Apolipoprotein E∗ϵ2 carriers exhibit high aspirin-treated platelet reactivity and low cardiovascular risk during long-term aspirin treatment

Abstract

Objective: Apolipoprotein E (APOE) loci, including rs429358 (ϵ4) and rs7412 (ϵ2), are involved in cardiovascular (CV) health. However, their effect on the CV-protective effect of aspirin remains unknown. Methods: A total of 515 aspirin-treated individuals with existing CV diseases were recruited, and their APOE genotypes, platelet functions and other routine laboratory parameters were assessed when they enrolled. The first major CV events (myocardial infarction, stroke, revascularisation and CV death) and all CV events (major CV events plus unstable angina and transient ischaemic attack) during a mean 5.2-year follow-up period were recorded. Results: After adjusting for age, gender, BMI, lifestyle, lipid profiles and other CV drugs and comorbidities, ϵ2 carriers were found to exhibit ~80% lower risk of major CV and 60% lower risk of all CV (HR = 0.186, CI: 0.048-0.715, P = 0.014; HR = 0.435, CI: 0.234-0.812, P = 0.009, respectively) than ϵ2 noncarriers. Furthermore, high incidence of high platelet reactivity assessed by arachidonic acid-induced light transmission aggregometry (23.4 vs. 13.7%, P = 0.038), triglyceride and haemoglobin and low low-density lipoprotein were observed. ϵ4 carriers had slightly increased cholesterol and hypercholesterolemia incidence relative to ϵ4 noncarriers. Conclusions: Our results demonstrated that APOE∗ϵ2 carriers can derive additional CV benefit from long-term aspirin treatment. Moreover, it was observed that APOE2 interacts with cyclooxygenase-1 (COX-1) and upregulates its activity. The CV-protective effect of aspirin in ϵ2 carriers is likely attributed to APOE2 upregulating vascular COX-1-mediated CV protective pathway, together with aspirin partially inhibiting platelet COX-1-mediated platelet aggregation.