Unraveling the Rapid Progression of Non-Target Lesions: Risk Factors and the Therapeutic Potential of PCSK9 Inhibitors in Post-PCI Patients

Abstract

Background Rapid progression of non-target lesions (NTLs) leads to a high incidence of NTL related cardiac events post-PCI, which accounting half of the recurrent cardiac events. It is important to identify the risk factors for the rapid progression of NTLs post-PCI. Proprotein convertase subtilisin-kexin 9(PCSK9) inhibitors lower low-density lipoprotein cholesterol(LDL-c) levels significantly, also show the anti-inflammation effect, and may have the potential to reduce the rapid progression of NTLs post-PCI. Methods This retrospective study included 1250 patients who underwent the first PCI and underwent repeat coronary angiography for recurrence of chest pain within 24 months. Machine learning (LASSO regression) was mainly employed to select the important characteristic risk factors for the rapid progression of NTLs post-PCI, and build prediction models. Finally, mediator analysis was employed to explore the potential mechanisms by which PCSK9 inhibitors reduce the rapid progression of NTLs post-PCI. Results There were more diabetes, less beta-blockers and PCSK9 inhibitors application, higher HbA1c, LDL-c, ApoB, TG, TC, uric acid ,higher hs-CRP, TNF-α, IL-6, IL-8, and sIL-2R in NTL progressed group.LDL-c, hs-CRP, IL-8, and sIL-2R were characteristic risk factors for rapid progression of NTLs post-PCI, combining LDL-c, hs-CRP, IL-8, and sIL-2R builds the optimal model for predicting the rapid progression of NTLs post-PCI (AUC = 0.632). LDL-c had a clear and incomplete mediating effect (95% CI, mediating effect: 51.56%) in the reduction of the progression of NTLs by PCSK9 inhibitors, and there was a possible mediating effect of IL-8 (90% CI), and sIL-2R (90% CI). Conclusions LDL-c, hs-CRP, IL-8, and sIL-2R may be the key characteristic risk factors for the rapid progression of NTLs post-PCI, and combining these parameters can predict the rapid progression of NTLs post-PCI. The application of PCSK9 inhibitors has a negative correlation with the rapid progression of NTLs. In addition to the significant LDL-c-lowering, PCSK9 inhibitors may reduce the rapid progression of NTLs by reducing local inflammation of plaque. Registration number: ChiCTR2200058529; Date of registration: 2022-04-10