Association of oxidized ApoB and oxidized ApoA-I with high-risk coronary plaque features in cardiovascular disease
Alexander V. Sorokin, Christin G. Hong, Angel M. Aponte, Elizabeth M. Florida, Jingrong Tang, Nidhi Patel, Irina N. Baranova, Haiou Li, Philip M. Parel, Vicky Chen, Sierra R. Wilson, Emily L. Ongstad, Anna Collén, Martin P. Playford, Thomas L. Eggerman, Marcus Y. Chen, Kazuhiko Kotani, Alexander V. Bocharov, Alan T. Remaley
Alexander V. Sorokin, Christin G. Hong, Angel M. Aponte, Elizabeth M. Florida, Jingrong Tang, Nidhi Patel, Irina N. Baranova, Haiou Li, Philip M. Parel, Vicky Chen, Sierra R. Wilson, Emily L. Ongstad, Anna Collén, Martin P. Playford, Thomas L. Eggerman, Marcus Y. Chen, Kazuhiko Kotani, Alexander V. Bocharov, Alan T. Remaley
View: Text | PDF
Clinical Research and Public Health Cardiology Inflammation

Association of oxidized ApoB and oxidized ApoA-I with high-risk coronary plaque features in cardiovascular disease

Abstract

BACKGROUND. Oxidized apolipoprotein B (oxLDL) and oxidized ApoA-I (oxHDL) are proatherogenic. Their prognostic value for assessing high-risk plaques by coronary computed tomography angiography (CCTA) is missing.METHODS. In a prospective, observational study, 306 participants with cardiovascular disease (CVD) had extensive lipoprotein profiling. Proteomics analysis was performed on isolated oxHDL, and atherosclerotic plaque assessment was accomplished by quantitative CCTA.RESULTS. Patients were predominantly White, overweight men (58.5%) on statin therapy (43.5%). Increase in LDL-C, ApoB, small dense LDL-C (P < 0.001 for all), triglycerides (P = 0.03), and lower HDL function were observed in the high oxLDL group. High oxLDL associated with necrotic burden (NB; β = 0.20; P < 0.0001) and fibrofatty burden (FFB; β = 0.15; P = 0.001) after multivariate adjustment. Low oxHDL had a significant reverse association with these plaque characteristics. Plasma oxHDL levels better predicted NB and FFB after adjustment (OR, 2.22; 95% CI, 1.27–3.88, and OR, 2.80; 95% CI, 1.71–4.58) compared with oxLDL and HDL-C. Interestingly, oxHDL associated with fibrous burden (FB) change over 3.3 years (β = 0.535; P = 0.033) when compared with oxLDL. Combined Met136 mono-oxidation and Trp132 dioxidation of HDL showed evident association with coronary artery calcium score (r = 0.786; P < 0.001) and FB (r = 0.539; P = 0.012) in high oxHDL, whereas Met136 mono-oxidation significantly associated with vulnerable plaque in low oxHDL.CONCLUSION. Our findings suggest that the investigated oxidized lipids are associated with high-risk coronary plaque features and progression over time in patients with CVD.TRIAL REGISTRATION. ClinicalTrials.gov NCT01621594.FUNDING. National Heart, Lung, and Blood Institute at the NIH Intramural Research Program.

Authors

Alexander V. Sorokin, Christin G. Hong, Angel M. Aponte, Elizabeth M. Florida, Jingrong Tang, Nidhi Patel, Irina N. Baranova, Haiou Li, Philip M. Parel, Vicky Chen, Sierra R. Wilson, Emily L. Ongstad, Anna Collén, Martin P. Playford, Thomas L. Eggerman, Marcus Y. Chen, Kazuhiko Kotani, Alexander V. Bocharov, Alan T. Remaley

×

Figure 3

Overview of the OMLs’ association with high-risk coronary plaque phenotype and potential mechanisms of action in cardiovascular disease.

Options: View larger image (or click on image) Download as PowerPoint
Overview of the OMLs’ association with high-risk coronary plaque phenoty...
Upon oxidation, both LDL (oxLDL) and HDL (oxHDL) sustain bidirectional exchange of the cholesteryl esters (CE) and TGs between each other and TG-rich lipoproteins (TRLP). This reaction is catalyzed by cholesteryl ester transfer protein (CETP), which could be altered by excessive oxidation and lipoprotein structural modifications. Indeed, oxidized ApoA-I sites (M136 and W132) may impair the reverse cholesterol transport pathway and alter cholesterol efflux capacity (CEC). Higher CETP activity results in elevated TG-rich LDL and HDL particle assembly accompanied by increased levels of TG-rich LDL (LDL-TG) and small dense LDL (sdLDL). Moreover, accumulated OMLs, specifically oxLDL, represent ligands for scavenger receptor activation on macrophages (CD36) and endothelial cells via intracellular lectin-like oxLDL receptor 1 (LOX-1). These biological reactions lead to proinflammatory cytokine and proteolytic enzyme production, which determines atherosclerotic plaque phenotype. Accumulation of OMLs, foam cells, and free lipids contributes to vulnerable plaque development characterized by lipid-rich necrotic core and thin fibrous cap. Under effective pharmacological treatment this phenotype can be switched to less rupture-prone plaque stabilized by calcium deposit and fibrous cap thickening. Indeed, newly developed therapeutics for CETP, LOX-1, and CD36 inhibition open exciting avenues for atherosclerotic coronary plaque management. Right: Representative CCTA images of atherosclerotic plaque in the left anterior descending artery of study cohort patients. Cross-sectional views demonstrate high-risk and stable plaque phenotypes. Yellow circles delineate vessel lumen, and orange circles delineate its wall. Plaque characteristics include fibrous (dark green), fibrofatty (light green), and necrotic (red) components.