Figure 1. Monocyte phenotypes in patients with familial hypercholesterolaemia (FH) and effects of PCSK9 inhibitors.

In patients with FH, hepatic clearance of LDLs is impaired, LDL levels are elevated, and LDLs can be modified in blood. Modified LDLs (mLDLs) are then taken up by circulating monocytes, possibly via scavenger receptors (SRs), such as platelet glycoprotein 4 (CD36) and macrophage scavenger receptor type 1, leading to lipid accumulation within monocytes and formation of foamy monocytes in the circulation. Lipid accumulation in monocytes can change the monocyte phenotype leading to upregulation of C-C chemokine receptor type 2 (CCR2) and SRs, and also of adhesion molecules such as integrin-α_X (CD11c). In patients with FH, foamy monocytes with upregulation of CCR2 and adhesion molecules show enhanced migration capacity and might, therefore, accelerate development of atherosclerosis by infiltrating into arterial walls and becoming foam cells. Treatment with PCSK9 monoclonal antibodies (mAbs) in patients with FH significantly lowers LDL levels and also reduces monocyte levels of intracellular lipids and CCR2, with reductions in monocyte migration capacity, and might, therefore, prevent progression and enhance regression of atherosclerosis. CCL2, C-C motif chemokine 2; ICAM, intercellular adhesion molecule; VCAM1, vascular cell adhesion protein 1.