Abstract 18736: Relationship of PCSK9 With Measures of Vascular Disease and Global Risk in 1574 Individuals Enrolled in the FATE (Fireman And Their Endothelium) Study
Background: Proprotein convertase subtilisin kexin-like 9 (PCSK9) is a secreted glycoprotein that is transcriptionally regulated by cholesterol status. Elevated PCSK9 levels lead to an increase in circulating LDL-C by inhibiting hepatic LDL-receptor recycling by targeting LDL-receptors for lysosomal degradataion. Since loss-of-function PCSK9 variants are associated with marked cardiovascular protection, we hypothesized that plasma PCSK9 levels may serve as a biomarker of structural and functional atherosclerosis, and would add prognostic value beyond conventional global risk scores.
Methods: The FATE cohort consisted of 1574 men (mean age, 49.4 years) free of vascular disease. Measurements included flow-mediated dilation (FMD) and its microvascular stimulus, hyperemic velocity (VTI), carotid intima-media thickness (CIMT), and high-sensitivity C-reactive protein (hs-CRP). Plasma PCSK9 was measured using a quantitative sandwich immunoassay technique, using a monoclonal antibody specific to PCSK9. Cox proportional hazard models evaluated the relationship between PCSK9, vascular markers, and Framingham risk score (FRS).
Results: Subjects had low-medium Framingham risk score (7.9%), with mean LDL-C (3.3±0.8 mM), HDL-C (1.2±0.3 mM), and hs-CRP mg/L 1.27 (0.67-2.27). Mean brachial artery FMD was 8.6±4.1%, nitroglycerin-mediated dilatation was 15.6±5.8% and CIMT 0.70 (0.6-0.77) mm. Plasma PCSK9 was normally distributed (median 286 ng/ml [231-355 ng/ml]). In univariate analysis, both PCSK9 and logPCSK9 were related to CIMT (pearson coefficient 0.073, p<0.005), but not to VTI (pearson coefficient -0.041, p=NS) or hs-CRP(pearson coefficient 0.003, p=NS). In multiple linear regression analysis, FRS was independently associated with both CIMT and VTI (both p<0.001). However, PCSK9 was not associated with either CIMT or VTI beyond FRS.
Conclusion: In a large cohort of 1574 otherwise healthy individuals, plasma PCSK9 levels were not related to measures of either microvascular or macrovascular dysfunction beyond the FRS score. Whether PCSK9 predicts cardiovascular events remains to be determined.
- © 2013 by American Heart Association, Inc.