for whom pretreatment lipid values could not be determined. Fibrinogen was measured by an immunoturbidimetric method using reagents from Kamiya Biomedical Co. on a Roche COBAS MIRA chemistry analyzer (absorbance, 700 nm). Lipoprotein-associated lipoprotein lipase A2 mass was measured with a commercial kit (Diadexus, Inc., South San Francisco, CA). Total plasma homocysteine was measured after reduction of the disulfide bonds by high-pressure liquid chromatography.

Determination of OxLDL autoantibody and apoB-IC levels
Chemiluminescence ELISAs were used to measure IgG and IgM autoantibodies to MDA-LDL, Cu-OxLDL, OxCL, and apoB-IC as described previously (16, 17). OxLDL-E06, measuring the oxidized phospholipid content on apoB particles, was measured as described previously (13, 17).

Statistical methods
Continuous variables with symmetric distributions are summarized as means ± SD and are compared by Student's t-test. Those with skewed distributions are summarized as medians and interquartile ranges and compared with the Mann-Whitney rank sum test. Discrete covariates are summarized as frequencies and group percentages and are compared using Pearson's Chi-square test. Spearman's correlation coefficient was used to measure the linear association between the rank values of OxLDL autoantibodies and apoB-IC and clinical and laboratory variables.

The association between OxLDL autoantibodies and CAD was assessed using logistic regression analysis. The laboratory values were collapsed into quartiles and assigned a value from 1 to 4. These values were then used in the logistic regression models. There was no evidence of a nonlinear trend over quartiles in any model. Models with OxLDL autoantibodies and hypercholesterolemia assume additivity between the two variables; there was no evidence of an interaction in any such model. Multiple logistic regression was used to estimate the partial associations between OxLDL autoantibodies and CAD adjusting for age, sex, smoking history, hypertension, LDL-C, HDL-C, log(triglycerides), and log(hsCRP).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Baseline patient characteristics
The baseline clinical characteristics, indications for coronary angiography, and lipid parameters of the study cohort have been described previously (13). For the purposes of this analysis, patients were dichotomized as those with <50% DS or >50% DS, and baseline characteristics are shown in Table 1 . There were 233 patients with nonobstructive CAD (<50% DS) and 271 with obstructive CAD (>50% DS). Of these, 122 patients had angiographically normal coronary arteries, 111 had mild CAD (10–50% DS), and 85, 80, and 106 had one-, two-, and three-vessel CAD, respectively (>=50% DS). As expected, patients with obstructive CAD were more likely to be older and male and had a higher frequency of hypertension and dyslipidemia (Table 1). Indications for angiography reflected typical clinical indications as described previously (13).


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  		TABLE 1. Baseline clinical and laboratory characteristics of patients with no or mild angiographically determined CAD and those with obstructive CAD (>50% DS)

 
Association of OxLDL autoantibody and apoB-IC levels with angiographically determined CAD
OxLDL autoantibodies and apoB-ICs were evaluated according to whether patients had >50% DS versus <50% DS and also as no CAD (angiographically normal arteries) versus any CAD (Table 2 ). In both analyses, IgM autoantibody levels to MDA-LDL, Cu-OxLDL, and OxCL as well as IgM apoB-IC were significantly lower in patients with obstructive versus nonobstructive CAD as well as any CAD versus no CAD (Table 2). In contrast, IgG autoantibody levels to Cu-OxLDL were higher in patients with obstructive versus nonobstructive CAD and any CAD versus no CAD (Table 2). The other IgG measures were not statistically significantly different among groups. Analyzing the data according to the extent of disease (no disease, mild disease, and one-, two-, or three-vessel disease) showed similar results (Table 3 ).


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  		TABLE 2. Association between OxLDL autoantibodies and apoB-IC levels and the presence of CAD

 

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  		TABLE 3. Association between OxLDL autoantibodies and apoB-IC levels and the extent of CAD

 
The association between OxLDL measures and obstructive CAD was also assessed using logistic regression analysis. Compared with the lowest quartile, the highest quartiles of all three types of IgM OxLDL autoantibodies and IgM apoB-ICs were associated with significantly or nearly significantly decreased odds ratio (OR) for obstructive CAD (Table 4 ), ranging in OR from 0.51 to 0.63. In contrast, no such relationships were noted with IgG OxLDL autoantibodies and apoB-ICs, except for a trend for IgG Cu-OxLDL autoantibodies (OR, 1.54; P = 0.07).


