CLINICAL RESEARCH: CORONARY ARTERY DISEASE
Relationship Between Biomarkers of Oxidized Low-Density Lipoprotein, Statin Therapy, Quantitative Coronary Angiography, and Atheroma VolumeObservations From the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) Study
Seung Hyuk Choi, MD*, ,
Andrew Chae, BS,
Elizabeth Miller, BS,
Michael Messig, PhD ,
Fady Ntanios, PhD,
Anthony N. DeMaria, MD, MACC,
Steven E. Nissen, MD, FACC*,
Joseph L. Witztum, MD and
Sotirios Tsimikas, MD, FACC,*
* Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Pfizer Inc, New York, New York
 Cleveland Clinic Foundation, Cleveland, Ohio
University of California–San Diego, San Diego, California.
Manuscript received November 21, 2007;
revised manuscript received February 8, 2008,
accepted February 13, 2008.
* Reprint requests and correspondence: Dr. Sotirios Tsimikas, Vascular Medicine Program, University of California—San Diego, 9500 Gilman Drive, BSB 1080, La Jolla, California 92093-0682. (Email: stsimikas{at}ucsd.edu).
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Abstract
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Objectives: This study was designed to test the hypothesis that circulating biomarkers of oxidized low-density lipoprotein (OxLDL) are affected by statin therapy and predict changes in atheroma volume.
Background: Oxidative stress is thought to play an important role in atherogenesis but the relationship between OxLDL, statin therapy, and atheroma volume in humans is not known.
Methods: In a subgroup of 214 patients from the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) trial, oxidized phospholipids (OxPL) and malondialdehyde (MDA) epitopes per apolipoprotein B-100 (apoB), immunoglobin (Ig) G and IgM apoB immune complexes, and OxLDL autoantibodies were measured at baseline and after 18 months of treatment with atorvastatin or pravastatin. Relationships between changes of OxLDL biomarkers and quantitative coronary angiography (QCA), total atheroma volume, and percentage atheroma volume were analyzed.
Results: There were no differences in QCA parameters or atheroma volume in the 2 groups at baseline. Compared with baseline values, OxPL/apoB and MDA/apoB, and lipoprotein (a) levels increased 21% to 48% (p < 0.001 for all) in response to atorvastatin and 17% to 39% (p < 0.001 for all) in response to pravastatin. In contrast, IgG apoB immune complexes, IgM apoB immune complexes, and IgM OxLDL autoantibodies were significantly reduced by both atorvastatin and pravastatin (p value range 0.003 to <0.001). There were no significant differences between the atorvastatin and pravastatin groups. In the entire cohort, there were no correlations between changes in any OxLDL biomarkers and changes in QCA parameters or atheroma volume.
Conclusions: Statin therapy results in significant increases in OxPL/apoB, MDA/apoB, and lipoprotein (a) levels and decreases in apoB immune complexes and OxLDL autoantibodies. However, these measures did not correlate with changes in QCA parameters or atheroma volume.
Key Words: lipoproteins • oxidation • atherosclerosis • lipoprotein (a) • oxidized phospholipids
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Abbreviations and Acronyms
| | apoB = apolipoprotein B-100 | | apoB-IC = apolipoprotein B-100-immune complexes | | EEM = external elastic membrane | | hsCRP = high sensitivity C-reactive protein | | IC/apoB = immune complexes per apolipoprotein B-100 | | Ig = immunoglobin | | IVUS = intravascular ultrasound | | Lp(a) = lipoprotein(a) | | MDA = malondialdehyde | | MDA/apoB = malondialdehyde epitopes per apolipoprotein B-100 | | OxLDL = oxidized low-density lipoprotein | | OxPL = oxidized phospholipids | | OxPL/apoB = oxidized phospholipid epitopes per apolipoprotein B-100 | | PAV = percentage change in atheroma volume | | PCI = percutaneous coronary intervention | | QCA = quantitative coronary angiography | | TAV = total atheroma volume |
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Quantitative coronary angiography (QCA) was initially applied to assess the effect of lipid-lowering therapies, such as statins, on coronary lumen dimensions (1,2). Because this is an indirect and relatively insensitive technique of assessing atheroma volume, it has been superseded by intravascular ultrasound (IVUS), which directly quantitates the size of the vessel lumen and atheroma. Recent IVUS trials have suggested that lipid-lowering therapy with statins reduces the progression of coronary atheroma volume (3,4). However, less invasive measures that reflect quantitative and qualitative changes of atherosclerotic lesions would provide useful tools to assess effects of statin therapy on regression of atherosclerosis.
