Oxidized Phospholipids, Lp(a) Lipoprotein, and Coronary Artery Disease
Sotirios Tsimikas, M.D., Emmanouil S. Brilakis, M.D., Elizabeth R. Miller, B.S., Joseph P. McConnell, Ph.D., Ryan J. Lennon, M.S., Kenneth S. Kornman, Ph.D., Joseph L. Witztum, M.D., and Peter B. Berger, M.D.
Background Lp(a) lipoprotein binds proinflammatory oxidizedphospholipids. We investigated whether levels of oxidized low-densitylipoprotein (LDL) measured with use of monoclonal antibody E06reflect the presence and extent of obstructive coronary arterydisease, defined as a stenosis of more than 50 percent of theluminal diameter.
Methods Levels of oxidized LDL and Lp(a) lipoprotein were measuredin a total of 504 patients immediately before coronary angiography.Levels of oxidized LDL are reported as the oxidized phospholipidcontent per particle of apolipoprotein B-100 (oxidized phospholipid:apoB-100 ratio).
Results Measurements of the oxidized phospholipid:apo B-100ratio and Lp(a) lipoprotein levels were skewed toward lowervalues, and the values for the oxidized phospholipid:apo B-100ratio correlated strongly with those for Lp(a) lipoprotein (r=0.83,P<0.001). In the entire cohort, the oxidized phospholipid:apoB-100 ratio and Lp(a) lipoprotein levels showed a strong andgraded association with the presence and extent of coronaryartery disease (i.e., the number of vessels with a stenosisof more than 50 percent of the luminal diameter) (P<0.001).Among patients 60 years of age or younger, those in the highestquartiles for the oxidized phospholipid:apo B-100 ratio andLp(a) lipoprotein levels had odds ratios for coronary arterydisease of 3.12 (P<0.001) and 3.64 (P<0.001), respectively,as compared with patients in the lowest quartile. The combinedeffect of hypercholesterolemia and being in the highest quartilesof the oxidized phospholipid:apo B-100 ratio (odds ratio, 16.8;P<0.001) and Lp(a) lipoprotein levels (odds ratio, 14.2;P<0.001) significantly increased the probability of coronaryartery disease among patients 60 years of age or younger. Inthe entire study group, the association of the oxidized phospholipid:apoB-100 ratio with obstructive coronary artery disease was independentof all clinical and lipid measures except one, Lp(a) lipoprotein.However, among patients 60 years of age or younger, the oxidizedphospholipid:apo B-100 ratio remained an independent predictorof coronary artery disease.
Conclusions Circulating levels of oxidized LDL are stronglyassociated with angiographically documented coronary arterydisease, particularly in patients 60 years of age or younger.These data suggest that the atherogenicity of Lp(a) lipoproteinmay be mediated in part by associated proinflammatory oxidizedphospholipids.
Human coronary atherosclerosis is a chronic inflammatory diseasethat is superimposed on a background of lipid abnormalities.Proinflammatory oxidized low-density lipoprotein (LDL) may bea unifying link between lipid accumulation and inflammationin the vessel wall. In humans, oxidized LDL in plasma and withinatherosclerotic lesions is strongly associated with coronaryartery disease, acute coronary syndromes, and vulnerable plaques.1,2,3,4,5,6,7
Lp(a) lipoprotein is a lipoprotein of unknown physiologic functionthat is composed of apolipoprotein B-100 (apo B-100) to whichapolipoprotein(a) is covalently bound. Increased plasma levelsof Lp(a) lipoprotein are independent predictors of the presenceof angiographically documented and clinical coronary arterydisease, particularly in patients with hypercholesterolemia.8However, the underlying mechanisms by which Lp(a) lipoproteincontributes to the pathogenesis of atherosclerosis are not wellunderstood. We recently showed that proinflammatory oxidizedphospholipids are strongly associated with Lp(a) lipoproteinin human plasma.5,6,7,9 Therefore, we hypothesized that thepresence of oxidized phospholipids on apo B-100–containinglipoproteins may explain some of the atherogenic propertiesof Lp(a) lipoprotein, and we designed this study to evaluatethe relationship between circulating oxidized LDL, Lp(a) lipoprotein,and angiographically documented coronary artery disease.
Methods
Study Design
We designed the current study on the basis of a previous studyin which we had enrolled a total of 504 consecutive patients(97.2 percent of whom were white), 18 to 75 years of age, whowere undergoing clinically indicated coronary angiography atthe Mayo Clinic between June 1998 and December 1998.10 Racewas self-reported. The exclusion criteria, which have been describedpreviously, included prior coronary revascularization and thepresence of diabetes mellitus.10 Arterial plasma samples wereobtained from the femoral sheath before angiography and wereplaced in tubes containing EDTA and frozen at –70°Cuntil the analyses were performed. Hypercholesterolemia wasdefined as a total cholesterol level of at least 250 mg perdeciliter (6.5 mmol per liter), an LDL level of at least 150mg per deciliter (3.9 mmol per liter), or ongoing treatmentwith lipid-lowering agents. The study was approved by the MayoClinic institutional review board, and all patients gave writteninformed consent.
Angiographic Analysis
The maximal stenosis in each of 27 coronary-artery segmentswas assessed by a cardiologist, who was unaware of risk factors,with the use of handheld calipers or in visual analysis accordingto the segmental classification system of the Coronary ArterySurgery Study. The extent of angiographically documented coronaryartery disease was quantified as follows: normal coronary arteries(smooth, with either no stenosis or a stenosis of <10 percentof the luminal diameter), mild disease (a stenosis of 10 to50 percent of the luminal diameter in one or more coronary arteriesor their major branches), or one-vessel, two-vessel, or three-vesseldisease, defined as a stenosis of more than 50 percent of theluminal diameter in one, two, or three coronary arteries ortheir major branches.10
Laboratory Analyses
Analyses of apo B-100, Lp(a) lipoprotein, total cholesterol,high-density lipoprotein (HDL) cholesterol, and triglycerideswere performed with the use of commercially available kits.LDL cholesterol was estimated with the use of the Friedewaldformula. High-sensitivity C-reactive protein (CRP) (lower limitof detection, 0.15 mg per liter) was measured as described elsewhere.11
Our assay of oxidized LDL determines the content of oxidizedphospholipids per particle of apo B-100 (oxidized phospholipid:apoB-100 ratio) and is performed with the use of the murine monoclonalantibody E06, which specifically binds to the phosphorylcholinemoiety of oxidized but not native phospholipids.6,7 We havepreviously used the term OxLDL-E06 to describe the name of thisassay. In brief, a dilution of plasma at 1:50 in phosphate-bufferedsaline was added to microtiter wells coated with monoclonalantibody MB47, which specifically binds apo B-100 particles.Under these conditions, a saturating amount of apo B-100 wasadded to each well, and consequently, equal numbers of apo B-100particles were captured in each well for all assays. The oxidizedphospholipid:apo B-100 ratio was measured by chemiluminescentenzyme-linked immunosorbent assay with the use of biotinylatedE06, as described elsewhere.6,7
Statistical Analysis
Discrete data are presented as frequencies and percentages,and continuous variables as means and standard deviations oras medians and interquartile ranges if the distributions wereskewed. Spearman's correlation coefficient was used to measurethe linear associations between the rank values of the oxidizedphospholipid:apo B-100 ratio and Lp(a) lipoprotein levels aswell as lipid levels and other clinical risk factors. The associationof the oxidized phospholipid:apo B-100 ratio and Lp(a) lipoproteinlevels with the extent of coronary artery disease was testedby one-way analysis of variance of the log-transformed valuesfollowed by a one-degree-of-freedom test for trend. The percentagesof patients with obstructive coronary artery disease and theodds ratios were calculated for quartiles of the oxidized phospholipid:apoB-100 ratio and Lp(a) lipoprotein levels for all patients, accordingto age (60 years or >60 years), and according to the presenceor absence of hypercholesterolemia.
