Abstract 19015: Loss of Plasma Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) After LDL Apheresis

Abstract

Low-density lipoprotein (LDL) apheresis (LDL-A) is used to reduce LDL levels in patients with severe familial hypercholesterolemia (FH). We, and others, have previously reported that up to 40% of plasma PCSK9 is bound to LDL, while the rest is with the apoB-deficient fraction. Therefore, we examined whether LDL-A treatment using dextran-sulfate columns (Liposorber®) affects plasma PCSK9 levels. Pre and post apheresis plasma from five FH patients in three consecutive treatment cycles was used to determine changes in PCSK9 levels. Lipid, albumin, CK-MB, and creatinine levels were also evaluated. LDL-A treatment, as expected, significantly reduced plasma LDL (by 85±6%). In addition, PCSK9 levels fell by 52±7%, and this decrease was significantly correlated with the LDL drop (p=0.02, r 2 =0.304 ), but not with decreases in triglyceride or HDL levels. Levels of other plasma analytes (albumin, creatinine, CK-MB) did not show changes after apheresis treatment. Similar to LDL, PCSK9 levels returned to pre-treatment values between cycles (2-week intervals). Fractionation of pre and post plasma showed that 87±4% of LDL-bound PCSK9 and 38±14% of the PCSK9 associated with the apoB-deficient fraction were removed. From the column eluate we recovered more than 80% of the PCSK9 removed from the circulation. Running human plasma, isolated LDL and apoB-deficient plasma through a scaled-down apheresis column we again found a loss of 57% of total PCSK9, including 89% of LDL-bound PCSK9 and 41% of the PCSK9 associated with the apoB-deficient fraction. These decreases in PCSK9 levels are in the range of what is accomplished with current anti-PCSK9 antibody therapies. These results show for the first time that dextran-sulfate LDL apheresis substantially reduces levels of plasma PCSK9. This likely represents an additional benefit of the apheresis treatment in keeping LDL levels down over time and may contribute to the prevention of cardiovascular events in FH patients undergoing apheresis. We also provide additional proof that more than one third of plasma PCSK9 is on the circulating LDL. These findings may guide use of future anti-PCSK9 therapies in LDL-A patients, and should lead to wider indications for LDL-A, beyond the most severe FH presentations.