Author + information
- Received October 21, 2008
- Revision received February 5, 2009
- Accepted February 11, 2009
- Published online June 9, 2009.
- 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
- ↵⁎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
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.
Dr. Schwartz has received a research grant from Pfizer. Dr. Olsson is a member of the Speakers' Bureau for Pfizer and AstraZeneca; has received honoraria from Pfizer and AstraZeneca; is an expert witness for Pfizer and AstraZeneca; and is a consultant/Advisory Board member for Pfizer, AstraZeneca, and Merck. Dr. Kinlay has received a research grant from Pfizer, is on the Speakers' Bureau for Pfizer, and has received honorarium from Pfizer and Merck. Dr. Szarek is a former employee of Pfizer. Dr. Libby does not accept remuneration from the pharmaceutical industry and serves as an unpaid coinvestigator on clinical trials sponsored by AstraZeneca, Merck, and Pfizer. Dr. Ganz has received a research grant from Pfizer, is on the Speakers' Bureau of Pfizer, and is a consultant/Advisory Board member for Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, and Atherogenics. Dr. Witztum is a coinventor of patents and patent applications through the University of California for the commercial use of oxidation-specific antibodies; is a consultant/Advisory Board member for ISIS, Atherogenics, and Atherotope, Inc. (officer); and is a Speakers' Bureau member for Merck-Schering. Dr. Tsimikas is a coinventor of patents and patent applications through the University of California for the commercial use of oxidation-specific antibodies; has received research grants from Pfizer, ISIS, Novartis, and GlaxoSmithKlein; is a consultant/Advisory Board member for Pfizer, ISIS, and Atherotope, Inc. (officer); and is on the Speakers' Bureau for Merck-Schering. This investigation was supported by the Fondation Leducq, by an investigator-initiated research grant (Advances in Atorvastatin Research Grant) to Dr. Tsimikas from Pfizer, Inc., and in part by the General Clinical Research Center, University of California, San Diego with funding provided by the National Center for Research Resources, M01RR00827, USPHS. James K. Liao, MD, served as the Guest Editor for this article.
- Received October 21, 2008.
- Revision received February 5, 2009.
- Accepted February 11, 2009.
- American College of Cardiology Foundation