Logistic-regression models were used to estimate the associationsbetween patients' characteristics and lipid measurements andobstructive coronary artery disease. Multiple logistic-regressionanalysis was used to estimate the partial associations betweenthe oxidized phospholipid:apo B-100 ratio and Lp(a) lipoproteinlevels and obstructive coronary artery disease, with adjustmentfor age, sex, smoking status, the presence or absence of hypertension,and levels of LDL cholesterol, HDL cholesterol, triglycerides,and CRP. The base-2 logarithms (log2) of the oxidized phospholipid:apoB-100 ratio and the levels of Lp(a) lipoprotein, triglycerides,and CRP were used in all the logistic-regression models to accountfor skewness in the distributions. Thus, odds ratios for thesevariables reflect the change in odds for an increase of 1 log2(the equivalent of a doubling of the value) in the measure.
Results
The baseline clinical characteristics of the patients, indicationsfor coronary angiography, lipid measurements, and CRP levelsare shown in Table 1. The distributions of both the oxidizedphospholipid:apo B-100 ratio and Lp(a) lipoprotein levels wereskewed toward lower values, with 85 percent of the patientshaving levels lower than 0.4 and 45 mg per deciliter, respectively(Figure 1). In the entire population, a strong correlation (r=0.83,P<0.001) was noted between the oxidized phospholipid:apoB-100 ratio and Lp(a) lipoprotein levels.
Figure 1. Frequency Distribution of the Oxidized Phospholipid:Apo B-100 Ratio (Panel A) and Lp(a) Lipoprotein Levels (Panel B).
Oxidized phospholipid:apo B-100 ratio denotes the oxidized phospholipid content per particle of apolipoprotein B-100.
Association with the Extent of Angiographically Documented Disease
In the entire study group, the oxidized phospholipid:apo B-100ratio and Lp(a) lipoprotein levels were strongly associatedwith a graded increase in the extent of coronary artery disease(P<0.001 for both analyses) (data not shown). These relationshipswere markedly stronger for patients 60 years of age or youngerthan for patients older than 60 years (Figure 2).
Figure 2. Association of the Oxidized Phospholipid:Apo B-100 Ratio and Lp(a) Lipoprotein Levels to the Extent of Coronary Artery Disease (CAD) in 239 Patients 60 Years of Age or Younger and 265 Patients Older Than 60 Years.
The extent of coronary artery disease is categorized as no disease (stenosis of less than 10 percent of the luminal diameter), mild disease (stenosis of 10 to 50 percent of the luminal diameter), or one-vessel, two-vessel, or three-vessel disease (all patients with a stenosis of more than 50 percent of the luminal diameter). Each box represents the median and interquartile range of values, with the I bars (whiskers) extended to the minimum and maximum. Oxidized phospholipid:apo B-100 ratio denotes the oxidized phospholipid content per particle of apolipoprotein B-100. Values for the oxidized phospholipid:apo B-100 ratio and Lp(a) lipoprotein are shown on a logarithmic scale.
Association with Obstructive Coronary Artery Disease
The proportion of patients with obstructive coronary arterydisease increased consistently with increases in the oxidizedphospholipid:apo B-100 ratio and in Lp(a) lipoprotein levels(Table 2). This association was particularly evident among patients60 years of age or younger, among whom the highest quartilesof the oxidized phospholipid:apo B-100 ratio (odds ratio, 3.12;P<0.001) and Lp(a) lipoprotein levels (odds ratio, 3.64,P<0.001) were associated with a significantly higher risk,as compared with the lowest quartiles. This association wasnot present among patients older than 60 years.
Table 2. Odds Ratios for Obstructive Coronary Artery Disease (CAD) According to Quartiles for the Ratio of Oxidized Phospholipids to Apolipoprotein B-100 and Levels of Lp(a) Lipoprotein.
The combined effects of hypercholesterolemia plus either theoxidized phospholipid:apo B-100 ratio or Lp(a) lipoprotein levelsgreatly increased the probability of obstructive coronary arterydisease. When compared with patients in the lowest quartilewho did not have hypercholesterolemia, patients in the highestquartile of the oxidized phospholipid:apo B-100 ratio or Lp(a)lipoprotein levels who had hypercholesterolemia were significantlymore likely to have obstructive coronary artery disease (Table 3).These relationships were markedly accentuated among patients60 years of age or younger (for the oxidized phospholipid:apoB-100 ratio, odds ratio, 16.8 [P<0.001]; for Lp(a) lipoproteinlevels, odds ratio, 14.2 [P<0.001]), as compared with thoseolder than 60 years (for the oxidized phospholipid:apo B-100ratio, odds ratio, 4.95 [P=0.003]; for Lp(a) lipoprotein levels,odds ratio, 4.92 [P=0.007]).
Table 3. Odds Ratios for Obstructive Coronary Artery Disease (CAD) According to Quartiles of the Ratio of Oxidized Phospholipids to Apolipoprotein B-100 and Levels of Lp(a) Lipoprotein in Patients without and with Hypercholesterolemia (HC).
The relationship of the oxidized phospholipid:apo B-100 ratioand Lp(a) lipoprotein levels to coronary artery disease remainedfundamentally similar after the exclusion from analysis of 41patients with acute myocardial infarction within six weeks beforeenrollment. Also, there was a stronger association between theoxidized phospholipid:apo B-100 ratio and Lp(a) lipoproteinlevels and coronary artery disease in patients with hypercholesterolemiawho were taking statins than among such patients who were nottaking statins, but differences in the odds ratios were notstatistically significant (data not shown).
Predictors of Obstructive Coronary Artery Disease
Without adjustment for other risk factors, the oxidized phospholipid:apoB-100 ratio was predictive of obstructive coronary artery disease(odds ratio per doubling, 1.19; 95 percent confidence interval,1.05 to 1.34; P=0.005) as was the Lp(a) lipoprotein level (oddsratio per doubling, 1.22; 95 percent confidence interval, 1.07to 1.40; P=0.003). Similarly, male sex (odds ratio, 4.33; 95percent confidence interval, 2.95 to 6.35; P<0.001), age(odds ratio per decade, 1.48; 95 percent confidence interval,1.25 to 1.75; P<0.001), current smoking (odds ratio, 1.65;95 percent confidence interval, 1.16 to 2.35; P=0.006), hypertension(odds ratio, 1.81; 95 percent confidence interval, 1.27 to 2.58;P=0.001), LDL cholesterol (odds ratio per increase of 25 mgper deciliter [0.65 mmol per liter], odds ratio, 1.28; 95 percentconfidence interval, 1.12 to 1.45; P=0.003), and triglyceridelevels (odds ratio per doubling, 1.27; 95 percent confidenceinterval, 1.00 to 1.61; P=0.05) were also predictive, whereasHDL cholesterol (odds ratio per increase of 10 mg per deciliter[2.3 mmol per liter], 0.64; 95 percent confidence interval,0.56 to 0.74; P<0.001) was a negative predictor. CRP (oddsratio per doubling, 1.08; 95 percent confidence interval, 0.98to 1.19; P=0.12) was not a predictor of obstructive coronaryartery disease.
