Circulating Furin-Cleaved Proprotein Convertase Subtilisin/Kexin Type 9 Concentration Predicts Future Coronary Events in Japanese Subjects.

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulates as mature and furin-cleaved forms, which differ in their properties to degrade low-density lipoprotein (LDL) receptors.
Objectives: In this study, we sought to investigate whether PCSK9 subtypes associate with atherosclerotic cardiovascular events.
Methods: We investigated 1,436 statin-naive Japanese subjects without any cardiovascular disease in the Suita Study, an epidemiologic Japanese cohort study. Total, mature, and furin-cleaved PCSK9 levels were measured by means of enzyme-linked immunosorbent assay. The occurrence of coronary and stroke events were compared in subjects stratified by PCSK9 level tertile.
Results: Total, mature, and furin-cleaved PCSK9 levels were associated with non-high-density lipoprotein cholesterol (all P  < 0.001) and systolic blood pressure ( P  = 0.001, P  = 0.004, and P  < 0.001, respectively). Furthermore, only furin-cleaved PCSK9 level was correlated to high-sensitivity C-reactive protein (hs-CRP) ( P  < 0.001). During the 13.6-year observational period, furin-cleaved PCSK9 level predicted a greater likelihood of experiencing coronary events (tertile 2: hazard ratio [HR]: 2.84 [95% confidence interval [CI]: 1.21-6.65; P  = 0.01]; tertile 3: HR: 2.81 [95% CI: 1.17-6.74; P  = 0.02]), but not stroke (tertile 2: HR: 1.31 [95% CI: 0.72-2.40; P  = 0.36]; tertile 3: HR: 1.27 [95% CI: 0.68-2.38; P  = 0.44]). Total and mature PCSK9 levels were not associated with coronary events (total PCSK9: tertile 2: HR: 1.35 [95% CI: 0.68-2.68; P  = 0.39]; tertile 3: HR: 1.13 [95% CI: 0.54-2.34; P  = 0.73]; mature PCSK9: tertile 2: HR: 1.02 [95% CI: 0.52-2.02; P  = 0.93]; tertile 3: HR: 0.96 [95% CI: 0.47-1.95; P  = 0.92]) and stroke events (total PCSK9: tertile 2: HR: 0.90 [95% CI: 0.50-1.61; P  = 0.72]; tertile 3: HR: 0.99 [95% CI:0.54-1.80; P  = 0.97]; mature PCSK9: tertile 2: HR: 0.86 [95% CI: 0.47-1.57; P  = 0.63]; tertile 3: HR: 1.11 [95% CI: 0.61-1.99; P  = 0.72]), respectively.
Conclusions: Furin-cleaved but not total and mature PCSK9 was associated with both LDL cholesterol and hs-CRP and predicted future coronary events in the primary prevention settings. Our findings provide pathophysiological insights into the properties of PCSK9 subtypes in association with coronary events.
Competing Interests: Dr Kataoka has received research support from Nipro and Abbott; and honoraria from Nipro, Abbott, Kowa, Amgen, Sanofi, Astellas, Takeda, and Daiichi-Sankyo. Dr Miyamoto has research funding from Tokyo Marine and Nichido Fire Insurance Co, Fujitsu Co, Softbank Co, Meiji Yasuda Life Insurance Co, and Sara Ya Co. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
(© 2021 The Authors.)