Elevated Plasma PCSK9 Level Is Equally Detrimental for Patients With Nonfamilial Hypercholesterolemia and Heterozygous Familial Hypercholesterolemia, Irrespective of Low-Density Lipoprotein Receptor Defects

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• 作者：Gilles Lambert ; PhD^&lowast ; ; ^&dagger ; ; ^{gilles.lambert@univ-nantes.fr" class="auth_mail} ; Francine Petrides ; BSc^&dagger ; ; ^&Dagger ; ; Mathias Chatelais ; BSc^&lowast ; ; Dirk J. Blom ; MD ; PhD^&sect ; ; Benjamin Choque ; PhD^&dagger ; ; Fatiha Tabet ; PhD^&dagger ; ; ^&Dagger ; ; Gida Wong ; MD^&dagger ; ; Kerry-Anne Rye ; PhD^&dagger ; ; ^&Dagger ; ; Amanda J. Hooper ; PhD^鈥?/sup> ; ^¶ ; ; ^# ; John R. Burnett ; MD ; PhD^鈥?/sup> ; ^# ; Philip J. Barter ; MD ; PhD^&dagger ; ; ^&Dagger ; ; A. David Marais ; MD^&lowast ; &lowast ;
• 关键词：familial hypercholesterolemia ; LDL-cholesterol ; LDL receptor ; PCSK9
• 刊名：Journal of the American College of Cardiology
• 出版年：10 June 2014
• 年：2014
• 卷：63
• 期：22
• 页码：2365-2373
• 全文大小：928 K

文摘

Do elevated proprotein convertase subtilisin/kexin type 9 (PCSK9) levels constitute an even greater risk for patients who already have reduced low-density lipoprotein receptor (LDLR) levels, such as those with heterozygous familial hypercholesterolemia (HeFH)?

Background

As a circulating inhibitor of LDLR, PCSK9 is an attractive target for lowering LDL-cholesterol (LDL-C) levels.

Methods

Circulating PCSK9 levels were measured by enzyme-linked immunosorbent assay in nontreated patients with HeFH carrying a D206E (n = 237), V408M (n = 117), or D154N (n = 38) LDLR missense mutation and in normolipidemic controls (n = 152). Skin fibroblasts and lymphocytes were isolated from a subset of patients and grown in 0.5% serum and mevastatin with increasing amounts of recombinant PCSK9. LDLR abundance at the cell surface was determined by flow cytometry.

Results

PCSK9 reduced LDLR expression in a dose-dependent manner in control and FH fibroblasts to similar extents, by up to 77 ± 8% and 82 ± 7%, respectively. Likewise, PCSK9 reduced LDLR abundance by 39 ± 8% in nonfamilial hypercholesterolemia (non-FH) and by 45 ± 10% in HeFH lymphocytes, irrespective of their LDLR mutation status. We found positive correlations of the same magnitude between PCSK9 and LDL-C levels in controls (beta = 0.22; p = 0.0003), D206E (beta = 0.20; p = 0.0002), V408M (beta = 0.24; p = 0.0002), and D154N (beta = 0.25; p = 0.048) patients with HeFH. The strengths of these associations were all similar.

Conclusions

Elevated PCSK9 levels are equally detrimental for patients with HeFH or non-FH: a 100-ng/ml increase in PCSK9 will lead to an increase in LDL-C of 0.20 to 0.25 mmol/l in controls and HeFH alike, irrespective of their LDLR mutation. This explains why patients with non-FH or HeFH respond equally well to monoclonal antibodies targeting PCSK9.