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J Am Coll Cardiol, 2004; 44:1996-2002, doi:10.1016/j.jacc.2004.08.029
© 2004 by the American College of Cardiology Foundation
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BIOMARKERS

Serum levels of thiobarbituric acid reactive substances predict cardiovascular events in patients with stable coronary artery disease

A longitudinal analysis of the PREVENT study

Mary F. Walter, PhD*, Robert F. Jacob, PhD*, Barrett Jeffers, PhD{ddagger}, Mathieu M. Ghadanfar, MD{ddagger}, Gregory M. Preston, PhD§, Jan Buch, MD{ddagger} and R. Preston Mason, PhD*,{dagger},*

* Elucida Research, Beverly, Massachusetts
{dagger} Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
{ddagger} Pfizer Inc., New York, New York
§ Pfizer Central Research, Groton, Connecticut

Manuscript received July 9, 2004; revised manuscript received August 3, 2004, accepted August 10, 2004.

* Reprint requests and correspondence: Dr. R. Preston Mason, 100 Cummings Center, Suite 135L, Beverly, Massachusetts 01915 (Email: rpmason{at}elucidaresearch.com).

OBJECTIVES: The objective of this study was to test the predictive value of an oxidative stress biomarker in 634 patients from the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT).

BACKGROUND: Oxidative stress contributes to mechanisms of atherosclerosis and plaque instability. Biomarkers of oxidation, such as malondialdehyde (MDA), may represent independent indicators of risk for patients with stable coronary artery disease (CAD).

METHODS: Serum MDA levels were measured as thiobarbituric acid reactive substances (TBARS) in 634 patients with documented CAD using reverse-phase high-performance liquid chromatography and spectrophotometric approaches.

RESULTS: During the three-year study, there were 51 major vascular events such as fatal/nonfatal myocardial infarction, 149 hospitalizations for nonfatal vascular events, and 139 patients underwent a major vascular procedure. At baseline, patients with TBARS levels in the highest quartile had a relative risk (RR) of 3.30 (95% confidence interval [CI] 1.47 to 7.42; p = 0.038) for major vascular events, RR of 4.10 (95% CI 2.55 to 6.60; p < 0.0001) for nonfatal vascular events, and RR of 3.84 (95% CI 2.56 to 5.76; p < 0.0001) for major vascular procedures. The effect of TBARS on events and procedures was also seen in a multivariate model adjusted for inflammatory markers (C-reactive protein, soluble intercellular adhesion molecule-1, interleukin-6), and other risk factors (age, low-density lipoprotein, high-density lipoprotein, total cholesterol, triglycerides, body mass index, and blood pressure). This analysis showed an independent effect of TBARS on major vascular events (p = 0.0149), nonfatal vascular events (p < 0.0001), major vascular procedures (p < 0.001), and all vascular events and procedures (p < 0.0001).

CONCLUSIONS: Serum levels of TBARS were strongly predictive of cardiovascular events in patients with stable CAD, independently of traditional risk factors and inflammatory markers.

Abbreviations and Acronyms
  CABG = coronary artery bypass grafting
  CAD = coronary artery disease
  CI = confidence interval
  CRP = C-reactive protein
  HDL = high-density lipoprotein
  IL-6 = interleukin-6
  LDL = low-density lipoprotein
  MDA = malondialdehyde
  PTCA = percutaneous transluminal coronary angioplasty
  PREVENT = Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial
  QCA = quantitative coronary angiography
  RR = relative risk
  sICAM-1 = soluble intercellular adhesion molecule-1
  TBARS = thiobarbituric acid reactive substances




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