Oxidized low-density lipoprotein (OxLDL) is primarily present in the vessel wall and has proatherogenic and proinflammatory properties (5,6). One marker of oxidative stress is the content of oxidized phospholipids (OxPL) on apolipoprotein B-100 particles (OxPL/apoB). Increased levels of OxPL/apoB are positively associated with angiographically defined coronary artery disease (7), progression of carotid and femoral atherosclerosis (8), and prediction of new cardiovascular events (9). Several studies have demonstrated acute transient increases of OxPL/apoB levels in patients with acute coronary syndromes and after percutaneous coronary intervention (PCI), situations where one may propose plaque rupture resulting in release of plaque oxidized lipids into the circulation (10,11). Other biomarkers of OxLDL, such as apolipoprotein B-100-immune complexes (apoB-IC) or autoantibodies to specific epitopes of OxLDL, have been associated, albeit less consistently and not always independently, with atherosclerosis (12,13).
Interestingly, in studies done to date, OxPL/apoB levels also increase in response to low-fat diets in animals and humans or in response to statin therapy in humans, but at a slower rate than in acute coronary syndromes or PCI (14–17), consistent with a flux of such particles from the vessel wall to the vessel lumen. In this study, we hypothesized that statin-induced changes in OxLDL biomarkers may reflect changes in QCA parameters of atheroma volume measured by IVUS.
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Methods
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Patient population and blood samples.
The REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) trial enrolled 502 patients ages 30 to 75 years who required coronary angiography for a clinical indication and demonstrated at least 1 obstruction with angiographic luminal diameter narrowing of >20% to 60% (3). Patients were randomly assigned to either atorvastatin 80 mg or pravastatin 40 mg daily in a blinded fashion. After the 18-month treatment period, patients underwent repeat coronary angiography and IVUS examination of the matched segments under identical conditions. Of the 502 patients in the REVERSAL study, 214 (43% of the REVERSAL population) had available baseline and end-of-study blood samples and complete IVUS data and, therefore, composed the study group. The blood samples were placed in tubes containing ethylenediaminetetracetic acid, shipped on ice overnight to a central laboratory, divided into aliquots, and stored at –70°C until shipping to Dr. Tsimikas's laboratory. Previous studies have shown that shipping samples on ice (Online Table 1) prolonged storage (>5 years) and several freeze-thaw cycles do not affect the OxLDL measures used in this study (8,16). The Human Subjects Protection Program at the University of California–San Diego approved research using these blood samples.
Angiographic and IVUS analysis.
The acquisition and measurement methodology of QCA and IVUS images used in the REVERSAL study has been previously described in detail (3). Atheroma area was determined as the difference between external elastic membrane (EEM) and lumen areas. Total atheroma volume (TAV) was calculated as the sum of differences between EEM and lumen areas across all evaluable slices (i.e., total atheroma volume =  [EEM area – lumen area]) and atheroma volume in the most diseased segment was defined as TAV in the 10-mm subsegment of the coronary artery with the greatest plaque volume at baseline. Percent atheroma volume (PAV) was calculated as the percentage of the sum of EEM areas that was occupied by TAV (PAV = [ (EEM area – lumen area)/ (EEM area)] x 100). Arterial wall remodeling was assessed by comparing the EEM area at the lesion and reference sites. For serial assessment of remodeling, the remodeling index was defined as the change in EEM from baseline to month 18 divided by the change in TAV from baseline to month 18. Using this approach, for regressing plaques, a ratio >1 was considered expansive, 0 to 1 as incomplete, and <0 as constrictive remodeling (18).
Determination of OxLDL biomarkers: OxPL/apoB, MDA/apoB, apoB-IC, and IgG MDA-LDL autoantibody titers.
OxPL/apoB was measured as described in detail previously (7,15) by chemiluminescent enzyme-linked immunosorbent assay using the murine monoclonal antibody E06, which binds to the phosphorylcholine head group of oxidized but not native phospholipids. In brief, a 1:50 dilution of plasma was added to microtiter wells coated with the murine monoclonal antibody MB47 (5 µg/ml), which specifically binds apoB. Under these conditions, a saturating amount of apoB is added to each wall, and consequently, equal numbers of apoB particles were captured in each well for all samples. The content of OxPL/apoB is then determined with biotinylated E06, and the data are presented as relative light units per 100 ms. Thus, by design, the OxPL/apoB measurement is independent of apoB (and LDL cholesterol) levels (8,15).
