Oxidized Phospholipids on ApoB-100, Platelet Activation and Reactivity, and Long-Term Cardiovascular Outcomes

Abstract

Background: OxPL-apoB (oxidized phospholipids [OxPL] on apoB-100), which include OxPL present on Lp(a) (lipoprotein[a]), are associated with higher cardiovascular risk. Experimental studies suggest that OxPL may influence platelet function.

Methods: This observational study assessed the association of OxPL-apoB with intrinsic and on‑clopidogrel platelet reactivity and long-term cardiovascular events in patients undergoing coronary angiography with or without percutaneous coronary intervention in 2040 patients in the EXCELSIOR trial (Impact of Extent of Clopidogrel-Induced Platelet Inhibition During Elective Stent Implantation on Clinical Event Rate). The association of OxPL-apoB to expression of CD62P, CD41, or PAC-1 levels and intrinsic and on-clopidogrel platelet reactivity to collagen and ADP was determined. The relationship of OxPL-apoB and Lp(a) to myocardial infarction-free survival and all-cause mortality at a median of 7 years was assessed using Cox regression models.

Results: Elevated levels of OxPL-apoB were associated with the severity of coronary obstruction, and higher prevalence of prior myocardial infarction, percutaneous coronary intervention, and coronary artery bypass graft surgery. No significant associations were present between OxPL-apoB and intrinsic or on-clopidogrel platelet reactivity or activation of platelet receptors. Analyzed individually in separate multivariable models, both OxPL-apoB (hazard ratio, 1.022 [95% CI, 1.005-1.040]; P=0.010) and Lp(a) (hazard ratio, 1.002 [95% CI, 1.000-1.005]; P=0.032) were associated with worse myocardial infarction-free survival. However, in a joint multivariable model analyzed together, neither OxPL-apoB nor Lp(a) was significant. The optimal cut point for myocardial infarction-free survival for OxPL-apoB was 8 nmol/L (hazard ratio, 1.391 [95% CI, 1.086-1.780]; P=0.009) and for Lp(a) 30 mg/dL (hazard ratio, 1.261 [95% CI, 1.012-1.570]; P=0.038).

Conclusions: In patients undergoing coronary angiography with or without percutaneous coronary intervention, OxPL-apoB was not associated with intrinsic and on-clopidogrel platelet reactivity mediated by collagen or ADP. The association of OxPL-apoB and Lp(a) suggests that the accumulation of OxPL on Lp(a) may be a key determinant of long-term cardiovascular outcomes.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00457236.

Keywords: aspirin; atherosclerosis; clopidogrel; lipoproteins; myocardial infarction.