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  		TABLE 4. Odds ratios and (95% confidence intervals) for obstructive CAD (>50% DS) according to quartiles of IgM and IgG OxLDL markers

 
Combined effects of OxLDL autoantibodies and apoB-ICs and hypercholesterolemia on obstructive CAD
These relationships were further evaluated by determining ORs for obstructive CAD in patients with and without hypercholesterolemia using the lowest quartiles of OxLDL markers without hypercholesterolemia as the reference point. In the absence of hypercholesterolemia, the OR for obstructive CAD decreased progressively with increasing levels of IgM MDA-LDL autoantibodies and IgM apoB-IC (Fig. 1A ). In the presence of hypercholesterolemia, quartile 1 of all IgM autoantibodies and apoB-ICs had an OR of ~3.3 for CAD, consistent with a strong association between hypercholesterolemia and obstructive CAD. However, the OR decreased progressively with increasing levels of IgM autoantibodies and apoB-ICs. In contrast, the OR for obstructive CAD tended to increase progressively with increasing levels of IgG OxLDL autoantibody and IgG apoB-ICs, particularly Cu-OxLDL (Fig. 1B).


Figure 1
Figure 1
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  		Fig. 1. Odds ratio (OR) for the presence of >50% diameter stenosis (DS) for IgM (A) and IgG (B) autoantibodies to oxidized low density lipoprotein (OxLDL) and apolipoprotein B-100 immune complexes (apoB-ICs) in the presence or absence of hypercholesterolemia. Cu-OxLDL, copper oxidized low density lipoprotein; MDA, malondialdehyde; OxCL, oxidized cholesterol linoleate.

 
Correlation between OxLDL measures and clinical and laboratory variables
In general, IgM autoantibodies and IgM apoB-ICs were modestly inversely correlated with age, serum creatinine, and homocysteine but positively associated with HDL-C (Table 5 ). No correlations were noted between hsCRP and any IgM and IgG OxLDL autoantibodies, except for a weak inverse correlation with OxCL IgG (R = –0.09, P = 0.04). Weak but statistically significant correlations were noted between OxLDL-E06 and IgG MDA-LDL (R = 0.10, P = 0.021), IgG apoB-IC (R = 0.12, P = 0.009), IgM apoB-IC (R = 0.10, P = 0.026), IgG Cu-OxLDL (R = 0.12, P = 0.008), and IgM Cu-OxLDL (R = 0.09, P = 0.041). There were also no statistically significant correlations between any OxLDL autoantibodies and apoB-ICs with total cholesterol, triglycerides, fibrinogen, or lipoprotein-associated lipoprotein lipase A2.


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  		TABLE 5. Spearman correlation rank coefficients between OxLDL autoantibodies and apoB-ICs and clinical and laboratory variables

 
Correlations among OxLDL autoantibodies and apoB-ICs
There were strong correlations among all IgG classes of OxLDL autoantibodies and apoB-ICs as well as among all classes of IgM autoantibodies and IgM apoB-ICs. Less strong correlations were noted between IgG and IgM classes (Table 6 ).


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  		TABLE 6. Spearman rank correlations (above diagonal) and P values (footnotes) among OxLDL autoantibodies and apoB-ICs

 
Multivariable analysis
In multivariable analysis, age, LDL-C, smoking history, and hypertension were independent predictors of obstructive CAD, whereas female gender and HDL-C were independently associated with reduced risk of obstructive CAD (Fig. 2 ). There was no significant association between OxLDL measures and cardiovascular events in patients <60 or >60 years old. None of the IgG or IgM OxLDL measures or hsCRP was an independent predictor of obstructive CAD. There was no significant relationship between the OxLDL autoantibodies or apoB-IC variables and follow-up events after adjustment for covariates. Table 7 shows the event rates at years 1, 2, and 3 for each OxLDL variable above and below its respective median value and documents no independent association of these markers at each time point. In addition, there was no association based on whether patients were categorized as none/mild CAD versus obstructive CAD (>50% DS).


