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CLINICAL RESEARCH: CORONARY ARTERY DISEASE

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

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).

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

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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