OBJECTIVES: 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.
OBJECTIVES: 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: Daniel B Harmon; Prasad Srikakulapu; Jennifer L Kaplan; Stephanie N Oldham; Chantel McSkimming; James C Garmey; Heather M Perry; Jennifer L Kirby; Thomas A Prohaska; Ayelet Gonen; Peter Hallowell; Bruce Schirmer; Sotirios Tsimikas; Angela M Taylor; Joseph L Witztum; Coleen A McNamara Journal: Arterioscler Thromb Vasc Biol Date: 2016-02-11 Impact factor: 8.311
Authors: Calvin Yeang; Devin Hasanally; Xuchu Que; Ming-Yow Hung; Aleksandra Stamenkovic; David Chan; Rakesh Chaudhary; Victoria Margulets; Andrea L Edel; Masahiko Hoshijima; Yusu Gu; William Bradford; Nancy Dalton; Phuong Miu; David Yc Cheung; Davinder S Jassal; Grant N Pierce; Kirk L Peterson; Lorrie A Kirshenbaum; Joseph L Witztum; Sotirios Tsimikas; Amir Ravandi Journal: Cardiovasc Res Date: 2019-01-01 Impact factor: 10.787
Authors: Ayelet Gonen; Soo-Ho Choi; Phuong Miu; Colin Agatisa-Boyle; Daniel Acks; Angela M Taylor; Coleen A McNamara; Sotirios Tsimikas; Joseph L Witztum; Yury I Miller Journal: J Lipid Res Date: 2018-12-18 Impact factor: 5.922
Authors: Teemu J Niiranen; Danielle M Enserro; Martin G Larson; Ramachandran S Vasan Journal: J Gerontol A Biol Sci Med Sci Date: 2019-10-04 Impact factor: 6.053
Authors: Aditi Upadhye; Prasad Srikakulapu; Ayelet Gonen; Sabrina Hendrikx; Heather M Perry; Anh Nguyen; Chantel McSkimming; Melissa A Marshall; James C Garmey; Angela M Taylor; Timothy P Bender; Sotirios Tsimikas; Nichol E Holodick; Thomas L Rothstein; Joseph L Witztum; Coleen A McNamara Journal: Circ Res Date: 2019-09-24 Impact factor: 17.367