In a very similar fashion to our OxPL/apoB calculations, we also measured malondialdehyde (MDA) epitopes on apoB particles (MDA/apoB) using the well-characterized murine monoclonal antibody MDA2 (19,20), which binds MDA-lysine epitopes. In this assay, unlabeled MDA2 was added to the plates after apoB was captured, and the amount of MDA2 bound was detected with an alkaline phosphatase-labeled goat antimouse immunoglobin (Ig)G antibody.
Chemiluminescence enzyme-linked immunosorbent assays were also used to measure IgG and IgM autoantibodies to MDA-LDL and apoB-IC as described previously (13). The data for apoB-IC are presented in 2 ways: 1) as immune complexes per apolipoprotein B-100 (IC/apoB), which specifically quantify the content immune complexes on each captured apoB particle; and 2) as total apoB-IC, which reflects the IC content on all apoB-containing particles in plasma, by multiplying the plasma IC/apoB value by the plasma apoB levels measured independently by routine methods as noted. The intra-assay coefficients of variation for all assays were 6% to 10%.
Lipoprotein (a) [Lp(a)] and apoB levels.
Plasma Lp(a) levels were measured by a chemiluminescent enzyme-linked immunosorbent assay with monoclonal antibody LPA4, as described previously (11). In this assay, apoB is captured and biotinylated LPA4 is added to detect apo(a). apoB levels were measured by a commercial kit (Diasorin Inc., Saluggia, Italy).
Statistical analysis.
The OxLDL markers were log-transformed for analysis and back-transformed to yield geometric means and 95% confidence intervals (CIs) for baseline and percentage changes from baseline to month 18. Lipid measures at baseline and month 18 (expressed as percentage changes from baseline) were analyzed on their original scale. Inferential analyses of OxLDL markers and lipids were based on paired t tests for within treatment comparisons and 2-sample t tests for between treatment comparisons. Medians and 95% CIs were presented for the angiographic measures. Inferential analyses for the angiographic measures were based on the sign test for within-treatment comparisons and ranked-transformed analysis of covariance, with model terms for treatment group and the ranked-transformed baseline angiographic measure as a covariate, for between treatment comparisons (ranked-transformed analysis of variance was used for the remodeling index). All p values were 2-sided with p < 0.05 considered significant.
For a further description of bivariate relationships with ultrasonographic end points, we used the locally weighted scatter plot smoothing technique. This technique is designed to produce a smooth fit to the data and reduces the influence of extreme outliers.
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Results
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Patient characteristics and baseline OxLDL biomarkers.
Baseline clinical characteristics of this study population were similar between groups (Table 1) and similar to those of the entire REVERSAL population. Baseline levels of lipid variables and OxLDL biomarkers including OxPL/apoB, MDA/apoB, Lp(a), total apoB-IC, IC/apoB, and autoantibodies to MDA-LDL were similar between groups.
Angiographic and IVUS measurements in the atorvastatin and pravastatin groups.
There were no differences in the percent diameter stenosis, minimal lumen diameter, or the maximal lumen diameter between the atorvastatin and pravastatin groups (Table 2). Similarly, there were no differences between groups in TAV, PAV, or atheroma volume in the most diseased segment. Significant between-group differences were observed in the nominal change in PAV (1.29 in pravastatin vs. 0.11 in atorvastatin, p = 0.01), consistent with the primary end point of the overall REVERSAL results (Table 3).
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Table 3 Change in QCA Parameters, Atheroma Volume, and Remodeling Index 18 Months After Statin Therapy in the 2 Groups
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The effect of statin therapy on lipid parameters, OxLDL biomarkers, and Lp(a).
