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

Objectives 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. (C) 2014 by the American College of Cardiology Foundation