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

Abstract

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. In this study, we sought to investigate whether PCSK9 subtypes associate with atherosclerotic cardiovascular events. 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. 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. 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.