CLINICAL RESEARCH: ATHEROSCLEROSIS
Oxidized Low-Density Lipoprotein in Children With Familial Hypercholesterolemia and Unaffected Siblings
Effect of Pravastatin
Jessica Rodenburg, MD*,
Maud N. Vissers, PhD*,
Albert Wiegman, MD, PhD ,
Elizabeth R. Miller, BS ,
Paul M. Ridker, PhD, MD, FACC ,
Joseph L. Witztum, MD,
John J.P. Kastelein, PhD, MD* and
Sotirios Tsimikas, MD, FACC,*
* Department of Vascular Medicine, University of Amsterdam, Amsterdam, the Netherlands
Department of Paediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
Department of Medicine, University of California, San Diego, California
Center for Cardiovascular Disease Prevention and Department of Medicine, Harvard Medical School, Boston, Massachusetts
Manuscript received August 4, 2005;
revised manuscript received October 24, 2005,
accepted December 12, 2005.
* Reprint requests and correspondence: Dr. Sotirios Tsimikas, Vascular Medicine Program, University of California San Diego, 9350 Campus Point Drive, Cardiology Suite 2B, La Jolla, California 92037-0975 (Email: stsimikas{at}ucsd.edu).
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Abstract
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OBJECTIVES: To assess the role of oxidized phospholipids (OxPLs) in children with familial hypercholesterolemia (FH) and the effect of pravastatin.
BACKGROUND: Oxidized phospholipids are a major component of oxidized low-density lipoprotein (OxLDL) and are bound to lipoprotein (a) [Lp(a)]. The significance of OxPL markers in children is unknown.
METHODS: Children with FH were randomized to placebo (n = 88) or pravastatin (n = 90) after instruction on American Heart Association step II diet. Unaffected siblings (n = 78) served as controls. The OxPL content on apolipoprotein B-100 (apoB) detected by antibody E06 (OxPL/apoB ratio), immunoglobulin (Ig)G and IgM immune complexes per apoB (IC/apoB) and on all apoB particles (total apoB-IC = IC/apoB multiplied by plasma apoB levels), autoantibodies to malondialdehyde (MDA)–low-density lipoprotein (LDL), Lp(a), and apoB levels were measured at baseline and after two years of treatment.
RESULTS: Compared with unaffected siblings, children with FH had significantly lower levels of OxPL/apoB but higher levels of IgG and IgM total apoB-IC and IgM MDA-LDL autoantibodies. From baseline to two-year follow-up, compared with placebo pravastatin treatment resulted in a greater mean percentage change in apoB (–18.7% vs. 0.3%; p = 0.001), total IgG apoB-IC (–31.9% vs. –12.2%; p < 0.001), and total IgM apoB-IC (–25.5% vs. 13.2%; p = 0.001). Interestingly, pravastatin also resulted in higher OxPL/apoB (48.7% vs. 29.3%; p = 0.028) and Lp(a) levels (21.9% vs. 10.7%; p = 0.044).
CONCLUSIONS: Compared with unaffected siblings, children with FH are characterized by elevated levels of apoB-IC and IgM MDA-LDL autoantibodies. Compared with placebo, pravastatin led to a greater reduction in apoB-IC but also to a greater increase in OxPL/apoB and Lp(a), which may represent a novel mechanism of mobilization and clearance of OxPL.
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Abbreviations and Acronyms
| | ACS = acute coronary syndrome | | apoB = apolipoprotein B-100 | | CVD = cardiovascular disease | | FH = familial hypercholesterolemia | | IC = immune complexes | | Ig = immunoglobulin | | IMT = intima-media thickness | | LDL-C = low-density lipoprotein cholesterol | | Lp(a) = lipoprotein (a) | | MDA = malondialdehyde | | OxLDL = oxidized low-density lipoprotein | | OxPL = oxidized phospholipid |
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Children with heterozygous familial hypercholesterolemia (FH) are characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels that predispose to the early initiation of atherogenesis and premature cardiovascular disease (CVD). Although most children with this disorder are asymptomatic, they do manifest subclinical atherosclerosis, such as impaired endothelial dysfunction and increased intima-media thickness (IMT) (1–4). Carotid IMT is considered a valid surrogate marker for atherosclerosis and therefore employed to assess atherosclerosis in children with FH. We previously showed that pravastatin therapy induced a significant regression of carotid IMT in children with FH compared to placebo (4).