The influence of statin therapy on lipid parameters was consistent with the findings in the overall trial (Fig. 1). Compared with their respective baseline levels, levels of OxPL/apoB, MDA/apoB, and Lp(a) at 18 months were significantly increased in both the atorvastatin group (48%, 21%, and 14%, respectively; p < 0.001 for all) and pravastatin group (39%, 22%, and 14%, respectively; p < 0.001) (Fig. 2). A sensitivity analysis was performed on the relationship of OxPL/apoB to Lp(a) by analyzing the results as a percentage change in median values: pravastatin 40 mg (OxPL/apoB = 32.7 [95% CI: 22.9 to 46.0], p < 0.001; Lp(a) = 25.1 [95% CI: 13.2 to 33.0], p < 0.001); atorvastatin 80 mg (OxPL/apoB = 58.4 [95% CI: 30.1 to 78.3], p < 0.001; Lp(a) = 31.2 [95% CI: 14.8 to 39.1], p < 0.001). The results are quite similar to the main findings and are not influenced by outliers.
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Figure 1 Statins and Lipid Parameters
The influence of statin therapy on lipid parameters. ApoB = apolipoprotein B-100; CI = confidence interval; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol.
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Figure 2 Statins and Biomarkers
The influence of statin therapy on plasma oxidized low-density lipoprotein (OxLDL) biomarkers and high sensitivity C-reactive protein (CRP). apoB-IC = apolipoprotein B-100 immune complexes; CI = confidence interval; IC/apoB = immune complexes per apolipoprotein B-100; Ig = immunoglobin; Lp(a) = lipoprotein (a); MDA = malondialdehyde; MDA/apoB = malondialdehyde epitopes per apolipoprotein B-100; OxPL/apoB = oxidized phospholipid epitopes per apolipoprotein B-100.
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Total IgG and IgM apoB-IC, IgG and IgM IC/apoB, and IgM MDA-LDL autoantibodies were significantly reduced in response to both atorvastatin and pravastatin (p value range 0.003 to <0.001). There were significant reductions in Total IgG and IgM apoB-IC levels in the atorvastatin group compared with the pravastatin group (p < 0.001). However, there were no significant differences between the atorvastatin and pravastatin groups in the percent change of OxPL/apoB, MDA/apoB, Lp(a), IgG and IgM IC/apoB, or IgG and IgM MDA-LDL autoantibodies.
Relationship between the OxLDL biomarker levels and atheroma volume.
There were no significant correlations between the change in QCA parameters, TAV, or PAV with changes in levels of OxPL/apoB, MDA/apoB, and Lp(a) levels or in the change in TAV or change in OxLDL biomarkers (Fig. 3). Similarly, no relationships were noted between LDL cholesterol, HDL cholesterol, high sensitivity C-reactive protein (hsCRP), or other OxLDL biomarkers and QCA or IVUS measures of atheroma burden.
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Figure 3 Atheroma Volume and Oxidation-Specific Epitopes
Locally weighted scatter plots showing the relationship between the percentage change in atheroma volume and the percentage change in OxPL/apoB, MDA/apoB, and Lp(a) in the 214 patients. In each plot, the solid line represents the point estimates and the dashed lines the 95% confidence intervals. Abbreviations as in Figure 2.
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Correlation between OxPL/apoB levels and Lp(a).
Baseline plasma OxPL/apoB levels strongly correlated with baseline plasma Lp(a) levels (r = 0.83, p < 0.001) in the entire cohort of patients (Fig. 4). Interestingly, there was an inverse correlation between MDA/apoB levels and Lp(a) levels (r = –0.53, p < 0.001) (Fig. 4). There was also an inverse association between OxPL/apoB and MDA/apoB (r = –0.44, p < 0.001). Similar results were present at the 18-month point (OxPL/apoB and Lp(a), r = 0.86, p < 0.001; MDA/apoB levels and Lp(a) levels, r = –0.59, p < 0.001; and OxPL/apoB and MDA/apoB levels, r = –0.52, p < 0.001). There were no significant correlations between the remaining biochemical variables.
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Figure 4 Relationship of Lp(a) to Oxidation-Specific Epitopes
Spearman correlations between baseline levels of Lp(a) with OxPL/apoB and Lp(a) and MDA/apoB. Dashed lines represent the 95% confidence interval. RLU = relative light units; other abbreviations as in Figure 2.
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Correlation between hsCRP and OxLDL biomarkers.
At baseline, a weak inverse correlation was noted between hsCRP and Lp(a) (Table 4). When evaluating the data as the percentage change in hsCRP and OxLDL biomarkers, there was no correlation between hsCRP and either OxPL/apoB, MDA/apoB, or Lp(a), but there was a correlation of hsCRP with IC/apoB IgM and total levels of both IgG and IgM immune complexes.