Among patients 60 years of age or younger, the odds ratios perdoubling for the oxidized phospholipid:apo B-100 ratio (1.43;95 percent confidence interval, 1.20 to 1.71; P<0.001) andLp(a) lipoprotein level (1.41; 95 percent confidence interval,1.16 to 1.73; P<0.001) were significant, whereas among thoseolder than 60 years they were no longer significant (for theoxidized phospholipid:apo B-100 ratio: odds ratio per doubling,1.05; 95 percent confidence interval, 0.89 to 1.25; P=0.58;and for Lp[a] lipoprotein levels: odds ratio per doubling, 1.09;95 percent confidence interval, 0.90 to 1.32; P=0.37).
Multivariable analysis with the use of logistic-regression modelsto derive adjusted odds ratios for coronary artery disease showedthat an increase in the oxidized phospholipid:apo B-100 ratio(odds ratio per doubling, 1.21; 95 percent confidence interval,1.05 to 1.39; P=0.007) was an independent predictor of obstructivecoronary artery disease, as were male sex (odds ratio, 4.27;95 percent confidence interval, 2.59 to 7.03; P<0.001), age(odds ratio per decade, 1.72; 95 percent confidence interval,1.41 to 2.10; P<0.001), an increase in LDL cholesterol (oddsratio per 25 mg per deciliter, 1.28; 95 percent confidence interval,1.11 to 1.48; P<0.001), and hypertension (odds ratio, 1.67;95 percent confidence interval, 1.10 to 2.52; P=0.016), whereasan increase in HDL cholesterol levels (odds ratio per 10 mgper deciliter, 0.75; 95 percent confidence interval, 0.63 to0.90; P=0.002) was a negative predictor. An increase in CRP(odds ratio per doubling, 1.09; 95 percent confidence interval,0.97 to 1.22; P=0.16) was not a predictor of obstructive coronaryartery disease. When Lp(a) lipoprotein was added to the modeland the oxidized phospholipid:apo B-100 ratio was removed, Lp(a)lipoprotein was also an independent predictor (odds ratio perdoubling, 1.20; 95 percent confidence interval, 1.02 to 1.40;P=0.02). As in the unadjusted data, the odds ratios per doublingfor the oxidized phospholipid:apo B-100 ratio (1.49; 95 percentconfidence interval, 1.20 to 1.84; P<0.001) and for Lp(a)lipoprotein (1.42; 95 percent confidence interval, 1.12 to 1.81;P=0.004) among patients 60 years of age or younger were significantlyaccentuated, whereas among those older than 60 years they wereno longer significant (for the oxidized phospholipid:apo B-100ratio: odds ratio per doubling, 1.00; 95 percent confidenceinterval, 0.82 to 1.22; P=0.96; for Lp(a) lipoprotein: oddsratio per doubling, 1.05; 95 percent confidence interval, 0.84to 1.31; P=0.69).
Interestingly, in the entire study group, when Lp(a) lipoproteinwas forced into the model with the oxidized phospholipid:apoB-100 ratio, there was a trend toward significance of the oxidizedphospholipid:apo B-100 ratio (odds ratio per doubling, 1.21;95 percent confidence interval, 0.95 to 1.54; P=0.12), whereasLp(a) lipoprotein levels no longer remained an independent predictorof coronary artery disease (odds ratio per doubling, 1.00; 95percent confidence interval, 0.76 to 1.32; P=0.99). However,when patients were analyzed according to age, the oxidized phospholipid:apoB-100 ratio, but not Lp(a) lipoprotein levels, was an independentpredictor of obstructive coronary artery disease among those60 years of age or younger, but not among those older than 60years (Figure 3). CRP was also a predictor of obstructive coronaryartery disease among patients 60 years of age or younger, butnot among those older than 60 years. When the 41 patients withacute myocardial infarction, who also had the highest levelsof CRP, were removed from the analysis, CRP was no longer apredictor of obstructive coronary artery disease (odds ratioper doubling, 1.06; 95 percent confidence interval, 0.85 to1.33; P=0.58), but the oxidized phospholipid:apo B-100 ratio(odds ratio per doubling, 1.55; 95 percent confidence interval,1.05 to 2.27; P=0.03) remained a significant predictor. Whenthe data were evaluated according to the absence of coronaryartery disease, as compared with the presence of any coronaryartery disease, the odds ratios were slightly smaller, but ingeneral, the trends described were maintained, so that youngerpatients had higher odds ratios than older patients.
Figure 3. Odds Ratios for Obstructive Coronary Artery Disease (CAD) Associated with Selected Risk Factors among Patients 60 Years of Age or Younger and Those Older Than 60 Years, from the Multivariable Analysis.
CI denotes confidence interval, LDL low-density lipoprotein, CRP C-reactive protein, oxidized phospholipid:apo B-100 ratio the ratio of oxidized phospholipid content per particle of apolipoprotein B-100, and HDL high-density lipoprotein. Risk factors are shown in descending order of significance. In this analysis, Lp(a) lipoprotein was forced into the model with the oxidized phospholipid:apo B-100 ratio.
Correlations between Oxidized LDL Levels and Other Biomarkers
Levels of LDL cholesterol were weakly associated with levelsof Lp(a) lipoprotein (r=0.17, P<0.001), and with the oxidizedphospholipid:apo B-100 ratio (r=0.09, P=0.05). CRP levels correlatedweakly with LDL cholesterol levels (r=0.10, P=0.02) and triglyceridelevels (r=0.11, P=0.01). There were no significant correlationsbetween the oxidized phospholipid:apo B-100 ratio or Lp(a) lipoproteinlevels and CRP levels, age, body-mass index, blood pressure,and serum creatinine level.
Discussion
This study shows an association between the oxidized phospholipid:apoB-100 ratio in plasma and the presence and extent of angiographicallydocumented coronary artery disease. The association is independentof all clinical and lipid-related risk factors, except one,Lp(a) lipoprotein, which also has a strong association withangiographically documented coronary artery disease. The oddsratios for angiographically documented coronary artery diseaseassociated with the Lp(a) lipoprotein level were nearly identicalwith those associated with the oxidized phospholipid:apo B-100ratio. However, among patients younger than 60 years of age,the oxidized phospholipid:apo B-100 ratio remained an independentpredictor of obstructive coronary artery disease. There wasa strong correlation between levels of Lp(a) lipoprotein andthe oxidized phospholipid:apo B-100 ratio. These observations,in conjunction with previous studies from our laboratory showingthat in plasma such oxidized phospholipids are predominantlyphysically present on Lp(a) lipoprotein,5,6,7,9 as opposed toother lipoproteins, lend strong support to the hypothesis that,in the setting of enhanced oxidative stress, proinflammatoryoxidized phospholipids may, in part, mediate the atherogenicityof Lp(a) lipoprotein.