Figure 2
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  		Fig. 2. Multivariable analysis depicting cardiovascular risk factors and OxLDL markers and the OR for the presence of >50% DS. HDL-C, HDL cholesterol; LDL-C, LDL cholesterol; OCL, OxCL.

 

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  		TABLE 7. Association between OxLDL autoantibodies and apoB-IC levels (above or below the median value) and the combined events of death, myocardial infarction, and stroke during the follow-up period

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study assessed the relationship between both IgG and IgM OxLDL markers and angiographically determined CAD. In univariate analysis, a positive relationship of angiographically determined CAD with IgG Cu-OxLDL was present, whereas an inverse relationship existed between IgM OxLDL autoantibodies and IgM apoB-ICs, with ~40–50% reduction in the probability of the presence of >50% DS. However, in multivariable analysis taking into account other traditional risk factors, these OxLDL measures were no longer independent predictors of the presence of CAD or future cardiovascular events. This study provides a mechanistic framework to understand the disparate findings of previous studies by showing in a large population with robust statistical analysis that these OxLDL markers are univariate predictors of cardiovascular disease but, when viewed in the broad context of additional risk factors, likely play a secondary role rather than directly influencing CAD.

In contrast to the current study, we have shown from the same data set that circulating OxLDL-E06 levels, reflecting minimally oxidized LDL in the circulation, as opposed to OxLDL autoantibodies and apoB-ICs, which are indirect OxLDL markers, strongly and independently predicted the presence of angiographically determined CAD (13). This is consistent with a prior study showing that IgG and IgM autoantibodies to OxLDL were univariate but not independent predictors of carotid intima-media thickness (18), as opposed to OxLDL itself, which was an independent predictor (19). This suggests that direct OxLDL measures, such as circulating OxLDL (20), are more potent predictors of CAD than are indirect measures, such as OxLDL autoantibodies and immune complexes.

There are relatively few studies prospectively evaluating the prognostic value of autoantibodies to OxLDL and apoB-ICs and CAD. In this study, baseline OxLDL autoantibodies and apoB-ICs did not predict follow-up events, which occurred in 70 of 504 subjects followed over a median 4 year period. Previous studies evaluating clinical events suggested that IgG autoantibodies predicted the risk of future myocardial infarction (21). However, this has not been supported by all studies (12, 22). Our group showed previously that increased baseline levels of IgM apoB-ICs predicted a reduced risk of recurrent cardiovascular events over 4 months in patients with acute coronary syndromes in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Study (17). The current data are also consistent with a previous clinical but not angiographic study showing that baseline IgM OxLDL autoantibody titers and IgM apoB-ICs were lowest in patients with acute myocardial infarction and unstable angina compared with normal subjects (16).

This is the first study to evaluate IgM OxLDL autoantibodies and immune complexes in angiographically determined CAD. Previous studies had suggested that IgM autoantibody titers to OxLDL are inversely associated with noncoronary atherosclerosis, noted primarily in Finnish patients (23). For example, Karvonen et al. (23) showed in a population-based cohort of 1,022 subjects that IgM MDA-LDL autoantibodies were independently inversely predictive of mean carotid intima-media thickness, although statistical significance was not reached in all parts of the carotid artery. That study also showed that IgG OxLDL autoantibodies were not independent predictors of carotid intima-media thickness. In a recent study from the Bruneck population, we confirmed that IgG OxLDL autoantibody titers and apoB-ICs were positively associated with carotid atherosclerosis, whereas IgM autoantibody titers and apoB-ICs were inversely related, but in univariate but not multivariate analysis (24). In that study, there was also a positive relationship of IgG OxLDL markers with age and male gender, whereas an inverse association was noted with IgM OxLDL markers. In a smaller study of 389 asymptomatic middle-aged males, IgM Cu-OxLDL autoantibody titers were borderline (P = 0.05) inversely associated with femoral intima-media thickness, but neither IgG nor IgM MDA-LDL autoantibody titers were associated with either carotid or femoral intima-media thickness (18). As in the current study, these relationships were no longer present after adjusting for traditional risk factors.

