Yiming M Zhu1, Todd J Anderson2, Khokan Sikdar1, Marinda Fung1, Matthew J McQueen1, Eva M Lonn1, Subodh Verma1. 1. From the Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada (Y.M.Z., T.J.A., K.S., M.F.); Department of Laboratory Medicine (M.J.M.), Population Health Research Institute (M.J.M., E.M.L.) and Department of Medicine (E.M.L.), McMaster University Hamilton, Hamilton, Ontario, Canada (E.M.L.); and Department of Surgery, Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada (S.V.). 2. From the Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada (Y.M.Z., T.J.A., K.S., M.F.); Department of Laboratory Medicine (M.J.M.), Population Health Research Institute (M.J.M., E.M.L.) and Department of Medicine (E.M.L.), McMaster University Hamilton, Hamilton, Ontario, Canada (E.M.L.); and Department of Surgery, Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada (S.V.). todd.anderson@albertahealthservices.ca.
Abstract
OBJECTIVE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the modulation of low-density lipoprotein metabolism. This study was conducted to evaluate the relationship between serum PCSK9 concentrations and measures of vascular health, subclinical atherosclerosis, and adverse cardiovascular events. The relationship between traditional risk factors and PCSK9 concentrations was also examined. APPROACH AND RESULTS: The cohort consisted of 1527 middle-aged men enrolled in the Firefighters and Their Endothelium (FATE) study, who were free of vascular disease and followed up over a mean period of 7.2±1.7 years. Baseline evaluation included assessment of traditional cardiovascular risk factors and measurements of flow-mediated dilation, reactive hyperemic velocity time integral, and carotid intima-media thickness. Biochemical parameters, including serum PCSK9 concentrations, were analyzed to determine predictors of vascular measures and to evaluate the role of PCSK9 in the occurrence of adverse cardiovascular events. Multivariate linear regression analyses indicated that body mass index, insulin, low-density lipoprotein-cholesterol, and triglycerides were independent predictors of PCSK9. Further modeling revealed no correlation between PCSK9 concentration and carotid intima media thickness, flow-mediated dilation, or reactive hyperemic velocity time integral. Analyses indicated no significant association between PCSK9 concentrations and cardiovascular event occurrences. CONCLUSIONS: Although correlated with low-density lipoprotein-cholesterol, insulin, and triglycerides, PCSK9 was not associated with measures of vascular function or structure. There was also no significant relationship between PCSK9 concentrations and cardiovascular events. Thus, although PCSK9 is an important therapeutic target to reduce circulating low-density lipoprotein-cholesterol concentrations, it is unlikely to be a biomarker of atherosclerotic risk or vascular health.
OBJECTIVE:Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the modulation of low-density lipoprotein metabolism. This study was conducted to evaluate the relationship between serum PCSK9 concentrations and measures of vascular health, subclinical atherosclerosis, and adverse cardiovascular events. The relationship between traditional risk factors and PCSK9 concentrations was also examined. APPROACH AND RESULTS: The cohort consisted of 1527 middle-aged men enrolled in the Firefighters and Their Endothelium (FATE) study, who were free of vascular disease and followed up over a mean period of 7.2±1.7 years. Baseline evaluation included assessment of traditional cardiovascular risk factors and measurements of flow-mediated dilation, reactive hyperemic velocity time integral, and carotid intima-media thickness. Biochemical parameters, including serum PCSK9 concentrations, were analyzed to determine predictors of vascular measures and to evaluate the role of PCSK9 in the occurrence of adverse cardiovascular events. Multivariate linear regression analyses indicated that body mass index, insulin, low-density lipoprotein-cholesterol, and triglycerides were independent predictors of PCSK9. Further modeling revealed no correlation between PCSK9 concentration and carotid intima media thickness, flow-mediated dilation, or reactive hyperemic velocity time integral. Analyses indicated no significant association between PCSK9 concentrations and cardiovascular event occurrences. CONCLUSIONS: Although correlated with low-density lipoprotein-cholesterol, insulin, and triglycerides, PCSK9 was not associated with measures of vascular function or structure. There was also no significant relationship between PCSK9 concentrations and cardiovascular events. Thus, although PCSK9 is an important therapeutic target to reduce circulating low-density lipoprotein-cholesterol concentrations, it is unlikely to be a biomarker of atherosclerotic risk or vascular health.