The natural murine monoclonal IgM autoantibody E06, cloned fromapolipoprotein E-receptor–deficient mice,12 is functionallyidentical with classic natural T15 murine antibodies that bindphosphorylcholine on the cell-wall polysaccharide of pathogenssuch as pneumococcus and provide optimal protection from pneumococcalinfections.13 In vitro, E06 binds to and prevents the uptakeof oxidized LDL and apoptotic cells by scavenger receptors ofmacrophages. Binder et al. have also shown that the immunizationof mice with Streptococcus pneumoniae results in increased titersof IgM oxidized LDL autoantibodies and reduction in the progressionof atherosclerosis.14,15 These observations suggest that seeminglyunrelated proatherogenic processes, such as oxidation, apoptosis,and infection, share molecular mimicry of the phosphorylcholineepitopes found on proinflammatory oxidized phospholipids.16
Although previous studies have shown that plasma oxidized LDLlevels are elevated in patients with clinically manifest stablecoronary artery disease17,18 and acute coronary syndromes,2,4,5,19our study shows that oxidized phospholipids present on particlesof apo B-100 and primarily on Lp(a) lipoprotein correlate withboth the presence and extent of angiographically documentedcoronary artery disease. Although most of the oxidized LDL ispresent within the vessel wall,20 this study suggests that thesmall amounts of minimally modified LDL (e.g., particles ofapo B-100 that contain oxidized phospholipids) are present inthe circulation. This finding is also consistent with previousstudies from our laboratory showing that the oxidized phospholipid:apoB-100 ratio (with oxidized LDL measured with use of antibodyE06) rises abruptly after acute coronary events5 and immediatelyafter percutaneous coronary intervention6 — situationsin which the release of oxidized phospholipids (or oxidizedLDL, or both) from the vessel wall might be postulated.
A potential pathophysiological relationship between levels ofoxidized phospholipids and Lp(a) lipoprotein is strongly supportedby this study and by data from earlier studies from our laboratoryshowing that oxidized phospholipids are physically associatedwith Lp(a) lipoprotein5,6,7 bound to lysine residues on isolatedfragments of kringle V of apolipoprotein(a)9 and also in thelipid phase of Lp(a) lipoprotein (unpublished data). In addition,the kringle V fragments containing such oxidized phospholipidsinduce inflammatory responses by up-regulating secretion ofinterleukin-8 by cultured human macrophages.9,21
In this study, we have shown that the predictive abilities oflevels of oxidized LDL and Lp(a) lipoprotein for obstructivecoronary artery disease are highly interdependent. In the entirestudy group, when Lp(a) lipoprotein was excluded from the multivariableanalysis, the odds ratios for the oxidized phospholipid:apoB-100 ratio were similar to those for traditional risk factorssuch as age, hypertension, and LDL cholesterol. Similarly, withoutthe oxidized phospholipid:apo B-100 ratio in the analysis, Lp(a)lipoprotein levels stood as an independent predictor, as hasbeen shown in a recent meta-analysis.8 In the entire study group,with the oxidized phospholipid:apo B-100 ratio in the model,there was no added ability of Lp(a) lipoprotein levels to explainthe risk of obstructive coronary artery disease, suggestingthat measures of oxidized LDL and Lp(a) lipoprotein representa common path of biologic influence on the risk for coronaryartery disease. However, in patients 60 years of age or younger,the oxidized phospholipid:apo B-100 ratio maintained its independentpredictive power even with Lp(a) lipoprotein in the model. Thisobservation supports the hypothesis that much of the risk attributableto Lp(a) lipoprotein levels can be explained by the bindingof oxidized phospholipids by Lp(a) lipoprotein, but that inyounger patients, an additional risk associated with oxidizedphospholipids may be present, perhaps through proinflammatorypathways independent of Lp(a) lipoprotein.
The physiologic role of Lp(a) lipoprotein is unknown. We andothers have suggested that a potential physiologic role of Lp(a)lipoprotein may be to bind and detoxify proinflammatory oxidizedphospholipids.5,6,7,22 Lp(a) lipoprotein, which is present onlyin humans and Old World primates (although a partially relatedgene arose separately in hedgehogs), may have evolved to provideprotection against various oxidative stressors. For example,Lp(a) lipoprotein has been shown to be involved in wound healing23and possibly in preventing angiogenesis in tumor models,24 andelevated levels have been noted in centenarians in a mannerconsistent with human longevity.25
Similarly, oxidized phospholipids are generated not only duringatherogenesis but also in inflammation and apoptosis,13,26 whichsuggests that housekeeping functions involving the clearanceof such oxidized phospholipids may have evolved for maintaininggeneral health as well as vascular health. In this regard, Lp(a)lipoprotein may act in a way similar to CRP, which Chang etal. have shown also binds specifically to the phosphorylcholinemoiety of oxidized phospholipids and apoptotic cells.27 Indeed,we and others have shown that Lp(a) lipoprotein acts as an acute-phasereactant in patients with acute coronary syndromes.5,6,28 Ithas also been reported to be highly enriched (higher by a factorof 7 than LDL) in platelet-activating factor acetyl hydrolase,29,30an enzyme that potentially could detoxify such oxidized phospholipidsby removing the oxidized fatty acid.
Thus, when present at low levels, Lp(a) lipoprotein may servea protective function by binding and participating in the transferand possible degradation of oxidized phospholipids formed duringnormal homeostasis or in acutely stressful situations. However,when Lp(a) lipoprotein levels are chronically elevated (as determinedgenetically), especially in a milieu of chronically increasedoxidative stress, Lp(a) lipoprotein, with its content of oxidizedphospholipids, may be proatherogenic, particularly since ithas enhanced binding to the extracellular matrix of the arterywall.31,32,33
The association between the oxidized phospholipid:apo B-100ratio and angiographically documented coronary artery diseasein our study was much stronger for patients 60 years of ageor younger than for older patients. The reasons for this associationare not entirely clear, but many previous studies have documenteda strikingly similar relationship between Lp(a) lipoproteinlevels and angiographically documented disease among youngerpatients only.34,35,36,37,38,39,40 By excluding patients withdiabetes and previous coronary revascularization from our study,we may have preferentially enriched the study group with youngerpatients with fewer traditional risk factors. In addition, increasingage, which is a surrogate for known and unknown risk factors,is itself one of the strongest risk factors for coronary arterydisease. Thus, the independent effects of oxidized LDL and Lp(a)lipoprotein levels appear to diminish with age, presumably becauseof the cumulative contributions of additional risk factors thataffect the clinical expression of atherosclerosis.
The limitations of this study include the fact that angiographyis not a precise method for quantifying atherosclerosis. Inaddition, we have not yet defined the exact oxidized phospholipids,their physical location within Lp(a) lipoprotein, or the ratesof flux, binding, and removal of oxidized phospholipids thatare on Lp(a) lipoprotein.
In conclusion, we have documented that plasma levels of oxidizedphospholipids present on apo B-100–containing lipoproteinsand predominantly on Lp(a) lipoprotein reflect the presenceand extent of angiographically documented coronary artery disease.We propose that in settings of enhanced oxidative stress andelevated Lp(a) lipoprotein levels, a proinflammatory milieumay predominate that contributes to the clinical expressionof cardiovascular disease. Further studies are needed to explorethese mechanisms and to determine whether these measures ofoxidation predict clinical events.
Supported by grants from the La Jolla Specialized Center ofResearch in Molecular Medicine and Atherosclerosis (HL56989),the National Heart, Lung, and Blood Institute (HL69646, HL57505),the Donald W. Reynolds Foundation, and the Mayo Foundation.
Dr. Tsimikas reports having served as a consultant to and onthe speakers' bureau of Pfizer and General Electric and havingreceived investigator-initiated grants from these companies.Dr. Witztum reports having served as a consultant to AtheroGenicsand on the speakers' bureau of Merck. Dr. Berger reports havingreceived research funding and honoraria from Aventis, Bristol-MyersSquib, and Sanofi and having served on scientific advisory boardsfor Genentech and Johnson & Johnson. Dr. Kornman is an employeeof Interleukin Genetics and reports holding equity in the company.Dr. McConnell reports having received grant support from diaDexus.A patent for the potential use of the E06 antibody has beenawarded to the University of California in the names of Dr.Witztum and colleagues and has been licensed by the Universityof California to AtheroGenics.
