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CLINICAL RESEARCH: CORONARY ARTERY DISEASE

Circulating Lipid Hydroperoxides Predict Cardiovascular Events in Patients With Stable Coronary Artery Disease

The PREVENT Study

Mary F. Walter, PhD^_*, Robert F. Jacob, PhD^_*,, Rebekah E. Bjork, BS^_*, Barrett Jeffers, PhD, Jan Buch, MD, Yoshiko Mizuno, MD, PhD^_*,, R. Preston Mason, PhD^_*,,_* on behalf of the PREVENT Investigators

^_* Elucida Research, Beverly, Massachusetts
Pfizer Inc., New York, New York
Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.

Manuscript received June 19, 2007; revised manuscript received November 12, 2007, accepted November 12, 2007.

^_* Reprint requests and correspondence: Dr. R. Preston Mason, P.O. Box 7100, Beverly, Massachusetts 01915. (Email: rpmason{at}elucidaresearch.com).

Objectives: This study was designed to determine the predictive value of lipid hydroperoxide (LOOH) levels for adverse cardiovascular outcomes in patients with stable coronary artery disease (CAD).

Background: Oxidative modification of circulating lipids contributes to inflammation and endothelial dysfunction, which are hallmark features of atherosclerosis. A serum biomarker of oxidation is LOOH, which is a primary product of fatty acid peroxidation.

Methods: Serum LOOH levels were measured and correlated with clinical events over a 3-year period in 634 patients with angiographic evidence of CAD.

Results: Baseline LOOH levels in the highest quartile were associated with hazard ratios of 3.24 (95% confidence interval [CI] 1.86 to 5.65; p = 0.0001) for nonfatal vascular events (n = 149), 1.80 (95% CI 1.13 to 2.88; p = 0.014) for major vascular procedures (n = 139), and 2.23 (95% CI 1.44 to 3.44; p = 0.0003) for all vascular events and procedures. Baseline LOOH levels correlated with serum levels of soluble intercellular adhesion molecule-1 (p = 0.001) and thiobarbituric acid reactive substances (p = 0.001) as well as the mean percent change in stenosis for large segments >50% stenosed (p = 0.048). A multivariate proportional hazards model, adjusted for traditional risk factors and inflammatory markers, showed an independent effect of LOOH on nonfatal vascular events, vascular procedures, and all events or procedures. Amlodipine treatment was associated with reduced cardiovascular events and changes in LOOH levels compared with placebo.

Conclusions: Elevated LOOH levels were predictive of nonfatal vascular events and procedures in patients with stable CAD, independent of traditional risk factors and inflammatory markers.

Abbreviations and Acronyms   BMI = body mass index   CAD = coronary artery disease   CV = coefficients of variation   CVD = cardiovascular disease   DBP = diastolic blood pressure   FOX = ferrous oxidation of xylenol orange   HDL = high-density lipoprotein   HPLC = high-performance liquid chromatography   hs-CRP = high sensitivity C-reactive protein   IL = interleukin   LDL = low-density lipoprotein   LOOH = lipid hydroperoxide   Lp-PLA2 = lipoprotein-associated phospholipase A2   MDA = malondialdehyde   MI = myocardial infarction   QC = quality control   SBP = systolic blood pressure   sICAM = soluble intercellular adhesion molecule   TBA = thiobarbituric acid   TBARS = thiobarbituric acid reactive substances

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