Letter Regarding Article by Tsimikas 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”

Radboud University Medical Centre (Radboudumc), Nymegen, Gelderland, Netherlands
Circulation (Impact Factor: 14.43). 06/2005; 111(18):e284-5; author reply e284-5. DOI: 10.1161/01.CIR.0000164264.00913.6D
Source: PubMed


predominantly associated with Lp(a), 2 the increased OxPL/apoB ratio could be explained by the shift in the Lp(a)/LDL ratio. Similarly, in the placebo-treated group the decreased OxPL/apoB ratio results from a decrease in Lp(a) relative to LDL. It is therefore unlikely that the OxPL/apoB ratio is a surrogate marker of net removal of OxPL from the vessel wall. Moreover, the observed 30% decrease in total plasma apoB-OxPL also argues against an increased net efflux of OxPL from the vessel wall. Recently, using the OxLDL assay from Mercodia in which an oxidation epitope associated with apoB is detected with mono- clonal antibody 4E6, we found that atorvastatin (80 mg/d) and simvastatin (40 mg/d) reduced total plasma Ox-apoB (43% and 35%, respectively) in patients with familial hypercholesterol- emia from the ASAP study.3 Interestingly, we observed no change in the Ox-apoB/apoB ratio when we used the noncom- petitive version of the kit, in which the immobilized antibody captures Ox-apoB from the sample. We did, however, observe a small increase in the Ox-apoB/apoB ratio (18% for atorvastatin, 13% for simvastatin) when we used the competitive version, which unlike the noncompetitive version is sensitive to the number of oxidation epitopes associated with apoB. In addition, the increase in Ox-apoB/apoB ratio can be explained by an increase in Lp(a) relative to LDL. To further address this question, measurements of OxLDL with E06 and 4E6 in well- designed assays (eg, in isolated Lp(a) particles) at different time points after the start of statin treatment are required.

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Available from: Anton F H Stalenhoef
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    ABSTRACT: It has been suggested that high doses of statins can be more effective in reducing the incidence of new cardiovascular events than conventional doses. The present study analyzed the effect of increasing the atorvastatin dose to 80 mg/day on indices of inflammation (C-reactive protein or CRP), thrombogenesis (prothrombin fragment [F1+2]) and fibrinolysis (tissue-type plasminogen activator antigen, t-PA, and its inhibitor PAI-1) in high-risk patients with ischemic heart disease. We studied 27 patients with high-risk coronary heart disease who had lipid levels above those recommended despite treatment with atorvastatin at 40 mg/day. At baseline, patients were compared with 21 normocholesterolemic subjects without arteriosclerotic disease. Twenty-four patients were reevaluated 3 months after the atorvastatin dose was increased to 80 mg/day. The CRP, F1+2, t-PA and PAI-1 levels were significantly higher in patients than control subjects (all P<.05). After the atorvastatin dose was increased, significant reductions in CRP, F1+2, and PAI-1 levels were observed (P<.05). There was a significant positive correlation between the reduction in cholesterol level and that in F1+2 (r=0.43; P=.023). No other significant correlations were found. In a group of patient with high-risk heart disease and elevated lipid levels, increasing the atorvastatin dose led to significant improvements in inflammatory, thrombogenic, and hypofibrinolytic states.
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    ABSTRACT: The concept that the oxidation of lipoproteins is central in the pathogenesis of atherosclerosis was first reported over 25 years ago, initially by in vitro studies and subsequently through experimental models of atherosclerosis. The innate immune system plays a key role in atherogenesis as manifested by its atherosclerosis-modulating properties, the immunogenicity of oxidized low-density lipoprotein (LDL), and the presence of oxidized LDL autoantibodies in plasma and lesions of humans. In the past 10 years it has been possible to generate monoclonal antibodies to oxidized LDL to directly measure oxidized LDL in plasma. This has led to a rapidly accelerating pace of new reports on the relationship of circulating oxidized LDL and various cardiovascular pathologic processes, which are the focus of this review.
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    ABSTRACT: The purpose of this work was to determine the predictive value of oxidized phospholipids (OxPLs) present on apolipoprotein B-100 particles (apoB) in carotid and femoral atherosclerosis. The OxPLs are pro-inflammatory and pro-atherogenic and may be detected using the antibody E06 (OxPL/apoB). The Bruneck study is a prospective population-based survey of 40- to 79-year-old men and women initiated in 1990. Plasma levels of OxPL/apoB and lipoprotein (a) [Lp(a)] were measured in 765 of 826 (92.6%) and 671 of 684 (98.1%) subjects alive in 1995 and 2000, respectively, and correlated with ultrasound measures of carotid and femoral atherosclerosis. The distribution of the OxPL/apoB levels was skewed to lower levels and nearly identical to Lp(a) levels. The OxPL/apoB and Lp(a) levels were highly correlated (r = 0.87, p < 0.001), and displayed long-term stability and lacked correlations with most cardiovascular risk factors and lifestyle variables. The number of apolipoprotein (a) kringle IV-2 repeats was inversely related to Lp(a) mass (r = -0.48, p < 0.001) and OxPL/apoB levels (r = -0.46, p < 0.001). In multivariable analysis, OxPL/apoB levels were strongly and significantly associated with the presence, extent, and development (1995 to 2000) of carotid and femoral atherosclerosis and predicted the presence of symptomatic cardiovascular disease. Both OxPL/apoB and Lp(a) levels showed similar associations with atherosclerosis severity and progression, suggesting a common biological influence on atherogenesis. This study suggests that pro-inflammatory oxidized phospholipids, present primarily on Lp(a), are significant predictors of the presence and extent of carotid and femoral atherosclerosis, development of new lesions, and increased risk of cardiovascular events. The OxPL biomarkers may provide valuable insights into diagnosing and monitoring cardiovascular disease.
    Full-text · Article · Jun 2006 · Journal of the American College of Cardiology
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