Low-density lipoprotein receptor-related protein 1 and factor VIII are independent predictors of target vessel revascularization in myocardial infarction patients receiving PCSK9 inhibitors

Cao M, Ximei Liu, Ziyi Liu, Yuanqiang Guo, Lingli Zhang, Zhuhua Yao

Low-density lipoprotein receptor-related protein 1 (LRP1) mediates the clearance of circulating factor VIII (FVIII) and contributes to vascular thrombotic homeostasis. Although prior basic studies have confirmed that proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) can reverse PCSK9-induced LRP1 degradation, clinical evidence linking the LRP1–FVIII biomarker axis to target vessel revascularization (TVR) after myocardial infarction (MI), as well as the modifying effect of PCSK9i on this pathway, remains limited. This two-stage observational study aimed to characterize the clinical association between circulating LRP1/FVIII levels and post-MI TVR risk, and to quantify changes in LRP1 and FVIII following PCSK9i intervention. This study adopted a two-stage sequential design, comprising an exploratory mechanistic analysis and a subsequent clinical prognostic validation. The first stage was a single-center prospective pilot intervention study ( n = 87), enrolling acute MI patients who received evolocumab-based PCSK9i therapy ( n = 44) or standard statin-based secondary prevention (control group, n = 43). Plasma concentrations of LRP1 and FVIII antigens were measured via ELISA at baseline and at 30-day follow-up. The second stage was a real-world retrospective validation cohort study ( n = 227), designed to verify the prognostic value of routine clinical FVIII coagulant activity for TVR and to quantify the risk-reducing effect of PCSK9i. Key confounding variables, including general clinical data, baseline cardiovascular comorbidities, and concomitant medications, were comprehensively collected and adjusted for in multivariate models. The primary clinical endpoint was TVR. Statistical methods included paired t-test, multivariate logistic regression, Cox proportional hazards regression, Fine–Gray competing risk model, ROC curve analysis, and Kaplan–Meier survival estimation; decision curve analysis (DCA) and time-dependent ROC curves were additionally used to evaluate clinical net benefit and long-term predictive stability. In the pilot study, PCSK9i treatment significantly increased LRP1 levels (from 37.8 ± 4.5 to 82.1 ± 8.2 ng/mL, + 117%, P < 0.0001) and significantly reduced FVIII antigen concentrations (from 3680 ± 420 pg/mL to 3270 ± 380 pg/mL, − 11.2%, P = 0.008). Lower baseline LRP1 (OR = 0.85, 95% CI: 0.76–0.95, P = 0.004) and higher baseline FVIII antigen (OR = 1.08, 95% CI: 1.02–1.15, P = 0.012) were associated with TVR. Both LRP1 (AUC = 0.678) and FVIII antigen (AUC = 0.714) demonstrated moderate predictive ability. In the validation cohort ( n = 227, 35 TVR events), elevated FVIII coagulant activity (≥ 110%) was independently associated with increased TVR risk (adjusted HR = 12.02, 95% CI: 2.86–50.47, P = 0.0007). PCSK9i therapy reduced TVR risk by 85.1% (HR = 0.149, 95% CI: 0.061–0.361, P < 0.0001). In patients with elevated FVIII, PCSK9i reduced TVR from 31.7% to 7.89% (HR = 0.151, P < 0.001; NNT = 4.2). The combined FVIII–PCSK9i–HGB model achieved excellent discrimination (C-index = 0.798). PCSK9i administration was correlated with elevated circulating LRP1 and decreased FVIII levels in acute MI patients. Elevated baseline FVIII coagulant activity (≥ 110%) is a powerful independent predictor of post-MI TVR. PCSK9i yields a prominent risk reduction for TVR, particularly in patients with high FVIII. This study proposes a potential LRP1–FVIII–PCSK9i pathway linking PCSK9 inhibition to restenosis risk, and provides clinical evidence supporting FVIII-guided individualized PCSK9i administration after MI.