The Effect of Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Inhibitors on Endothelial Progenitor Cells

Background: Endothelial progenitor cells (EPCs) have an important role in the process of vascular repair by promoting re-endothelialization following endothelial injury. We hypothesized that proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors, which reduce cardiovascular events, will increase the level of active EPCs.

Methods: Study population included patients with stable coronary artery disease (CAD) who were initiated PCSK9 inhibitors. Blood samples were drawn and evaluated for EPCs at baseline and 1 month after the initiation of treatment. Circulating EPCs were assessed quantitatively by the expression of VEGFR-2 and CD34 using flow cytometry, and functionally by the formation of colony forming units (CFUs). MTT assay was used to demonstrate cell viability.

Results: Our cohort included 20 patients with median age of 67 (IQR 62, 75) years and male predominance (n=14, 70%). At baseline, total cholesterol and low density lipoprotein levels were 200 (IQR 180, 247) mg/dL and 132 (IQR 108, 156) mg/dL, respectively. Following 1-month of treatment with a PCSK9 inhibitor, LDL levels decreased to a median of 53 (IQR 26, 65) mg/dL. Moreover, we observed the up-regulation of CD34⁽⁺⁾/VEGFR-2⁽⁺⁾ cells [1.2% (IQR 0.6, 1.6) to 2.3% (IQR 1.2, 4.2), P=0.013]. Functionally, active EPCs were evident microscopically by their ability to form colonies (from 1 CFUs [IQR 0.5, 1) to 1.5 CFUs (IQR 1, 2.3), P<0.001]. EPCs’ viability was demonstrated by an MTT assay [0.13 (IQR 0.11, 0.19) to 0.19 (IQR 0.17, 0.21), p<0.001].

Conclusions: Patients with CAD treated with PCSK9 inhibitors demonstrate higher levels of active EPCs, possibly reflecting the promotion of endothelial repair. This finding may represent a novel mechanism of action of PCSK9 inhibitors, which might have important future clinical implications for the treatment of CAD or other atherosclerotic diseases.