We are indebted to Claes Bergmark for advice on this project.
Source Information
From the Divisions of Cardiovascular Diseases (S.T.) and Endocrinology and Metabolism (E.R.M., J.L.W.), University of California, San Diego; the Division of Cardiovascular Diseases (E.S.B.), the Department of Laboratory Medicine and Pathology (J.P.M.), and the Division of Biostatistics (R.J.L.), Mayo Clinic, Rochester, Minn.; Interleukin Genetics, Waltham, Mass. (K.S.K.); and the Division of Cardiovascular Diseases, Duke Clinical Research Institute, Durham, N.C. (P.B.B.).
Address reprint requests to Dr. Tsimikas at the Vascular Medicine Program, University of California, San Diego, 9500 Gilman Dr., Basic Sciences Bldg., Rm. 1080, La Jolla, CA 92093-0682, or at stsimikas{at}ucsd.edu.
References
Tsimikas S, Witztum JL. Measuring circulating oxidized low-density lipoprotein to evaluate coronary risk. Circulation 2001;103:1930-1932. [Free Full Text]
Ehara S, Ueda M, Naruko T, et al. Elevated levels of oxidized low density lipoprotein show a positive relationship with the severity of acute coronary syndromes. Circulation 2001;103:1955-1960. [Free Full Text]
Holvoet P, Collen D, Van de Werf F. Malondialdehyde-modified LDL as a marker of acute coronary syndromes. JAMA 1999;281:1718-1721. [Free Full Text]
Nishi K, Itabe H, Uno M, et al. Oxidized LDL in carotid plaques and plasma associates with plaque instability. Arterioscler Thromb Vasc Biol 2002;22:1649-1654. [Free Full Text]
Tsimikas S, Bergmark C, Beyer RW, et al. Temporal increases in plasma markers of oxidized low-density lipoprotein strongly reflect the presence of acute coronary syndromes. J Am Coll Cardiol 2003;41:360-370. [Free Full Text]
Tsimikas S, Lau HK, Han KR, et al. 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 2004;109:3164-3170. [Free Full Text]
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. [Free Full Text]
Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary artery disease: meta-analysis of prospective studies. Circulation 2000;102:1082-1085. [Free Full Text]
Edelstein C, Pfaffinger D, Hinman J, et al. Lysine-phosphatidylcholine adducts in Kringle V impart unique immunological and potential pro-inflammatory properties to human apolipoprotein(a). J Biol Chem 2003;278:52841-52847. [Free Full Text]
Wolk R, Berger P, Lennon RJ, Brilakis ES, Somers VK. Body mass index: a risk factor for unstable angina and myocardial infarction in patients with angiographically confirmed coronary artery disease. Circulation 2003;108:2206-2211. [Free Full Text]
McConnell JP, Branum EL, Ballman KV, Lagerstedt SA, Katzmann JA, Jaffe AS. Gender differences in C-reactive protein concentrations -- confirmation with two sensitive methods. Clin Chem Lab Med 2002;40:56-59. [CrossRef][Web of Science][Medline]
Palinski W, Hörkkö S, Miller E, et al. Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice: demonstration of epitopes of oxidized low density lipoprotein in human plasma. J Clin Invest 1996;98:800-814. [Web of Science][Medline]
Shaw PX, Hörkkö S, Chang MK, et al. Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity. J Clin Invest 2000;105:1731-1740. [Web of Science][Medline]
Binder CJ, Horkko S, Dewan A, et al. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat Med 2003;9:736-743. [CrossRef][Web of Science][Medline]
Binder CJ, Hartvigsen K, Chang MK, et al. IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis. J Clin Invest 2004;114:427-437. [CrossRef][Web of Science][Medline]
Binder CJ, Chang MK, Shaw PX, et al. Innate and acquired immunity in atherogenesis. Nat Med 2002;8:1218-1226. [CrossRef][Web of Science][Medline]
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. [Free Full Text]
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. [Free Full Text]
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. [Free Full Text]
Tsimikas S, Glass C, Steinberg D, Witztum JL. Lipoproteins, lipoprotein oxidation and atherogenesis. In: Chien KR, ed. Molecular basis of cardiovascular disease: a companion to Braunwald's Heart Disease. Philadelphia: W.B. Saunders, 2004:385-413.
Klezovitch O, Edelstein C, Scanu AM. Stimulation of interleukin-8 production in human THP-1 macrophages by apolipoprotein(a): evidence for a critical involvement of elements in its C-terminal domain. J Biol Chem 2001;276:46864-46869. [Free Full Text]
Yano Y, Shimokawa K, Okada Y, Noma A. Immunolocalization of lipoprotein(a) in wounded tissues. J Histochem Cytochem 1997;45:559-568. [Free Full Text]
Trieu VN, Uckun FM. Apolipoprotein(a), a link between atherosclerosis and tumor angiogenesis. Biochem Biophys Res Commun 1999;257:714-718. [CrossRef][Medline]
Thillet J, Doucet C, Chapman J, Herbeth B, Cohen D, Faure-Delanef L. Elevated lipoprotein(a) levels and small apo(a) isoforms are compatible with longevity: evidence from a large population of French centenarians. Atherosclerosis 1998;136:389-394. [CrossRef][Web of Science][Medline]
Chang MK, Binder CJ, Miller YI, et al. Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory. J Exp Med 2004;200:1359-1370. [Free Full Text]
Chang MK, Binder CJ, Torzewski M, Witztum JL. C-reactive protein binds to both oxidized LDL and apoptotic cells through recognition of a common ligand: phosphorylcholine of oxidized phospholipids. Proc Natl Acad Sci U S A 2002;99:13043-13048. [Free Full Text]
Maeda S, Abe A, Seishima M, Makino K, Noma A, Kawade M. Transient changes of serum lipoprotein(a) as an acute phase protein. Atherosclerosis 1989;78:145-150. [CrossRef][Web of Science][Medline]
Blencowe C, Hermetter A, Kostner GM, Deigner HP. Enhanced association of platelet-activating factor acetylhydrolase with lipoprotein(a) in comparison with low density lipoprotein. J Biol Chem 1995;270:31151-31157. [Free Full Text]
Karabina SA, Liapikos TA, Grekas G, Goudevenos J, Tselepis AD. Distribution of PAF-acetylhydrolase activity in human plasma low-density lipoprotein subfractions. Biochim Biophys Acta 1994;1213:34-38. [Medline]
Dangas G, Mehran R, Harpel PC, et al. Lipoprotein(a) and inflammation in human coronary atheroma: association with the severity of clinical presentation. J Am Coll Cardiol 1998;32:2035-2042. [Free Full Text]
Cushing GL, Gaubatz JW, Nava ML, et al. Quantitation and localization of apolipoproteins [a] and B in coronary artery bypass vein grafts resected at re-operation. Arteriosclerosis 1989;9:593-603. [Free Full Text]
Berg K, Dahlen G, Christophersen B, Cook T, Kjekshus J, Pedersen T. Lp(a) lipoprotein level predicts survival and major coronary events in the Scandinavian Simvastatin Survival Study. Clin Genet 1997;52:254-261. [Web of Science][Medline]
Hearn JA, DeMaio SJ Jr, Roubin GS, Hammarstrom M, Sgoutas D. Predictive value of lipoprotein(a) and other serum lipoproteins in the angiographic diagnosis of coronary artery disease. Am J Cardiol 1990;66:1176-1180. [CrossRef][Web of Science][Medline]
Sandkamp M, Funke H, Schulte H, Kohler E, Assmann G. Lipoprotein(a) is an independent risk factor for myocardial infarction at a young age. Clin Chem 1990;36:20-23. [Free Full Text]
Foody JM, Milberg JA, Robinson K, Pearce GL, Jacobsen DW, Sprecher DL. Homocysteine and lipoprotein(a) interact to increase CAD risk in young men and women. Arterioscler Thromb Vasc Biol 2000;20:493-499. [Free Full Text]
Rhoads GG, Dahlen G, Berg K, Morton NE, Dannenberg AL. Lp(a) lipoprotein as a risk factor for myocardial infarction. JAMA 1986;256:2540-2544. [Free Full Text]
Dahlen GH, Guyton JR, Attar M, Farmer JA, Kautz JA, Gotto AM Jr. Association of levels of lipoprotein Lp(a), plasma lipids, and other lipoproteins with coronary artery disease documented by angiography. Circulation 1986;74:758-765. [Free Full Text]
Sunayama S, Daida H, Mokuno H, et al. Lack of increased coronary atherosclerotic risk due to elevated lipoprotein(a) in women > or = 55 years of age. Circulation 1996;94:1263-1268. [Free Full Text]
Assmann G, Schulte H, von Eckardstein A. Hypertriglyceridemia and elevated lipoprotein(a) are risk factors for major coronary events in middle-aged men. Am J Cardiol 1996;77:1179-1184. [CrossRef][Web of Science][Medline]
Srivastava, S., Vladykovskaya, E., Barski, O. A., Spite, M., Kaiserova, K., Petrash, J. M., Chung, S. S., Hunt, G., Dawn, B., Bhatnagar, A.