A wealth of experimental and recently derived clinical data suggest that lipoprotein oxidation plays an important role in atherogenesis(5). Importantly, circulating oxidized low-density lipoproteins (OxLDLs) are associated with subclinical atherosclerosis in adults (6,7) angiographically determined coronary artery disease (8), symptomatic CVD, acute coronary syndromes (ACS), and vulnerable plaques (7,9–13) and may also predict acute myocardial infarction (7,14).
The role of circulating OxLDL in the pathogenesis of early atherosclerosis in children and the effect of statins are unknown. In the current study, we investigated the effect of pravastatin on plasma levels of several direct and indirect markers of OxLDL in a cohort of FH children, treated with pravastatin or placebo, as well as in a group of unaffected siblings.
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Methods
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Study population and design.
We previously performed a double-blind randomized placebo-controlled trial to determine the 2-year efficacy and safety of pravastatin versus placebo in 214 children age 8 to 18 years with heterozygous FH (4). Children younger than 14 years received 20 mg pravastatin, and those age 14 years or older received 40 mg pravastatin daily. Children were also instructed to assume or continue a low-fat diet (ingesting 32.6% total fat and 12.1% saturated fat after counseling on an American Heart Association step II diet) and to maintain habitual physical activity during the intervention period. In addition, relevant information was assembled for 80 unaffected siblings in whom FH was definitely excluded by deoxyribonucleic acid analysis. Carotid intima-media thickness (IMT) was determined as previously described (1,3,4).
Lipids, lipoproteins, and C-reactive protein.
From the original cohort, plasma samples from 178 FH children at baseline and at 2 years and from 78 unaffected siblings at a single time point were available for OxLDL measurements. Plasma levels of cholesterol and triglycerides were determined by standardized enzymatic procedures as previously described (4). Lipoprotein (a) [Lp(a)] concentrations were determined using chemiluminescent enzyme-linked immunosorbent assay (ELISA) as previously described (15). High-sensitivity C-reactive protein (hsCRP) was measured by latex-enhanced nephelometry (Dade Behring, Newark, Delaware).
Determination of oxidized phospholipid (OxPL)/apolipoprotein B-100 (apoB) levels, apoB-immune complexes, and malondialdehyde (MDA)-LDL autoantibody titers.
Chemiluminescent ELISA was used to measure plasma titers of IgG and IgM apoB-immune complexes (IC), and IgG and IgM MDA-LDL (1:200 plasma dilution) autoantibodies were measured as previously described (16). Each sample was assayed in triplicate, and data are expressed as relative light units (RLU) in 100 ms. The content of OxPLs per apoB particle was determined using the murine monoclonal antibody E06 (OxLDL-E06), which specifically binds to the phosphocholine head group of oxidized but not native phospholipids (13,15,16). A 1:50 dilution of plasma in phosphate-buffered saline is added to microtiter wells coated with the monoclonal antibody MB47, which specifically binds apoB particles. Under these conditions, a saturating amount of apoB is added to each well and consequently an equal number of apoB particles are captured in each well for all assays. The content of OxPL per apoB is then determined with biotinylated E06 as previously described (13,15,16). Because the amount of apoB bound to each plate is essentially identical for each plasma sample, we arbitrarily assigned the apoB RLU value in the denominator as 1 and report the OxPL/apoB values as OxPL RLU counts only.
The data for apoB-IC are presented in two ways: 1) as IC/apoB, which specifically quantifies the content of apoB-IC on each captured apoB particle; and 2) as total apoB-IC, which reflects the apoB-IC content on all apoB-containing particles in plasma, by multiplying the plasma IC/apoB value by the plasma apoB levels measured independently. We have previously also reported total levels of apoB-OxPL (16), derived by multiplying the OxPL/apoB ratio by plasma levels of apoB, in patients treated with statins. Because of the difficulty in determining the exact amount of OxPL on non–Lp(a)-apoB lipoproteins versus on Lp(a), this parameter may not completely reflect the plasma levels of apoB-associated OxPL. Therefore it is not reported here pending further validation.
To assess the stability of frozen samples, we repeated all of the OxLDL measures on the same samples 6 months after the initial determination in a second freeze-thaw cycle and in a subset of samples at 8 months in a third freeze-thaw cycle. The data are remarkably consistent, with little variability (correlation coefficients [r value] between first and second run: OxPL/apoB 0.93, MDA-LDL IgG 0.96, MDA-LDL IgM 0.96, apoB-IC IgG 0.96, and apoB-IC IgM 0.81).