In this study, IgG Cu-OxLDL autoantibodies and apoB-IC levels were higher in patients with angiographically determined CAD but did not modulate atherogenesis or independently predict the presence of CAD. Although most studies have shown a positive association of IgG OxLDL autoantibodies with CAD, particularly smaller angiographic studies (25–27), others have shown no association (28–31). Several studies have also shown that IgG OxLDL autoantibodies are increased at baseline in patients with acute myocardial infarction (16, 32). In addition, we have also shown that circulating OxLDL, as well as both IgG and IgM autoantibodies to OxLDL, have a characteristic rise-and-fall pattern after myocardial infarction (16), which may be a confounding factor in some studies if the levels were not determined at the earliest time point possible. In addition, differences in antigen preparation and assay procedures, as well as inadequate sample size, may partially explain some of the findings (33). In this study, however, we performed a rigorous multivariable analysis with a large sample size, and the evidence suggests that IgG OxLDL autoantibodies do not predict angiographically determined CAD.

Why are IgM autoantibody titers lower in patients with manifestations of subclinical and symptomatic atherosclerosis and higher in patients without manifestations of atherosclerosis? One possibility is that in patients with risk factors for or with established CAD, there is increased consumption of IgM autoantibodies and ultimate clearance and/or uptake in the vessel wall. This is supported by data showing the presence of autoantibodies in the vessel wall (34) and by a previous study in our laboratory in which it was shown that in patients undergoing percutaneous coronary intervention, there was an acute decrease immediately after the procedure in both IgG and IgM OxLDL autoantibodies, with a simultaneous acute increase in apoB-ICs as well as increased OxLDL-E06 levels (35). It is possible that a similar situation occurs more slowly over time in patients with progressing atherosclerosis. Alternatively, there may be genetically determined differences in basal natural IgM autoantibody levels, and subjects with high levels of atheroprotective IgM autoantibodies may have less disease. Further research is required to understand why differences in basal levels of IgG and IgM autoantibodies to OxLDL exist and whether augmenting such titers above physiological levels may provide atheroprotection. For example, several groups have shown that immunization of rabbits and mice with autologous OxLDL or MDA-LDL provides atheroprotective effects (36–40). In addition, Binder et al. (41) subsequently showed that immunization of mice with Streptococcus pneumoniae results in a robust and predominant T15/E06 IgM autoantibody response and protection against atherosclerosis progression.

In conclusion, we have shown that OxLDL autoantibodies are not independent predictors of the presence of angiographically determined CAD or cardiovascular events. These findings need to be confirmed in studies with larger numbers of cardiovascular events measuring both IgG and IgM autoantibodies. Further studies are being carried out in several laboratories to assess whether passive immunization with antibodies to OxLDL may lead to reduced atherosclerosis (12).


   ACKNOWLEDGMENTS
 
This study was supported by Grant HL-56989 from the La Jolla Specialized Center of Research in Molecular Medicine and Atherosclerosis, the Donald W. Reynolds Foundation, and the Mayo Foundation.

Manuscript received August 14, 2006 and in revised form November 1, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
  1. Tsimikas, S., C. Glass, D. Steinberg, and J. L. Witztum. 2004. Lipoproteins, lipoprotein oxidation and atherogenesis. In Molecular Basis of Cardiovascular Disease. A Companion to Braunwald's Heart Disease. K. R. Chien, editor. W. B. Saunders Company, Philadelphia, PA. 385–413.

  2. Navab, M., G. M. Ananthramaiah, S. T. Reddy, B. J. Van Lenten, B. J. Ansell, G. C. Fonarow, K. Vahabzadeh, S. Hama, G. Hough, N. Kamranpour, et al. 2004. Thematic review series. The pathogenesis of atherosclerosis. The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL. J. Lipid Res. 45: 993–1007.[Abstract/Free Full Text]

  3. Palinski, W., and C. Napoli. 2002. The fetal origins of atherosclerosis: maternal hypercholesterolemia and cholesterol-lowering or antioxidant treatment during pregnancy influence in utero programming and postnatal susceptibility to atherogenesis. FASEB J. 16: 1348–1360.[Abstract/Free Full Text]

