Coronary Endothelial Dysfunction Is Associated With Elevated Serum PCSK9 Levels in People With HIV Independent of Low‐Density Lipoprotein Cholesterol

Abstract

Background HIV + people are at increased risk of coronary artery disease, but the responsible mechanisms are incompletely understood. Proprotein convertase subtilisin/kexin type 9 ( PCSK 9) is traditionally recognized for its importance in cholesterol metabolism; however, recent data suggest an additional, low‐density lipoprotein receptor–independent adverse effect on endothelial cell inflammation and function. We tested the hypotheses that PCSK 9 levels are increased and that abnormal coronary endothelial function is related to PCSK 9 serum levels in HIV + individuals. Methods and Results Forty‐eight HIV + participants receiving antiretroviral therapy with suppressed viral replication, without coronary artery disease, and 15 age‐ and low‐density lipoprotein cholesterol–matched healthy HIV− subjects underwent magnetic resonance imaging to measure coronary endothelial function, quantified as percentage change in coronary artery cross‐sectional area during isometric handgrip exercise, an endothelial‐dependent stressor; and blood was obtained for serum PCSK 9 and systemic vascular biomarkers. Data are presented as mean±SD. Mean serum PCSK 9 was 65% higher in the HIV + subjects (302±146 ng/ mL ) than in the HIV − controls (183±52 ng/ mL , P <0.0001). Coronary endothelial function was significantly reduced in the HIV + versus HIV − subjects (percentage change in coronary artery cross‐sectional area, 2.9±9.6% versus 11.1±3.7%; P <0.0001) and inversely related to PCSK 9 ( R =−0.51, P <0.0001). Markers of endothelial activation and injury, P‐selectin and thrombomodulin, were also significantly increased in the HIV + subjects; and P‐selectin was directly correlated with serum PCSK 9 ( R =0.31, P =0.0144). Conclusions Serum PCSK 9 levels are increased in treated HIV + individuals and are associated with abnormal coronary endothelial function, an established measure of vascular health.