(2009). Aldose Reductase Protects Against Early Atherosclerotic Lesion Formation in Apolipoprotein E-Null Mice. Circ. Res.
105: 793-802
[Abstract][Full Text]
Greco, T. P., Conti-Kelly, A. M., Greco, T. Jr, Doyle, R., Matsuura, E., Anthony, J. R., Lopez, L. R.
(2009). Newer Antiphospholipid Antibodies Predict Adverse Outcomes in Patients With Acute Coronary Syndrome. Am J Clin Pathol
132: 613-620
[Abstract][Full Text]
The Emerging Risk Factors Collaboration,
(2009). Lipoprotein(a) Concentration and the Risk of Coronary Heart Disease, Stroke, and Nonvascular Mortality. JAMA
302: 412-423
[Abstract][Full Text]
Fraley, A. E., Schwartz, G. G., Olsson, A. G., Kinlay, S., Szarek, M., Rifai, N., Libby, P., Ganz, P., Witztum, J. L., Tsimikas, S., MIRACL Study Investigators,
(2009). Relationship of oxidized phospholipids and biomarkers of oxidized low-density lipoprotein with cardiovascular risk factors, inflammatory biomarkers, and effect of statin therapy in patients with acute coronary syndromes: Results from the MIRACL (Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering) trial.. J Am Coll Cardiol
53: 2186-2196
[Abstract][Full Text]
Stoletov, K., Fang, L., Choi, S.-H., Hartvigsen, K., Hansen, L. F., Hall, C., Pattison, J., Juliano, J., Miller, E. R., Almazan, F., Crosier, P., Witztum, J. L., Klemke, R. L., Miller, Y. I.
(2009). Vascular Lipid Accumulation, Lipoprotein Oxidation, and Macrophage Lipid Uptake in Hypercholesterolemic Zebrafish. Circ. Res.
104: 952-960
[Abstract][Full Text]
Tsimikas, S., Clopton, P., Brilakis, E. S., Marcovina, S. M., Khera, A., Miller, E. R., de Lemos, J. A., Witztum, J. L.
(2009). Relationship of Oxidized Phospholipids on Apolipoprotein B-100 Particles to Race/Ethnicity, Apolipoprotein(a) Isoform Size, and Cardiovascular Risk Factors: Results From the Dallas Heart Study. Circulation
119: 1711-1719
[Abstract][Full Text]
Berliner, J. A., Leitinger, N., Tsimikas, S.
(2009). The role of oxidized phospholipids in atherosclerosis. J. Lipid Res.
50: S207-S212
[Abstract][Full Text]
Wilson, P. W.F.
(2008). Progressing From Risk Factors to Omics. Circ Cardiovasc Genet
1: 141-146
[Full Text]
Yoshida, T., Gan, Q., Owens, G. K.
(2008). Kruppel-like factor 4, Elk-1, and histone deacetylases cooperatively suppress smooth muscle cell differentiation markers in response to oxidized phospholipids. Am. J. Physiol. Cell Physiol.
295: C1175-C1182
[Abstract][Full Text]
Bergmark, C., Dewan, A., Orsoni, A., Merki, E., Miller, E. R., Shin, M.-J., Binder, C. J., Horkko, S., Krauss, R. M., Chapman, M. J., Witztum, J. L., Tsimikas, S.
(2008). A novel function of lipoprotein [a] as a preferential carrier of oxidized phospholipids in human plasma. J. Lipid Res.
49: 2230-2239
[Abstract][Full Text]
Cote, C, Pibarot, P, Despres, J-P, Mohty, D, Cartier, A, Arsenault, B J, Couture, C, Mathieu, P
(2008). Association between circulating oxidised low-density lipoprotein and fibrocalcific remodelling of the aortic valve in aortic stenosis. Heart
94: 1175-1180
[Abstract][Full Text]
Merki, E., Graham, M. J., Mullick, A. E., Miller, E. R., Crooke, R. M., Pitas, R. E., Witztum, J. L., Tsimikas, S.
(2008). Antisense Oligonucleotide Directed to Human Apolipoprotein B-100 Reduces Lipoprotein(a) Levels and Oxidized Phospholipids on Human Apolipoprotein B-100 Particles in Lipoprotein(a) Transgenic Mice. Circulation
118: 743-753
[Abstract][Full Text]
Choi, S. H., Chae, A., Miller, E., Messig, M., Ntanios, F., DeMaria, A. N., Nissen, S. E., Witztum, J. L., Tsimikas, S.
(2008). Relationship Between Biomarkers of Oxidized Low-Density Lipoprotein, Statin Therapy, Quantitative Coronary Angiography, and Atheroma Volume Observations From the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) Study.. J Am Coll Cardiol
52: 24-32
[Abstract][Full Text]
Briley-Saebo, K. C., Shaw, P. X., Mulder, W. J.M., Choi, S.-H., Vucic, E., Aguinaldo, J. G. S., Witztum, J. L., Fuster, V., Tsimikas, S., Fayad, Z. A.
(2008). Targeted Molecular Probes for Imaging Atherosclerotic Lesions With Magnetic Resonance Using Antibodies That Recognize Oxidation-Specific Epitopes. Circulation
117: 3206-3215
[Abstract][Full Text]
Ky, B., Burke, A., Tsimikas, S., Wolfe, M. L., Tadesse, M. G., Szapary, P. O., Witztum, J. L., FitzGerald, G. A., Rader, D. J.