Statistical analysis.
In the FH group, mean values between the pravastatin group and the placebo group were compared using an independent-sample t test. Chi-square tests were applied for comparing distributions of dichotomous data between these groups. Differences in baseline characteristics and OxLDL markers between FH children and healthy siblings were analyzed using linear or logistic regression analyses. Because some of these children were from the same family, these analyses were performed with generalized estimating equations in the Statistical Analyses System (SAS Institute, Cary, North Carolina) procedure GENMOD to account for correlations within families. In a stepwise multivariate analysis, we adjusted for potential confounders.
The effect of pravastatin on OxLDL markers, apoB, and Lp(a) levels was studied by comparing the difference in mean change between the pravastatin and the placebo group after two-year treatment by analysis of covariance, in which independent variables were treatment and baseline levels. Pearson and Spearman correlations were used to summarize the relationship between OxLDL markers and Lp(a) and CRP at baseline and after two years.
Variables with a skewed distribution were log-transformed before the analysis. A p level of 0.05 was considered statistically significant (two sided). Statistical analyses were done with the SAS package version 9.1 (SAS Institute, Cary, North Carolina).
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Results
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Baseline clinical characteristics.
The baseline demographics and physical characteristics of the study group were described previously (2) and were not significantly different between children with FH in the pravastatin group and the placebo group. There were no significant differences in those children with (n = 178) and without (n = 36) available blood samples for OxLDL measurements. Children with FH did not differ from unaffected siblings with regard to baseline characteristics, except for mean carotid IMT, age, and lipid levels (Table 1). A molecular diagnosis of FH was obtained in 95% of the children. None of the children with FH suffered from cardiovascular disease or had any cardiovascular symptoms. At baseline, 5.6% of the FH children had tendinous xanthomas at physical examination and 6.1% smoked regularly. Smoking status (p = 0.80) as well as clinical characteristics (p = 0.55) were equally distributed between both treatment groups.
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Table 1. Baseline Characteristics, OxLDL Markers, Lipids, and Lipoprotein Levels in FH Children and Unaffected Siblings
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Baseline OxLDL markers and lipoprotein levels in the study group and in unaffected siblings.
The baseline lipid levels, apoB, CRP, OxPL/apoB, apoB-IC, and MDA-LDL autoantibodies were similar between the pravastatin and placebo groups. However, the Lp(a) levels were borderline higher in the pravastatin group (median levels 8.1 vs. 7.4 mg/dl; p = 0.049) (Table 1). The unaffected siblings, as expected, had lower levels of all lipoproteins, except Lp(a), which was similar, and lower levels of CRP and carotid IMT (Table 1) (4).
Interestingly, compared with their unaffected siblings, children with FH had significantly lower levels of OxPL/apoB (p < 0.001) and IgG IC/apoB (p = 0.016) but higher levels of total IgG apoB-IC, total IgM apoB-IC, and IgM MDA-LDL autoantibodies (p < 0.001 for all) (Table 1). No significance differences were present in IgM IC/apoB, IgG MDA-LDL autoantibodies, or Lp(a).
Effect of pravastatin on absolute changes in OxLDL markers and Lp(a) in children with FH.
As previously described, total cholesterol, LDL-C, and apoB levels decreased significantly in the pravastatin group (p < 0.001 for all) after two years, whereas no significant change occurred in the placebo group (Table 2) (2).
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Table 2. Baseline and Two-Year Treatment Mean Levels of Lipids, Lipoproteins, and OxLDL Markers in Children With FH
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The absolute median values of OxPL/apoB increased significantly in the placebo group from baseline to 2-year follow-up (p = 0.003) (Table 2). The only intervention in this group was an emphasis on a low-fat diet. Such a change in OxPL/apoB in response to low-fat diets was previously observed (17). In subjects on pravastatin, there was a greater increase in the OxPL/apoB ratio from baseline to 2 years (p < 0.001) (Table 2), which was significantly higher compared with placebo (p = 0.003) (Table 2). We previously observed similar findings in adult patients with ACS in response to atorvastatin (16).
