title: Oxidation-specific biomarkers, prospective 15-year cardiovascular and stroke outcomes, and net reclassification of cardiovascular events.
abstract: OBJECTIVE
  This study sought to assess the long-term predictive value and net reclassification for risk of cardiovascular disease (CVD) of biomarkers reflecting oxidation-specific epitopes (OSEs).
  
  
  BACKGROUND
  OSEs are immunogenic, proinflammatory, and proatherogenic. The long-term predictive value and net reclassification of OSEs for risk of CVD events are not known.
  
  
  METHODS
  Oxidized phospholipids on apolipoprotein B-100 (OxPL/apoB) and immunoglobulin (Ig)-G (IgG) and IgM autoantibodies to malondialdehyde-modified, low-density lipoprotein (MDA-LDL) and copper-oxidized LDL (Cu-OxLDL) were measured in 765 subjects in 1995 and 656 subjects in 2000 in the Bruneck study, representing 45- to 84-year-old men and women from the general community.
  
  
  RESULTS
  Over 15 years of follow-up, 138 subjects reached the primary endpoint of incident CVD (ischemic stroke, myocardial infarction, new-onset unstable angina, acute coronary interventions, and vascular death). In a multivariable Cox model, the highest tertile of OxPL/apoB was associated with higher risk of CVD (hazard ratio [HR]: 2.4; 95% confidence interval [CI]: 1.5 to 3.7) and stroke (HR: 3.6; 95% CI: 1.8 to 7.4) compared with the lowest tertile. IgG Cu-OxLDLs were associated with higher risk of CVD, whereas IgM MDA-LDLs were associated with lower risk. Using OxPL/apoB, IgG Cu-OxLDL, and IgM MDA-LDL variables, the area under the curve (AUC) for CVD risk prediction increased from 0.664 (95% CI: 0.629 to 0.697) to 0.705 (95% CI: 0.672 to 0.737) (p = 0.048). The net reclassification index (NRI) was 0.163 (p = 0.0044) and 0.332 (p < 0.0001) in all subjects (n = 765) and in subjects with intermediate risk (n = 305), respectively. Of 627 subjects who remained free of CVD, 108 were correctly reclassified to a lower risk category, and 83 were reclassified to a higher category (categories: 15-year risk <15%, 15% to 30%, >30%).
  
  
  CONCLUSIONS
  OSE biomarkers predict 15-year CVD and stroke outcomes and provide potential clinical utility by reclassifying a significant proportion of individuals into higher or lower risk categories after traditional risk assessment.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA, USA. stsimikas@ucsd.edu
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tsimikas
authors.forename: Peter
authors.initials: P
authors.lastname: Willeit
authors.forename: Johann
authors.initials: J
authors.lastname: Willeit
authors.forename: Peter
authors.initials: P
authors.lastname: Santer
authors.forename: Manuel
authors.initials: M
authors.lastname: Mayr
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Xu
authors.forename: Agnes
authors.initials: A
authors.lastname: Mayr
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.forename: Stefan
authors.initials: S
authors.lastname: Kiechl
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood*; D002318:Cardiovascular Diseases / Q000097:blood / Q000145:classification* / Q000453:epidemiology; D000939:Epitopes; D005260:Female; D005500:Follow-Up Studies; D005544:Forecasting / Q000379:methods*; D006801:Humans; D015994:Incidence; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000097:blood*; D011446:Prospective Studies; D020521:Stroke / Q000097:blood* / Q000145:classification / Q000453:epidemiology; D015996:Survival Rate / Q000639:trends
chemical_list: D015415:Biomarkers; D000939:Epitopes; D010743:Phospholipids