(2008). The Influence of Pravastatin and Atorvastatin on Markers of Oxidative Stress in Hypercholesterolemic Humans. J Am Coll Cardiol
51: 1653-1662
[Abstract][Full Text]
Castilla, P., Davalos, A., Teruel, J. L., Cerrato, F., Fernandez-Lucas, M., Merino, J. L., Sanchez-Martin, C. C., Ortuno, J., Lasuncion, M. A
(2008). 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. Clin. Nutr.
87: 1053-1061
[Abstract][Full Text]
Bennet, A., Di Angelantonio, E., Erqou, S., Eiriksdottir, G., Sigurdsson, G., Woodward, M., Rumley, A., Lowe, G. D. O., Danesh, J., Gudnason, V.
(2008). Lipoprotein(a) Levels and Risk of Future Coronary Heart Disease: Large-Scale Prospective Data. Arch Intern Med
168: 598-608
[Abstract][Full Text]
Kamstrup, P. R., Benn, M., Tybjaerg-Hansen, A., Nordestgaard, B. G.
(2008). Extreme Lipoprotein(a) Levels and Risk of Myocardial Infarction in the General Population: The Copenhagen City Heart Study. Circulation
117: 176-184
[Abstract][Full Text]
Grau, M., Guxens, M., Subirana, I., Fito, M., Covas, M.-I., Jacquemin, B., Sunyer, J., Lanki, T., Picciotto, S., Bellander, T., Katsouyanni, K., Schneider, A., Peters, A., Marrugat, J., on behalf of the AIRGENE Study Group,
(2007). South-to-North gradient in lipid peroxidation in men with stable coronary artery disease in Europe. Eur Heart J
28: 2841-2849
[Abstract][Full Text]
Spagnoli, L. G., Bonanno, E., Sangiorgi, G., Mauriello, A.
(2007). Role of Inflammation in Atherosclerosis. JNM
48: 1800-1815
[Abstract][Full Text]
Tabas, I., Williams, K. J., Boren, J.
(2007). Subendothelial Lipoprotein Retention as the Initiating Process in Atherosclerosis: Update and Therapeutic Implications. Circulation
116: 1832-1844
[Abstract][Full Text]
Tsimikas, S., Tsironis, L. D., Tselepis, A. D.
(2007). New Insights Into the Role of Lipoprotein(a)-Associated Lipoprotein-Associated Phospholipase A2 in Atherosclerosis and Cardiovascular Disease. Arterioscler. Thromb. Vasc. Bio.
27: 2094-2099
[Abstract][Full Text]
Saougos, V. G., Tambaki, A. P., Kalogirou, M., Kostapanos, M., Gazi, I. F., Wolfert, R. L., Elisaf, M., Tselepis, A. D.
(2007). Differential Effect of Hypolipidemic Drugs on Lipoprotein-Associated Phospholipase A2. Arterioscler. Thromb. Vasc. Bio.
27: 2236-2243
[Abstract][Full Text]
Vlachopoulos, C., Aznaouridis, K., Dagre, A., Vasiliadou, C., Masoura, C., Stefanadi, E., Skoumas, J., Pitsavos, C., Stefanadis, C.
(2007). Protective effect of atorvastatin on acute systemic inflammation-induced endothelial dysfunction in hypercholesterolaemic subjects. Eur Heart J
28: 2102-2109
[Abstract][Full Text]
Luke, M. M., Kane, J. P., Liu, D. M., Rowland, C. M., Shiffman, D., Cassano, J., Catanese, J. J., Pullinger, C. R., Leong, D. U., Arellano, A. R., Tong, C. H., Movsesyan, I., Naya-Vigne, J., Noordhof, C., Feric, N. T., Malloy, M. J., Topol, E. J., Koschinsky, M. L., Devlin, J. J., Ellis, S. G.
(2007). A Polymorphism in the Protease-Like Domain of Apolipoprotein(a) Is Associated With Severe Coronary Artery Disease. Arterioscler. Thromb. Vasc. Bio.
27: 2030-2036
[Abstract][Full Text]
Parastatidis, I., Thomson, L., Fries, D. M., Moore, R. E., Tohyama, J., Fu, X., Hazen, S. L., Heijnen, H. F.G., Dennehy, M. K., Liebler, D. C., Rader, D. J., Ischiropoulos, H.
(2007). Increased Protein Nitration Burden in the Atherosclerotic Lesions and Plasma of Apolipoprotein A-I Deficient Mice. Circ. Res.
101: 368-376
[Abstract][Full Text]
Kiechl, S., Willeit, J., Mayr, M., Viehweider, B., Oberhollenzer, M., Kronenberg, F., Wiedermann, C. J., Oberthaler, S., Xu, Q., Witztum, J. L., Tsimikas, S.
(2007). Oxidized Phospholipids, Lipoprotein(a), Lipoprotein-Associated Phospholipase A2 Activity, and 10-Year Cardiovascular Outcomes: Prospective Results From the Bruneck Study. Arterioscler. Thromb. Vasc. Bio.
27: 1788-1795
[Abstract][Full Text]
Dieplinger, B., Lingenhel, A., Baumgartner, N., Poelz, W., Dieplinger, H., Haltmayer, M., Kronenberg, F., Mueller, T.
(2007). Increased Serum Lipoprotein(a) Concentrations and Low Molecular Weight Phenotypes of Apolipoprotein(a) Are Associated with Symptomatic Peripheral Arterial Disease. Clin. Chem.
53: 1298-1305
[Abstract][Full Text]
Gharavi, N. M., Gargalovic, P. S., Chang, I., Araujo, J. A., Clark, M. J., Szeto, W. L., Watson, A. D., Lusis, A. J., Berliner, J. A.
(2007). High-Density Lipoprotein Modulates Oxidized Phospholipid Signaling in Human Endothelial Cells From Proinflammatory to Anti-inflammatory. Arterioscler. Thromb. Vasc. Bio.
27: 1346-1353
[Abstract][Full Text]
Michel, J.-B., Thaunat, O., Houard, X., Meilhac, O., Caligiuri, G., Nicoletti, A.
(2007). Topological Determinants and Consequences of Adventitial Responses to Arterial Wall Injury. Arterioscler. Thromb. Vasc. Bio.
27: 1259-1268
[Abstract][Full Text]
Fredrikson, G. N., Hedblad, B., Berglund, G., Alm, R., Nilsson, J.-A., Schiopu, A., Shah, P. K., Nilsson, J.
(2007). Association Between IgM Against an Aldehyde-Modified Peptide in Apolipoprotein B-100 and Progression of Carotid Disease. Stroke
38: 1495-1500
[Abstract][Full Text]
Jones, G. T., van Rij, A. M., Cole, J., Williams, M. J.A., Bateman, E. H., Marcovina, S. M., Deng, M., McCormick, S. P.A.
(2007). Plasma Lipoprotein(a) Indicates Risk for 4 Distinct Forms of Vascular Disease. Clin. Chem.
53: 679-685
[Abstract][Full Text]
Pulido, J. S., McConnell, J. P., Peterson, L. M., Highsmith, W. E., Lennon, R. J., Bryant, S. C., Berger, P. B., Somers, V.
(2007). Relationship Between Age-Related Macular Degeneration-Associated Variants of Complement Factor H and LOC387715 With Coronary Artery Disease. Mayo Clin Proc.
82: 301-307
[Abstract][Full Text]
Tsimikas, S., Brilakis, E. S., Lennon, R. J., Miller, E. R., Witztum, J. L., McConnell, J. P., Kornman, K. S., Berger, P. B.
(2007). Relationship of IgG and IgM autoantibodies to oxidized low density lipoprotein with coronary artery disease and cardiovascular events. J. Lipid Res.
