Circulating levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with monocyte subsets in patients with stable coronary artery disease

Konstantin A Krychtiuk,Max Lenz,Philipp Hohensinner,Klaus Distelmaier,Lore Schrutka,Stefan P Kastl,Kurt Huber,Elisabeth Dostal,Stanislav Oravec,Christian Hengstenberg,Johann Wojta,Walter S Speidl

doi:10.1016/j.jacl.2021.02.005

Abstract

BackgroundProprotein convertase subtilisin/kexin type-9 (PCSK9) is an enzyme promoting the degradation of low-density lipoprotein receptors (LDL-R) in hepatocytes. Inhibition of PCSK9 has emerged as a novel target for lipid-lowering therapy. Monocytes are crucially involved in the pathogenesis of atherosclerosis and can be divided into three subsets. ObjectiveThe aim of this study was to examine whether circulating levels of PCSK9 are associated with monocyte subsets. MethodsWe included 69 patients with stable coronary artery disease. PCSK9 levels were measured and monocyte subsets were assessed by flow cytometry and divided into classical monocytes (CD14++CD16-; CM), intermediate monocytes (CD14++CD16+; IM) and non-classical monocytes (CD14+CD16++; NCM). ResultsMean age was 64 years and 80% of patients were male. Patients on statin treatment (n = 55) showed higher PCSK9-levels (245.4 (206.0–305.5) ng/mL) as opposed to those without statin treatment (186.1 (162.3–275.4) ng/mL; p = 0.05). In patients on statin treatment, CM correlated with circulating PCSK9 levels (R = 0.29; p = 0.04), while NCM showed an inverse correlation with PCSK9 levels (R = -0.33; p = 0.02). Patients with PCSK9 levels above the median showed a significantly higher proportion of CM as compared to patients with PCSK9 below the median (83.5 IQR 79.2–86.7 vs. 80.4, IQR 76.5–85.2%; p = 0.05). Conversely, PCSK9 levels >median were associated with a significantly lower proportion of NCM as compared to those with PCSK9 <median (10.2, IQR 7.3-14.6 vs. 14.3, IQR 10.9–18.7%; p = 0.02). In contrast, IM showed no association with PCSK9 levels. ConclusionsWe hereby provide a novel link between PCSK9 regulation, innate immunity and atherosclerotic disease in statin-treated patients.

Highlights

Cardiovascular diseases including coronary artery disease (CAD) are the leading cause of morbidity and mortality in the Western world.[1]
We stratified them according to statin treatment into patients on statins (n = 55) and in patients with newly diagnosed CAD without statin treatment (n = 14)
Values are given as median (IQR) CAD coronary artery disease; VD vessel disease; BMI body mass index; low-density lipoprotein (LDL) low density lipoprotein; high density lipoprotein-cholesterol (HDL) high density lipoprotein; highsensitive C-reactive protein (hsCRP) high sensitive C-reactive protein

Summary

Introduction

Cardiovascular diseases including coronary artery disease (CAD) are the leading cause of morbidity and mortality in the Western world.[1] Atherosclerosis, the underlying pathology of CAD, is considered to be an inflammatory disease of the vessel wall.[2] It is thought that circulating low-density lipoprotein (LDL)-particles enter the innermost layer of the vessel wall where they are trapped and undergo oxidative modification. This event causes a strong inflammatory activation causing monocyte adhesion and trans-migration into the intimal layer.[3] Ongoing inflammatory processes involving cytokines and cellular processes cause the lesion to grow and become clinically apparent, either as stable angina pain or an acute coronary syndrome (ACS).[4]. Monocytes are crucially involved in the pathogenesis of atherosclerosis and can be divided into three subsets

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