Proteome Profiles of Hypercholesterolemic Patients with and Without FH Treated with a PCSK9 Inhibitor: A Comparison of Depleted and Nondepleted Samples in a Pilot Study

Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors offer a novel approach for reducing low‐density lipoprotein cholesterol (LDL‐C) levels in patients with familial hypercholesterolemia (FH). In our study, we aimed to compare the plasma proteome profiles of heterozygous FH (HeFH) patients and non‐FH patients treated with PCSK9 inhibitors (PCSK9i). Methods We analyzed 132 plasma samples from 38 patients. Samples were collected before the start of the PCSK9i treatment and then again at the third, sixth, and 12 th months of treatment. Using LC‒MS technology, we compared two approaches: depleted and nondepleted samples. Results Across all time points of treatment, numerous differentially expressed proteins were detected regardless of the FH status compared to baseline. We identified only three proteins with downregulated expression—PCSK9, CRTAC1, and PON1—with p adj <0.05 in both the depleted and nondepleted datasets after one year of treatment. NRP1 and IGHV3‐49 were differently expressed in HeFH patients compared to non‐FH patients across the entire year of treatment in depleted samples ( p <0.05). Conclusions Our study suggests that there might be differences in the proteomes between individuals with HeFH and those without FH in response to PCSK9i treatment. Furthermore, PCSK9i treatment is likely to affect the plasma proteome, regardless of FH status.