  4. Torzewski, M., P. X. Shaw, K. R. Han, B. Shortal, K. J. Lackner, J. L. Witztum, W. Palinski, and S. Tsimikas. 2004. Reduced in vivo aortic uptake of radiolabeled oxidation-specific antibodies reflects changes in plaque composition consistent with plaque stabilization. Arterioscler. Thromb. Vasc. Biol. 24: 2307–2312.[Abstract/Free Full Text]

  5. Ehara, S., M. Ueda, T. Naruko, K. Haze, A. Itoh, M. Otsuka, R. Komatsu, T. Matsuo, H. Itabe, T. Takano, et al. 2001. Elevated levels of oxidized low density lipoprotein show a positive relationship with the severity of acute coronary syndromes. Circulation. 103: 1955–1960.[Abstract/Free Full Text]

  6. Nishi, K., H. Itabe, M. Uno, K. T. Kitazato, H. Horiguchi, K. Shinno, and S. Nagahiro. 2002. Oxidized LDL in carotid plaques and plasma associates with plaque instability. Arterioscler. Thromb. Vasc. Biol. 22: 1649–1654.[Abstract/Free Full Text]

  7. Berliner, J. A., G. Subbanagounder, N. Leitinger, A. D. Watson, and D. Vora. 2001. Evidence for a role of phospholipid oxidation products in atherogenesis. Trends Cardiovasc. Med. 11: 142–147.[CrossRef][Medline]

  8. Binder, C. J., P. X. Shaw, M. K. Chang, A. Boullier, K. Hartvigsen, S. Horkko, Y. I. Miller, D. A. Woelkers, M. Corr, and J. L. Witztum. 2005. The role of natural antibodies in atherogenesis. J. Lipid Res. 46: 1353–1363.[Abstract/Free Full Text]

  9. Palinski, W., R. K. Tangirala, E. Miller, S. G. Young, and J. L. Witztum. 1995. Increased autoantibody titers against epitopes of oxidized LDL in LDL receptor-deficient mice with increased atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 15: 1569–1576.[Abstract/Free Full Text]

  10. Tsimikas, S., W. Palinski, and J. L. Witztum. 2001. Circulating autoantibodies to oxidized LDL correlate with arterial accumulation and depletion of oxidized LDL in LDL receptor-deficient mice. Arterioscler. Thromb. Vasc. Biol. 21: 95–100.[Abstract/Free Full Text]

  11. Cyrus, T., D. Praticó, L. Zhao, J. L. Witztum, D. J. Rader, J. Rokach, G. A. FitzGerald, and C. D. Funk. 2001. Absence of 12/15-lipoxygenase expression decreases lipid peroxidation and atherogenesis in apolipoprotein E-deficient mice. Circulation. 103: 2277–2282.[Abstract/Free Full Text]

  12. Shoenfeld, Y., R. Wu, L. D. Dearing, and E. Matsuura. 2004. Are anti-oxidized low-density lipoprotein antibodies pathogenic or protective? Circulation. 110: 2552–2558.[Free Full Text]

  13. Tsimikas, S., E. S. Brilakis, E. R. Miller, J. P. McConnell, R. J. Lennon, K. S. Kornman, J. L. Witztum, and P. B. Berger. 2005. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N. Engl. J. Med. 353: 46–57.[Abstract/Free Full Text]

  14. Brilakis, E. S., J. P. McConnell, R. J. Lennon, A. A. Elesber, J. G. Meyer, and P. B. Berger. 2005. Association of lipoprotein-associated phospholipase A2 levels with coronary artery disease risk factors, angiographic coronary artery disease, and major adverse events at follow-up. Eur. Heart J. 26: 137–144.[Abstract/Free Full Text]

  15. McConnell, J. P., E. L. Branum, K. V. Ballman, S. A. Lagerstedt, J. A. Katzmann, and A. S. Jaffe. 2002. Gender differences in C-reactive protein concentrations—confirmation with two sensitive methods. Clin. Chem. Lab. Med. 40: 56–59.[CrossRef][Medline]

  16. Tsimikas, S., C. Bergmark, R. W. Beyer, R. Patel, J. Pattison, E. Miller, J. Juliano, and J. L. Witztum. 2003. Temporal increases in plasma markers of oxidized low-density lipoprotein strongly reflect the presence of acute coronary syndromes. J. Am. Coll. Cardiol. 41: 360–370.[Abstract/Free Full Text]

