Abstract
ObjectiveProprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein that promotes degradation of the low density lipoprotein (LDL) receptor. Mutations that block PCSK9 secretion reduce LDL-cholesterol and the incidence of myocardial infarction (MI). However, it remains unclear whether elevated plasma PCSK9 associates with coronary atherosclerosis (CAD) or more directly with rupture of the plaque causing MI.Methods and ResultsPlasma PCSK9 was measured by ELISA in 645 angiographically defined controls (<30% coronary stenosis) and 3,273 cases of CAD (>50% stenosis in a major coronary artery) from the Ottawa Heart Genomics Study. Because lipid lowering medications elevated plasma PCSK9, confounding association with disease, only individuals not taking a lipid lowering medication were considered (279 controls and 492 with CAD). Replication was sought in 357 controls and 465 with CAD from the Emory Cardiology Biobank study. PCSK9 levels were not associated with CAD in Ottawa, but were elevated with CAD in Emory. Plasma PCSK9 levels were elevated in 45 cases with acute MI (363.5±140.0 ng/ml) compared to 398 CAD cases without MI (302.0±91.3 ng/ml, p = 0.004) in Ottawa. This finding was replicated in the Emory study in 74 cases of acute MI (445.0±171.7 ng/ml) compared to 273 CAD cases without MI (369.9±139.1 ng/ml, p = 3.7×10−4). Since PCSK9 levels were similar in CAD patients with or without a prior (non-acute) MI, our finding suggests that plasma PCSK9 is elevated either immediately prior to or at the time of MI.ConclusionPlasma PCSK9 levels are increased with acute MI.
Highlights
By promoting the degradation of low density lipoprotein (LDL) receptors (LDL-R) in the liver, proprotein convertase subtilisin/ kexin type 9 (PCSK9) elevates plasma levels of LDL-cholesterol (LDL–C) [1]
Plasma PCSK9 levels are increased with acute myocardial infarction (MI)
Plasma PCSK9 levels are not associated with coronary atherosclerosis in the Ottawa Heart Genomics Study (OHGS) for individuals not taking a statin
Summary
By promoting the degradation of low density lipoprotein (LDL) receptors (LDL-R) in the liver, proprotein convertase subtilisin/ kexin type 9 (PCSK9) elevates plasma levels of LDL-cholesterol (LDL–C) [1]. The MIGen consortium found markedly reduced risk of MI associated with this allele [3] In another independent study, a large meta-analysis of several Danish cohorts found that carriers of the 46L allele had a 12% reduction in LDL-C that predicted a 5% reduction, but that was associated with a 28% reduction, in ischemic heart disease [4]. A large meta-analysis of several Danish cohorts found that carriers of the 46L allele had a 12% reduction in LDL-C that predicted a 5% reduction, but that was associated with a 28% reduction, in ischemic heart disease [4] These similar findings have been hypothesized to result from a lifetime reduction in LDL-C, reducing the burden of atherosclerosis, but could be explained if PCSK9 does more than control LDL-R levels. Plasma PCSK9 accounts for less than 8% of the variance of plasma LDL-C [5]
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