The total IgG apoB-IC decreased significantly in both the placebo (p < 0.001) (Table 2) and pravastatin groups (p < 0.001) (Table 2) but was significantly lower in the pravastatin group (p < 0.001) compared to placebo (Table 2). The total IgM apoB-IC only decreased in the pravastatin group (p < 0.001) compared to placebo (Table 2). The IgG IC/apoB decreased significantly in both the control and pravastatin groups (Table 2). There were no significant differences between the pravastatin and placebo groups in IgM IC/apoB or IgG and IgM MDA-LDL autoantibodies.
Interestingly, absolute median values of Lp(a) also increased significantly in the pravastatin arm (8.1 [interquartile range 4.4 to 20.5] to 10.5 [5.9 to 22.1]; p < 0.001) but not in the control group. An increase in Lp(a) levels was also documented previously in response to low-fat diets and atorvastatin (16,17). In the entire FH cohort, a strong correlation was noted between OxPL/apoB and Lp(a) at baseline (r = 0.84; p < 0.001) and two years (r = 0.92; p < 0.001) (Fig. 1). This relationship was also true of the unaffected siblings (r = 0.89; p < 0.001).
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Figure 1 Relationship between oxidized phospholipid (OxPL)/apoprotein B-100 (apoB) and lipoprotein (a) [Lp(a)] in the entire cohort of children with familial hypercholesterolemia at baseline (top) and after two years of pravastatin therapy (bottom). RLU = relative light units.
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Effect of pravastatin on relative changes in OxLDL markers and Lp(a).
As compared with placebo, pravastatin significantly increased OxPL/apoB (absolute mean increase of 19.4%; p = 0.028) and Lp(a) (absolute mean increase of 11.2%; p = 0.044) but significantly decreased total IgM apoB-IC and total IgG apoB-IC (Fig. 2). No significant changes were noted in IgG and IgM apoB-IC or IgG and IgM MDA-LDL autoantibodies from baseline to two years.
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Figure 2 Mean percent change (with 95% confidence intervals [CIs]) in OxLDL markers from baseline to two years in the placebo and pravastatin groups. Abbreviations as in Table 1.
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Relationship among OxLDL markers, CRP, and carotid IMT.
In the entire FH cohort, OxPL/apoB correlated weakly with IgG MDA-LDL (r = 0.17; p = 0.023) but not with other OxLDL markers or lipid parameters. The IgM MDA-LDL autoantibodies correlated with IgM apoB-IC (r = 0.62; p < 0.001), and similarly IgG MDA-LDL autoantibodies correlated with IgG apoB-IC (r = 0.34; p < 0.001). An inverse but weak correlation was noted between LDL-C and IgG MDA-LDL (r = –0.15; p = 0.0049). In contrast, in the unaffected siblings, there was a positive correlation between LDL-C and IgG MDA-LDL (r = 0.29; p = 0.013). There was a modest positive correlation of hsCRP with OxPL/apoB (r = 0.16; p = 0.038) and Lp(a) (r = 0.17; p = 0.025) at baseline in the FH group but not with the other OxLDL markers. None of the OxLDL markers, Lp(a), or hsCRP predicted the baseline or the change in carotid IMT following pravastatin treatment.
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Discussion
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This study demonstrates that children with FH have significantly higher concentrations of apoB-IC and IgM MDA-LDL autoantibodies but lower levels of OxPL/apoB than unaffected siblings. Furthermore, pravastatin treatment of children with FH decreased total levels of apoB-associated immune complexes but actually increased OxPL/apoB levels, in parallel with similar increases in Lp(a) levels. Consistent with our previous hypothesis, these changes may represent mobilization of OxPL into the circulation following treatment with statins (16) and low-fat diets (17). It also suggests up-regulation of Lp(a) levels by statins and/or by OxPL which have been shown to be strongly bound by Lp(a) (8,13,15,16,18), as opposed to other apoB-containing lipoproteins.
Children with FH are characterized by elevated LDL-C levels at birth and more rapid progression to clinical CVD as they become young adults compared to normocholesterolemic children. Even in the pediatric period, they exhibit evidence of subclinical atherosclerosis with increased carotid IMT (3,4) and endothelial dysfunction compared with similar-aged controls (1,19,20). Recent statin trials in children with FH demonstrated significant decreases in LDL-C levels without apparent adverse effects over one- to two-year treatment periods (1,4,21,22). Pravastatin has been shown to induce carotid IMT regression (4) and simvastatin to improve endothelial function in children with FH (1,23). In addition, oral antioxidant vitamins C (500 mg/day) and E (400 IU/day) have also been shown to improve brachial flow-mediated dilatation in children with FH (24) but, interestingly, did not affect the levels of the same OxLDL markers, as measured in this study, nor other markers of oxidation such as F2-isoprostanes.
