Proprotein convertase subtilisin/kexin type 9 (PCSK9), platelet activation and interaction with the vascular endothelium: the impact of PCSK9 inhibition with evolocumab in acute coronary syndrome

Abstract

Abstract Background/Introduction Platelet activation and endothelial dysfunction may contribute to adverse outcomes in patients with acute myocardial infarction. Pre-clinical studies indicate PCSK9 enhances platelet activation. Purpose Our goals were (1) to examine the role of PCSK9 as a potential mediator of platelet activation in patients with acute coronary syndrome (ACS) and (2) to perform immunohistochemical studies of left internal mammary artery (LIMA) specimens to examine interactions among PCSK9, platelets, and endothelial cells in specimens obtained during coronary bypass surgery. Methods Participants from the Evolocumab in Acute Coronary Syndrome trials (EVACS; NCT03515304, NCT04082442), with a NSTEMI and a troponin-I of >5 ng/ml or a STEMI were randomized to placebo or to 420 mg SC of evolocumab, a monoclonal anti-PCSK9 antibody, within 24 hours of hospitalization. We performed serial ex vivo analysis of PF4, a marker of platelet activation, in serum samples obtained at baseline (prior to study drug administration) and at day 30. PF4 values were normalized to total platelet count. All of the participants were on guideline-directed therapies for ACS. Additionally, LIMA samples from patients undergoing coronary bypass surgery were immunostained with PCSK9, the endothelial cell transmembrane glycoprotein CD31 (platelet endothelial cell adhesion molecule-1) and the platelet surface marker CD61 (integrin beta-3). Outcome data were summarized using medians and interquartile ranges. Results Forty-six participants were randomized in a 1:1 fashion to placebo or to evolocumab. Mean (±SD) age of the cohort was 60±13 years, 48% were women and 22% were African American. Baseline PF4 levels (expressed as ng/1k platelets) were similar between the two groups (placebo: 9.3 [4–12] vs evolocumab 8.0 [4–12], p=0.8). In the placebo group, there was a significant increase in PF4 at 30 days to 13.1 [11–14], p<0.01 (baseline vs 30 days). In contrast, there was no significant change from baseline in the evolocumab group at 30 days (10.7 [6–13]), which was significantly lower than the placebo group (p=0.04). Furthermore, immunostaining of LIMA specimens obtained from patients during coronary artery bypass surgery revealed colocalization of PCSK9, CD31, and CD61 on the vascular endothelial cell surface (see Figure). Conclusion PCSK9 inhibition with evolocumab decreases platelet activation in ACS patients on dual anti-platelet therapy. PCSK9 is associated with platelets and endothelial cells at the vascular endothelium. PCSK9 is a potential mediator of the interaction between platelets and vascular endothelial cells in patients with coronary artery disease. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Amgen