Abstract 401: Hypercholesterolemia Induces Pro-Inflammatory Changes in Monocytes Which Are Reversed by PCSK9 Antibody Treatment

Abstract

Aims: Migration of monocytes into the arterial wall contributes to arterial inflammation and atherosclerosis progression. Since elevated LDL levels have been associated with activation of monocytes, intensive LDL lowering may reverse these pro-inflammatory changes. Subjects with elevated LDL levels are currently treated with statins, which are also described to have pleiotropic effects. Using proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies which selectively reduce LDL we studied the impact of LDL lowering on monocyte phenotype and function in patients with familial hypercholesterolemia (FH). Methods and Results: We assessed monocyte phenotype and function using flow cytometry for a broad range of monocyte-relevant markers and a trans-endothelial migration assay in FH patients (n=22: LDL-C 6.8±1.9mmol/L) and healthy controls (n=18, LDL-C 2.9±0.8mmol/L). Interestingly, monocyte chemokine receptor (CCR) 2 expression was approximately 3-fold increased in FH patients compared with controls (ΔMFI 605±214 vs 236±155 P <0.001). CCR2 expression correlated significantly with plasma LDL-C levels (r=0.709) and positively associated with intracellular lipid accumulation. Monocytes from FH patients also displayed enhanced migratory capacity ex vivo. After 24 weeks of PCSK9 monoclonal antibody treatment (n=17), plasma LDL-C was reduced by 49% (from 6.7±1.3 mmol/L to 3.4±1.3 mmol/L P <0.001), which coincided with reduced monocyte intracellular lipid accumulation and suppressed CCR2 expression (ΔMFI: baseline 607±209, post PCSK9 mAbs: 207±180, P <0.001). Functional relevance was substantiated by the reversal of enhanced migratory capacity of monocytes following PCSK9 monoclonal antibody therapy. All changes were comparable in subjects who were treated with statins (n=14: LDL-C 2.8±0.6mmol/L) indicating that the anti-inflammatory effects were mainly mediated through LDL lowering. Conclusions: Elevated LDL levels in FH induce pro-inflammatory changes in monocytes, which is dampened by PCSK9 monoclonal antibody therapy. LDL lowering was paralleled by reduced intracellular lipid accumulation, suggesting that LDL lowering itself is associated with anti-inflammatory effects on circulating monocytes.