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CLINICAL RESEARCH: BIOMARKERS

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

Alexander E. Fraley, MD^_*, Gregory G. Schwartz, MD, PhD, Anders G. Olsson, MD, PhD, Scott Kinlay, MD^||,#, Michael Szarek, MS^¶, Nader Rifai, PhD^_**, Peter Libby, MD^#, Peter Ganz, MD^#,, Joseph L. Witztum, MD, Sotirios Tsimikas, MD^_*,_* MIRACL Study Investigators

^_* Division of Cardiovascular Diseases, University of California San Diego, San Diego, California
Division of Endocrinology and Metabolism, University of California San Diego, San Diego, California
Cardiology Division, Veterans Affairs Medical Center and University of Colorado, Denver, Colorado
Department of Medicine and Care, Faculty of Health Sciences, University of Linköping, Linköping, Sweden
^|| Cardiovascular Division, Veterans Affairs Boston Healthcare System, Boston, Massachusetts
^¶ Pfizer Pharmaceuticals Group, New York, New York
^# Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
^_** Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts
Cardiology Division, San Francisco General Hospital and University of California, San Francisco, California

Manuscript received October 21, 2008; revised manuscript received February 5, 2009, accepted February 11, 2009.

^_* 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 sought to define the relationship between oxidative biomarkers, cardiovascular disease (CVD) risk factors, and inflammatory and thrombosis biomarkers.

Background: Elevated levels of oxidized phospholipids (OxPL) on apolipoprotein B particles (apoB) represent a novel biomarker of CVD. Previous studies suggest that an increase in OxPL/apoB reflects a positive response to statins and a low-fat diet.

Methods: This study measured OxPL/apoB, lipoprotein (a) [Lp(a)], and oxidized low-density lipoprotein (OxLDL) biomarkers, consisting of immunoglobulin (Ig)G and IgM autoantibodies to malondialdehyde (MDA)-low-density lipoprotein (LDL) and IgG and IgM apoB-100 immune complexes (IC/apoB), at baseline and after 16 weeks of treatment with atorvastatin 80 mg/day or placebo in 2,342 patients with acute coronary syndromes (ACS) enrolled in the MIRACL (Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering) trial.

Results: At baseline, potentially atheroprotective IgM autoantibodies and IgM IC/apoB were lower in male patients, diabetic patients, and patients >65 years of age. Patients with an LDL level greater than the median (122 mg/dl) had higher levels of OxPL/apoB, Lp(a), and OxLDL biomarkers compared with those who had an LDL level less than the median. Atorvastatin resulted in significantly larger changes in all biomarkers in female patients, patients age <65 years, patients with LDL cholesterol <122 mg/dl, nonsmokers, and nondiabetic patients (p < 0.0001 for all). In particular, a significant increase in OxPL/apoB in response to atorvastatin was noted in all 20 subgroups evaluated. Weak or no significant correlations were noted between all OxLDL biomarkers and C-reactive protein, serum amyloid A, tissue plasminogen activator, interleukin-6, intercellular adhesion molecule, vascular cell adhesion molecule, P-selectin, and E-selectin at randomization and 16 weeks.

Conclusions: In patients with ACS, baseline levels of oxidative biomarkers varied according to specific CVD risk factors and were largely independent of inflammatory biomarkers. Atorvastatin uniformly increased OxPL/apoB levels in all subgroups studied. Future studies are warranted to assess whether the increase in OxPL/apoB levels reflects the benefit of effective therapeutic interventions and prediction of new CVD events.

Key Words: risk factors • acute coronary syndromes • lipoproteins • oxidation • statins

Abbreviations and Acronyms   ACS = acute coronary syndrome   apoB = apolipoprotein B-100   CI = confidence interval   CVD = cardiovascular disease   IC/apoB = apolipoprotein B-immune complexes   Ig = immunoglobulin   Lp(a) = lipoprotein (a)   MDA = malondialdehyde   OxLDL = oxidized low-density lipoprotein   OxPL = oxidized phospholipids

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J. Am. Coll. Cardiol. 2009 53: A24. [Full Text] [PDF]