  17. Tsimikas, S., J. L. Witztum, E. R. Miller, W. J. Sasiela, M. Szarek, A. G. Olsson, and G. G. Schwartz. 2004. 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. 110: 1406–1412.[Abstract/Free Full Text]

  18. Hulthe, J., L. Bokemark, and B. Fagerberg. 2001. Antibodies to oxidized LDL in relation to intima-media thickness in carotid and femoral arteries in 58-year-old subjectively clinically healthy men. Arterioscler. Thromb. Vasc. Biol. 21: 101–107.[Abstract/Free Full Text]

  19. Hulthe, J., and B. Fagerberg. 2002. Circulating oxidized LDL is associated with subclinical atherosclerosis development and inflammatory cytokines (AIR Study). Arterioscler. Thromb. Vasc. Biol. 22: 1162–1167.[Abstract/Free Full Text]

  20. Tsimikas, S. 2006. Oxidized low-density lipoprotein biomarkers in atherosclerosis. Curr. Atheroscler. Rep. 8: 55–61.[Medline]

  21. Puurunen, M., M. Manttari, V. Manninen, L. Tenkanen, G. Alfthan, C. Ehnholm, O. Vaarala, K. Aho, and T. Palosuo. 1994. Antibody against oxidized low-density lipoprotein predicting myocardial infarction. Arch. Intern. Med. 154: 2605–2609.[Abstract/Free Full Text]

  22. Erkkila, A. T., O. Narvanen, S. Lehto, J. Uusitupa, and S. Yla-Herttuala. 2005. Antibodies against oxidized LDL and cardiolipin and mortality in patients with coronary heart disease. Atherosclerosis. 183: 157–162.[CrossRef][Medline]

  23. Karvonen, J., M. Paivansalo, Y. A. Kesaniemi, and S. Hörkkö. 2003. Immunoglobulin M type of autoantibodies to oxidized low-density lipoprotein has an inverse relation to carotid artery atherosclerosis. Circulation. 108: 2107–2112.[Abstract/Free Full Text]

  24. Mayr, M., S. Kiechl, S. Tsimikas, E. Miller, J. Sheldon, J. Willeit, J. L. Witztum, and Q. Xu. 2006. Oxidized low-density lipoprotein autoantibodies, chronic infections, and carotid atherosclerosis in a population-based study. J. Am. Coll. Cardiol. 47: 2436–2443.[Abstract/Free Full Text]

  25. Bui, M. N., M. N. Sack, G. Moutsatsos, D. Y. Lu, P. Katz, R. McCown, J. A. Breall, and C. E. Rackley. 1996. Autoantibody titers to oxidized low-density lipoprotein in patients with coronary atherosclerosis. Am. Heart J. 131: 663–667.[CrossRef][Medline]

  26. Inoue, T., T. Uchida, H. Kamishirado, K. Takayanagi, T. Hayashi, and S. Morooka. 2001. Clinical significance of antibody against oxidized low density lipoprotein in patients with atherosclerotic coronary artery disease. J. Am. Coll. Cardiol. 37: 775–779.[Abstract/Free Full Text]

  27. Lehtimaki, T., S. Lehtinen, T. Solakivi, M. Nikkila, O. Jaakkola, H. Jokela, S. Yla-Herttuala, J. S. Luoma, T. Koivula, and T. Nikkari. 1999. Autoantibodies against oxidized low density lipoprotein in patients with angiographically verified coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 19: 23–27.[Abstract/Free Full Text]

  28. Boullier, A., M. Hamon, E. Walters-Laporte, F. Martin-Nizart, R. Mackereel, J. C. Fruchart, M. Bertrand, and P. Duriez. 1995. Detection of autoantibodies against oxidized low-density lipoproteins and of IgG-bound low density lipoproteins in patients with coronary artery disease. Clin. Chim. Acta. 238: 1–10.[CrossRef][Medline]

  29. Uusitupa, M. I., L. Niskanen, J. Luoma, P. Vilja, M. Mercuri, R. Rauramaa, and S. Yla-Herttuala. 1996. Autoantibodies against oxidized LDL do not predict atherosclerotic vascular disease in non-insulin-dependent diabetes mellitus. Arterioscler. Thromb. Vasc. Biol. 16: 1236–1242.[Abstract/Free Full Text]