Oxidized LDL is both immunogenic (25,26) and proinflammatory (27,28). In adults, a significant amount of data exist on the role of autoantibodies to OxLDL and their impact on atherogenesis. Although results are equivocal, it appears that IgG autoantibodies are positively associated with various manifestations of CVD (29), whereas IgM autoantibodies may be atheroprotective (30). However, although they may play a role in modifying atherogenesis, it has not been conclusively established if autoantibodies to OxLDL have independent predictive value as biomarkers for CVD above and beyond traditional cardiovascular risk factors. In addition, data are now emerging from several laboratories that circulating OxLDL, measured by different antibodies, is associated with clinical and angiographic CVD and plaque disruption as noted in ACS and percutaneous coronary intervention (PCI) (7,9–14).
A major limitation in this field is the scarcity of prospective studies, which limits our understanding of the role of OxLDL in the development of CVD. In addition, although these measures are clearly interrelated, most studies do not measure circulating OxLDL, immune complexes, and OxLDL autoantibodies in the same dataset, which would provide a more complete assessment and a better definition of their role in atherogenesis. In children, particularly in those with FH where a clinical imperative is present to identify mechanisms of disease progression to initiate preventative measures early in the disease process, similar information is not available.
Baseline levels of OxLDL markers in children with FH and unaffected siblings.
To our knowledge, this study is the first to show that children with FH are characterized by higher levels of apoB-IC and IgM MDA-LDL autoantibodies and lower levels of OxPL/apoB than their unaffected siblings, even after adjustment for age. The higher levels of apoB-IC and MDA-LDL autoantibodies are potentially attributed to immunologic responses to the presence of OxLDL in the vessel wall and possibly to smaller quantities of OxLDL in the circulation. Consistent with this, it has been shown that aortas from human fetuses, in whom the mothers were hypercholesterolemic, contain OxLDL even before monocyte recruitment (31), suggesting that OxLDL is present a priori in early human lesions before inflammatory components.
Interestingly, OxPL/apoB levels were lower at baseline in the children with FH than in unaffected siblings. This may reflect the fact that the pool of apoB was larger, but the OxPL levels similar, in children with FH than in unaffected siblings. We have documented previously that the majority of OxPL resides on Lp(a) (8,13,15,16,18). Because Lp(a) levels were similar in both groups at baseline, this may simply be reflected by a lower OxPL/apoB ratio in children with FH. Another possibility is generation of immune complexes as a mechanism of reduced OxPL/apoB levels, as implied by higher levels of apoB-IC in children with FH. In adults, it has been shown that a weak but significant inverse correlation exists between OxLDL autoantibodies and OxLDL levels, measured by antibody DLH3, which binds a similar epitope as antibody E06 (32). One may also postulate that the lower OxPL/apoB ratio occurs because of enhanced deposition of OxPL in the artery wall. Further study is needed to understand the underlying mechanisms of these observations.
OxLDL markers in response to pravastatin in children with FH.
The OxPL/apoB levels strongly correlate with the presence and extent of angiographic coronary artery disease (8) and are increased in ACS (13), immediately following PCI (15), and, interestingly, in response to atorvastatin and low-fat diets (16,17). In the Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL) study (16), we evaluated the role of oxidized phospholipids present on apolipoprotein B-100 (OxPL/apoB) in response to high-dose atorvastatin and showed that the OxPL/apoB ratio was significantly increased in response to 80 mg atorvastatin, in concert with a proportional increase in Lp(a) levels. The reasons for the increase in OxPL/apoB and Lp(a) in response to statins (or low-fat diet) is not yet determined, but several other statin studies have also suggested small and even moderate increases in Lp(a) levels (33–36). For example, Kostner et al. (34) showed a dose-response in the increase in Lp(a) levels with lovastatin (0 mg: no change; 20 mg: +27%; 40 mg: +23%; 60 mg: +29%; 80 mg: +34%). We have shown that OxPL are preferentially bound to Lp(a) as opposed to other apoB-containing lipoproteins, both bound to apolipoprotein (a) (18) as well as in the lipid phase of Lp(a) (Tsimikas and Witztum, unpublished observations). Consistent with the observations in this study, atorvastatin was also shown to significantly decrease total IgG and IgM apoB-IC compared with placebo in the MIRACL study.
