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.
OBJECTIVE
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.
Fraley
Alexander E
AE
University of California San Diego, 92093-0682, USA.
Schwartz
Gregory G
GG
Olsson
Anders G
AG
Kinlay
Scott
S
Szarek
Michael
M
Rifai
Nader
N
Libby
Peter
P
Ganz
Peter
P
Witztum
Joseph L
JL
Tsimikas
Sotirios
S
D054058:Acute Coronary Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D000368:Aged; D000369:Aged, 80 and over; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001055:Apolipoproteins B / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D000069059:Atorvastatin; D001323:Autoantibodies / Q000032:analysis; D015415:Biomarkers / Q000032:analysis; D008078:Cholesterol, LDL / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D006538:Heptanoic Acids / Q000627:therapeutic use*; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D007249:Inflammation / Q000503:physiopathology; D017270:Lipoprotein(a) / Q000032:analysis; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000032:analysis / Q000378:metabolism; D011758:Pyrroles / Q000627:therapeutic use*; D017382:Reactive Oxygen Species; D012307:Risk Factors; D013923:Thromboembolism
D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; D001323:Autoantibodies; D015415:Biomarkers; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D017270:Lipoprotein(a); D010743:Phospholipids; D011758:Pyrroles; D017382:Reactive Oxygen Species; D000069059:Atorvastatin