48: 425-433
[Abstract][Full Text]
Thomson, L., Christie, J., Vadseth, C., Lanken, P. N., Fu, X., Hazen, S. L., Ischiropoulos, H.
(2007). Identification of Immunoglobulins that Recognize 3-Nitrotyrosine in Patients with Acute Lung Injury after Major Trauma. Am. J. Respir. Cell Mol. Bio.
36: 152-157
[Abstract][Full Text]
Zimman, A., Mouillesseaux, K. P., Le, T., Gharavi, N. M., Ryvkin, A., Graeber, T. G., Chen, T. T., Watson, A. D., Berliner, J. A.
(2007). Vascular Endothelial Growth Factor Receptor 2 Plays a Role in the Activation of Aortic Endothelial Cells by Oxidized Phospholipids. Arterioscler. Thromb. Vasc. Bio.
27: 332-338
[Abstract][Full Text]
Tsimikas, S., Aikawa, M., Miller, F. J. Jr, Miller, E. R., Torzewski, M., Lentz, S. R., Bergmark, C., Heistad, D. D., Libby, P., Witztum, J. L.
(2007). Increased Plasma Oxidized Phospholipid:Apolipoprotein B-100 Ratio With Concomitant Depletion of Oxidized Phospholipids From Atherosclerotic Lesions After Dietary Lipid-Lowering: A Potential Biomarker of Early Atherosclerosis Regression. Arterioscler. Thromb. Vasc. Bio.
27: 175-181
[Abstract][Full Text]
Chretien, J-P, Coresh, J, Berthier-Schaad, Y, Kao, W H L, Fink, N E, Klag, M J, Marcovina, S M, Giaculli, F, Smith, M W
(2006). Three single-nucleotide polymorphisms in LPA account for most of the increase in lipoprotein(a) level elevation in African Americans compared with European Americans. J. Med. Genet.
43: 917-923
[Abstract][Full Text]
McMahon, M, Grossman, J, Chen, W, Hahn, B H
(2006). Inflammation and the pathogenesis of atherosclerosis in systemic lupus erythematosus. Lupus
15: 59-69
[Abstract]
Gargalovic, P. S., Gharavi, N. M., Clark, M. J., Pagnon, J., Yang, W.-P., He, A., Truong, A., Baruch-Oren, T., Berliner, J. A., Kirchgessner, T. G., Lusis, A. J.
(2006). The Unfolded Protein Response Is an Important Regulator of Inflammatory Genes in Endothelial Cells. Arterioscler. Thromb. Vasc. Bio.
26: 2490-2496
[Abstract][Full Text]
Libby, P., Ridker, P. M.
(2006). Inflammation and Atherothrombosis: From Population Biology and Bench Research to Clinical Practice. J Am Coll Cardiol
48: A33-A46
[Abstract][Full Text]
Ng, C. J., Bourquard, N., Grijalva, V., Hama, S., Shih, D. M., Navab, M., Fogelman, A. M., Lusis, A. J., Young, S., Reddy, S. T.
(2006). Paraoxonase-2 Deficiency Aggravates Atherosclerosis in Mice Despite Lower Apolipoprotein-B-containing Lipoproteins: ANTI-ATHEROGENIC ROLE FOR PARAOXONASE-2. J. Biol. Chem.
281: 29491-29500
[Abstract][Full Text]
Watson, A. D.
(2006). Thematic review series: Systems Biology Approaches to Metabolic and Cardiovascular Disorders. Lipidomics: a global approach to lipid analysis in biological systems. J. Lipid Res.
47: 2101-2111
[Abstract][Full Text]
Suk Danik, J., Rifai, N., Buring, J. E., Ridker, P. M
(2006). Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women.. JAMA
296: 1363-1370
[Abstract][Full Text]
Otsuka, F., Sugiyama, S., Kojima, S., Maruyoshi, H., Funahashi, T., Matsui, K., Sakamoto, T., Yoshimura, M., Kimura, K., Umemura, S., Ogawa, H.
(2006). Plasma Adiponectin Levels Are Associated With Coronary Lesion Complexity in Men With Coronary Artery Disease. J Am Coll Cardiol
48: 1155-1162
[Abstract][Full Text]
Wu, T., Willett, W. C., Rifai, N., Shai, I., Manson, J. E., Rimm, E. B.
(2006). 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?. J Am Coll Cardiol
48: 973-979
[Abstract][Full Text]
Tuominen, A., Miller, Y. I., Hansen, L. F., Kesaniemi, Y. A., Witztum, J. L., Horkko, S.
(2006). A Natural Antibody to Oxidized Cardiolipin Binds to Oxidized Low-Density Lipoprotein, Apoptotic Cells, and Atherosclerotic Lesions. Arterioscler. Thromb. Vasc. Bio.
26: 2096-2102
[Abstract][Full Text]
Mackness, B., Quarck, R., Verreth, W., Mackness, M., Holvoet, P.
(2006). Human Paraoxonase-1 Overexpression Inhibits Atherosclerosis in a Mouse Model of Metabolic Syndrome. Arterioscler. Thromb. Vasc. Bio.
26: 1545-1550
[Abstract][Full Text]
Tsimikas, S., Kiechl, S., Willeit, J., Mayr, M., Miller, E. R., Kronenberg, F., Xu, Q., Bergmark, C., Weger, S., Oberhollenzer, F., Witztum, J. L.
(2006). Oxidized Phospholipids Predict the Presence and Progression of Carotid and Femoral Atherosclerosis and Symptomatic Cardiovascular Disease: Five-Year Prospective Results From the Bruneck Study. J Am Coll Cardiol
47: 2219-2228
[Abstract][Full Text]
Rodenburg, J., Vissers, M. N., Wiegman, A., Miller, E. R., Ridker, P. M., Witztum, J. L., Kastelein, J. J.P., Tsimikas, S.
(2006). Oxidized Low-Density Lipoprotein in Children With Familial Hypercholesterolemia and Unaffected Siblings: Effect of Pravastatin. J Am Coll Cardiol
47: 1803-1810
[Abstract][Full Text]
Tsimikas, S., Willerson, J. T., Ridker, P. M.
(2006). C-reactive protein and other emerging blood biomarkers to optimize risk stratification of vulnerable patients.. J Am Coll Cardiol
47: C19-C31
[Abstract][Full Text]
Jaffer, F. A., Libby, P., Weissleder, R.
(2006). Molecular and Cellular Imaging of Atherosclerosis: Emerging Applications. J Am Coll Cardiol
47: 1328-1338
[Abstract][Full Text]
Ashfaq, S., Abramson, J. L., Jones, D. P., Rhodes, S. D., Weintraub, W. S., Hooper, W. C., Vaccarino, V., Harrison, D. G., Quyyumi, A. A.
(2006). The Relationship Between Plasma Levels of Oxidized and Reduced Thiols and Early Atherosclerosis in Healthy Adults. J Am Coll Cardiol
47: 1005-1011
[Abstract][Full Text]
Friedman, A., Moe, S.
(2006). Review of the Effects of Omega-3 Supplementation in Dialysis Patients. CJASN
1: 182-192
[Abstract][Full Text]
Armstrong, E. J., Morrow, D. A., Sabatine, M. S.
(2006). Inflammatory Biomarkers in Acute Coronary Syndromes: Part III: Biomarkers of Oxidative Stress and Angiogenic Growth Factors. Circulation
113: e289-e292
[Full Text]
60 years or >60 years), and according to the presence or absence of hypercholesterolemia. 
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