Based on the above studies, we have postulated that Lp(a) may function to bind, transport, and potentially detoxify OxPL that are generated through oxidative stress (8,16). The reason for this increased OxPL/apoB in response to statins, which may seem paradoxical with other beneficial properties of statins, has not been fully elucidated but is clearly now a consistent finding in response to atorvastatin and pravastatin as well as in response to low-fat diets, conditions where one might postulate a flux of OxPL from peripheral storage sites, such as the vessel wall. For example, the control group of this study, after counseling on an American Heart Association step II diet (4) also had increases in OxPL/apoB and Lp(a) but less of an increase than the pravastatin group. This is consistent with the data by Silaste et al. (17) showing a median increase in OxPL/apoB and Lp(a) by approximately 25% and 9%, respectively, after 5 weeks of medically supervised low-fat diets. The explanations for these findings still need to be determined. One possibility is that Lp(a) is up-regulated in response to statins or low-fat diet and binds OxPL that may be derived from peripheral sources, such as the vessel wall, tendon xanthomas, the reticuloendothelial system, or even remote sites of inflammation. Consistent with this, we have also shown an increase in OxPL/apoB in nonatherogenic mice transgenic for human Lp(a) (37). We have recently shown that placing LDLR–/– mice with preexisting atherosclerosis on low-fat diets results in a marked reduction in OxPL immunostaining of atherosclerotic plaques, even before complete lesion regression or cholesterol removal from the vessel wall, suggesting that efflux of OxPL from the vessel wall is a very early phenomenon during atherosclerosis regression (38). Additional animal data from our laboratory (Tsimikas and Witztum, unpublished observations) in several atherosclerotic animal models with or without Lp(a), also suggests that with increased plasma OxPL/apoB levels following low-fat diets there are concomitant reductions of OxPL immunostaining in the vessel wall, suggesting an efflux of OxPL from the vessel wall to the circulation.
In the current study, none of the OxLDL markers, Lp(a), or hsCRP predicted change in carotid IMT. There are several potential explanations for these findings. First, in this group of subjects the LDL-C levels were exceedingly high, even in the group treated with pravastatin (2-year LDL-C results were 237 mg/dl in the placebo and 181 mg/dl in the pravastatin arm), which may have been the primary driver of increased carotid IMT. Second, the follow-up period was only two years, which may not have been long enough to see a significant relationship in the change in OxLDL markers and carotid IMT. In fact, we have shown that in adults from the general community ranging from 40 to 79 years of age derived from the Bruneck (Italy) population (39) that OxLDL-E06 predicts the presence of carotid atherosclerosis at baseline as well as the 5-year rate of progression (40). This is consistent with our recent observation that OxLDL-E06 levels are independent predictors of angiographically determined coronary atherosclerosis (8). Third, the wide age range of the subjects (from 8 to 18 years of age) may have introduced unmeasured variables in the progression of IMT and its relationship to OxLDL markers. Fourth, the IMT thickness at this age group was quite modest at  0.5 mm, which may not be sensitive enough to detect a relationship between OxLDL and vessel wall changes. Finally, it is possible that these OxLDL measures are simply not predictive of carotid IMT at this very early stage of atherogenesis. From a clinical perspective, although this study provides unique and interesting pathophysiologic insights into the role of OxLDL in children with FH, further studies are needed to fully evaluate their potential clinical value.
In summary, this study suggests that children with FH are characterized by unique changes in OxLDL markers which suggest immune activation to OxLDL. Furthermore, pravastatin treatment decreased total levels of apoB-associated immune complexes but actually increased OxPL/apoB levels, in parallel with similar increases in Lp(a) levels, which may represent a potential novel mechanism of mobilization and clearance of OxPL. Additional long-term studies in children are needed to establish whether these markers ultimately predict cardiovascular outcomes.
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Footnotes
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A patent has been awarded to the University of California in Dr. Witztum and colleagues’ names for the potential use of the E06 antibody. The patent was licensed by the University of California to Atherogenics. Dr. Witztum is a consultant to Atherogenics. This investigation was supported by NHLBI grant HL56989 to the La Jolla Specialized Center of Research in Molecular Medicine and Atherosclerosis and the Donald W. Reynolds Foundation. Dr. Alan Fogelman acted as the Guest Editor for this paper.
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