  30. van de Vijver, L. P. L., R. Steyger, G. van Poppel, J. M. A. Boer, D. A. C. M. Kruijssen, J. C. Seidell, and H. M. G. Princen. 1996. Autoantibodies against MDA-LDL in subjects with severe and minor atherosclerosis and healthy population controls. Atherosclerosis. 122: 245–253.[CrossRef][Medline]

  31. Rossi, G. P., M. Cesari, R. De Toni, M. Zanchetta, G. Maiolino, L. Pedon, C. Ganzaroli, P. Maiolino, and A. C. Pessina. 2003. Antibodies to oxidized low-density lipoproteins and angiographically assessed coronary artery disease in white patients. Circulation. 108: 2467–2472.[Abstract/Free Full Text]

  32. Erkkila, A. T., O. Narvanen, S. Lehto, M. I. Uusitupa, and S. Ylä-Herttuala. 2000. Autoantibodies against oxidized low-density lipoprotein and cardiolipin in patients with coronary heart disease. Arterioscler. Thromb. Vasc. Biol. 20: 204–209.[Abstract/Free Full Text]

  33. Tsimikas, S., and J. L. Witztum. 2001. Measuring circulating oxidized low-density lipoprotein to evaluate coronary risk. Circulation. 103: 1930–1932.[Free Full Text]

  34. Ylä-Herttuala, S., W. Palinski, S. W. Butler, S. Picard, D. Steinberg, and J. L. Witztum. 1994. Rabbit and human atherosclerotic lesions contain IgG that recognizes epitopes of oxidized LDL. Arterioscler. Thromb. 14: 32–40.[Abstract/Free Full Text]

  35. Tsimikas, S., H. K. Lau, K. R. Han, B. Shortal, E. R. Miller, A. Segev, L. K. Curtiss, J. L. Witztum, and B. H. Strauss. 2004. Percutaneous coronary intervention results in acute increases in oxidized phospholipids and lipoprotein(a): short-term and long-term immunologic responses to oxidized low-density lipoprotein. Circulation. 109: 3164–3170.[Abstract/Free Full Text]

  36. Freigang, S., S. Hörkkö, E. Miller, J. L. Witztum, and W. Palinski. 1998. Immunization of LDL receptor-deficient mice with homologous malondialdehyde-modified and native LDL reduces progression of atherosclerosis by mechanisms other than induction of high titers of antibodies to oxidative neoepitopes. Arterioscler. Thromb. Vasc. Biol. 18: 1972–1982.[Abstract/Free Full Text]

  37. Nilsson, J., F. Calara, J. Regnstrom, A. Hultgardh-Nilsson, S. Ameli, B. Cercek, and P. K. Shah. 1997. Immunization with homologous oxidized low density lipoprotein reduces neointimal formation after balloon injury in hypercholesterolemic rabbits. J. Am. Coll. Cardiol. 30: 1886–1891.[Abstract]

  38. Palinski, W., E. Miller, and J. L. Witztum. 1995. Immunization of LDL receptor-deficient rabbits with homologous malondialdehyde-modified LDL reduces atherogenesis. Proc. Natl. Acad. Sci. USA. 92: 821–825.[Abstract/Free Full Text]

  39. Zhou, X., G. Caligiuri, A. Hamsten, A. K. Lefvert, and G. K. Hansson. 2001. LDL immunization induces T-cell-dependent antibody formation and protection against atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 21: 108–114.[Abstract/Free Full Text]

  40. Shoenfeld, Y., D. Harats, and J. George. 2000. Heat shock protein 60/65, beta 2-glycoprotein I and oxidized LDL as players in murine atherosclerosis. J. Autoimmun. 15: 199–202.[CrossRef][Medline]

  41. Binder, C. J., S. Horkko, A. Dewan, M. K. Chang, E. P. Kieu, C. S. Goodyear, P. X. Shaw, W. Palinski, J. L. Witztum, and G. J. Silverman. 2003. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat. Med. 9: 736–743.[CrossRef][Medline]


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