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Discussion
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This study tested the hypothesis that statin therapy would result in changes in OxLDL biomarkers and that these changes would be reflected in QCA parameters of lumen dimensions and IVUS-derived measures of atheroma volume. Indeed, it was demonstrated that statin therapy significantly increased the content of OxPL/apoB and MDA/apoB on the remaining plasma apoB particles in the setting of an overall decrease in apoB levels. Furthermore, levels of apoB-IC and IgM autoantibodies to OxLDL were significantly reduced with statin therapy. However, no differences were noted between the atorvastatin and pravastatin groups and these changes in OxLDL biomarkers did not reflect the changes in QCA parameters or atheroma volume.
OxLDL and oxidation-specific epitopes are primarily present in atherosclerotic lesions but not normal arteries and are associated with increased plaque inflammation and features of plaque vulnerability (5,21–23). It has also been demonstrated that depletion of OxLDL in atherosclerotic aortic plaques may occur following low-fat, low-cholesterol diets in LDL receptor(–/–) mice (24), New Zealand White Rabbits (25), and cynomolgus monkeys (17). In these studies, it was documented that both OxPL/apoB (17) and MDA/apoB epitopes (24,25) were removed from atherosclerotic plaques, as documented by immunostaining, following the low-fat, low-cholesterol diet, and in higher proportion to removal of apoB. Interestingly, this occurred relatively quickly (i.e., within 6 months) and prior to significant decreases in plaque burden. Furthermore, concomitant with the reduction in oxidation-specific epitopes, there was also reduction in reactive oxygen species and evidence of a change in the plaque characteristics, where lipid-rich, macrophage-rich plaques were converted to a more stable phenotype, with increases in smooth muscle cells and collagen and decreases in macrophages. In human studies, Crisby et al. (26) have shown that immunostaining for oxidation-specific epitopes present in carotid plaques was significantly reduced following 3 months of treatment with pravastatin prior to carotid endarterectomy. Therefore, a strong rationale exists to suggest that oxidation-specific epitopes may be viable targets to follow within atherosclerotic lesions following therapeutic interventions.
The link between circulating OxLDL biomarkers, which reflect the global extent of atherosclerosis, and changes in atherosclerotic plaques in specific regions of interest, is less well established. In regression studies in cynomolgus monkeys and New Zealand White rabbits that had established atherosclerosis, increases in plasma OxPL/apoB levels (50% to 100%) were observed following 6 months of low-fat, low-cholesterol regression diets, which were associated with reduced OxPL/apoB content in aortic atherosclerotic plaques, suggesting efflux of OxPL/apoB from the vessel wall into the lumen (17). In humans, at least those recognized by antibody E06, increases in OxPL/apoB ranging from 9% to 48% have been noted following either low-fat diets or atorvastatin and pravastatin therapy (14–16). In these human studies, the increase in OxPL/apoB occurred concomitantly with increases in Lp(a) levels, which bind most of OxPL/apoB in human plasma (7,8,10,11,15,16,27,28). It is possible that Lp(a) levels may increase in response to statins and ultimately bind OxPL/apoB, which may be released independently. For example, in a study of patients undergoing PCI (11), a significant increase in OxPL/apoB and Lp(a) occurred immediately after PCI, which is consistent with release from the plaque due to plaque disruption. In the post-PCI time frame, only 50% of the OxPL/apoB were present on Lp(a), whereas the other 50% were on non-Lp(a) apoB particles. However, by 6 h, the vast majority of OxPL/apoB were physically present on Lp(a), which is consistent with a net transfer of OxPL/apoB to Lp(a). However, this phenomenon also occurs in New Zealand White rabbits, which do not have Lp(a), as well as in cynomolgus monkeys, whose Lp(a) is not associated with increased binding of OxPL/apoB. This suggests that Lp(a) may be the ultimate acceptor of such OxPL/apoB in humans, but is not needed to mediate changes in OxPL/apoB following therapeutic interventions.
Although the mechanisms underlying these changes in OxPL/apoB in response to therapeutic interventions have not been fully delineated, it is possible that enhancement of the antiatherogenic functions of HDL may lead to increased OxPL/apoB efflux (6). Consistent with this potential mechanism, apo A-I mimetic peptides promote OxPL/apoB efflux from macrophages to pre-beta HDL in vitro (29) and apo A-I Milano infusion produced a decrease in atheroma volume in only 5 weeks of therapy (30).
