Abstract 11067: Plasma Pcsk9 Levels Do Not Associate With Angiographic Coronary Artery Disease but Rather With Myocardial Infarction Independent of Ldl-cholesterol in Postmenopausal Women

Abstract

Background - Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the LDL-receptor (LDL-R) and causes it to be degraded, leading to elevation in plasma low density lipoprotein cholesterol (LDL-C). Statins, while lowering LDL-C, increase plasma PCSK9 levels. Current clinical trials are targeting PCSK9 interaction with the LDL-R to further lower LDL-C in patients taking a statin. Mutations that prevent secretion of PCSK9 are associated with a 30-40% reduction in LDL-C but a surprising 88% reduction in events associated with coronary artery disease (CAD), suggesting that plasma PCSK9 may have additional risk effects beyond LDL-C. Methods and Results - Plasma PCSK9 levels were measured by ELISA in 652 angiographically defined controls (less than 30% coronary stenosis) age and sex matched to 1297 cases of CAD ( more than 50% stenosis in a major coronary artery) selected from 5,211 subjects of the Ottawa Heart Genomics Study. Multivariate analysis revealed higher PCSK9 levels in women, in CAD cases and with statin use. Among individuals taking a statin, PCSK9 levels were higher in CAD cases than controls, likely due to higher statin dose or compliance among CAD cases. Surprisingly, for individuals not taking a statin (405 CAD cases and 285 controls), plasma PCSK9 levels were not associated with angiographically defined CAD. Importantly, in women not taking a statin, elevated plasma PCSK9 levels were associated with increased incidence of myocardial infarction (MI) without elevating LDL-C. Conclusion - Our study is the first to document a direct association between increased plasma PCSK9 levels and the risk of MI in women independent of the known effect of PCSK9 on LDL-C. Our study cautions against the use of antibodies to block PCSK9 interaction with the LDL-R to further lower LDL-C, currently in clinical trials. Since degradation with the LDL-R is one of the main PCSK9 clearance mechanisms, this approach would elevate plasma PCSK9 and potentially increase the risk of MI, particularly in women.