In the present study, the change in OxLDL biomarkers levels did not predict changes in QCA parameters or coronary atheroma volume. These findings may simply reflect the fact that these OxLDL biomarkers do not reflect QCA or IVUS measured changes in atheroma burden in response to statins. There are several other potential explanations for these findings. First, changes in these biomarkers may represent the entire atherosclerotic process, which may not be entirely reflected in the coronary arteries, that would compose a very small portion of atherosclerotic burden. Second, changes in OxPL/apoB levels may reflect early changes in atheromatous plaque composition, which occur even before physical plaque regression, as supported by the findings noted previously in animal models, and therefore, the changes in atheroma volume noted with IVUS may not be sensitive enough to detect this. Third, the change in OxLDL biomarker levels may be attenuated at the later phases of statin therapy, compared with the levels in the earlier phases. Because serial samples were not available in this study, it is possible that the peak in changes in these OxLDL biomarkers was missed. Finally, it is possible that fundamental antiatherogenic changes did occur in the vessel wall but that the current IVUS methodology cannot adequately characterize plaque characteristics such as the lipid content. Newer imaging modalities, such as "virtual histology," integrated backscatter analysis, wavelet analysis, and palpography (31,32), and molecular imaging approaches may be able to characterize various histologic components of atherosclerotic lesions, but full validation in patients is pending (33,34).
The present study revealed significant elevations of Lp(a) levels in response to both statins, and a strong correlation was noted between OxPL/apoB and Lp(a), which is consistent with previous observations (7,8,10,11,14–16). It has been previously postulated that Lp(a) may function at a primordial level to bind and perhaps mediate the removal of oxidized fatty acids from OxPL/apoB, particularly as it is enriched in lipoprotein-associated phospholipase A2, an enzyme with the ability to hydrolyze oxidized fatty acids from OxPL/apoB (35). However, patients with persistently high Lp(a) (36), which has a strong predilection for binding to matrix components of the vessels wall, are at increased risk of cardiovascular disease and development of new cardiac events, such as death, myocardial infarction, and stroke, a relationship which seems to be accentuated by increased Lp-PLA2 activity (9).
In this study, we also report for the first time results of a novel assay that measures MDA epitopes on apoB particles. Similar to the changes in OxPL/apoB levels, MDA/apoB levels also increased with both statins, although not to the same extent, and changes were similar between atorvastatin and pravastatin. These results need to be validated in other studies, but it may reflect a similar phenomenon to the OxPL/apoB changes. Of further interest, MDA/apoB levels were inversely associated with Lp(a) levels, suggesting that MDA/apoB epitopes are not present on Lp(a), unlike OxPL/apoB, which are present almost exclusively on Lp(a).
Study limitations.
Limitations of this study include the fact that only a subgroup of the REVERSAL population (214 of 502 patients) was available and that only baseline and end-of-study blood samples but no interim samples were available for analysis. Additionally, in this subgroup of patients, only the nominal change in PAV, and not TAV, was significantly different between statin groups, which along with the modest changes in measures of atheroma volume may have limited power to see relationships with OxLDL biomarkers.
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Conclusions
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This study demonstrates that statin therapy results in significant increases in OxPL/apoB and MDA/apoB levels, in parallel with similar increases in Lp(a) levels, and in significant reductions in apoB-IC and autoantibodies to OxLDL. However, these changes did not correlate with the changes in QCA parameters or atheroma volume measured by IVUS. Prospective studies are needed to assess whether changes in plasma OxLDL biomarkers predict statin-induced early changes in plaque characteristics using novel imaging modalities that are capable of quantitating specific plaque characteristics and whether these changes predict clinical benefit.
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Appendix
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For a supplementary table, please see the online version of this article.
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Footnotes
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Drs. Tsimikas and Witztum are named as inventors of patents related to antibodies to oxidized low-density lipoprotein owned by the University of California. Supported by an investigator-initiated grant from Pfizer Inc and from the Fondation Leducq. Assistance in developing the figures, but not content development support, was provided by Envision Pharma and was funded by Pfizer Inc. Drs. Messig and Ntanios are employees of Pfizer Inc. Peter Libby, MD, served as Guest Editor for this article.
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