0447: Elevated plasma PCSK9 is equally detrimental for non-familial hypercholesterolemic (non-FH) and heterozygous FH patients, irrespective of their LDL receptor defects

Abstract

Do elevated PCSK9 levels constitute an even greater risk for people who already have reduced LDL receptor (LDLR) levels, such as heterozygous familial hypercholesterolemic (HeFH) patients? Circulating PCSK9 was measured by ELISA in non-treated HeFH patients carrying either 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. PCSK9 dose-dependently reduced LDLR expression in control and FH fibroblasts to similar extents, by up to 77 ± 8% and 82 ± 7%. Likewise, PCSK9 reduced LDLR abundance by 39±8% in 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 in controls (b = 0·22, p = 0·0003), D206E (b = 0·20, p = 0·0002), V408M (b = 0·24, p = 0·0002), and D154N (b = 0·25, p = 0·048) HeFH patients. The strengths of these associations were all similar. Elevated PCSK9 levels are equally detrimental for HeFH and non-FH patients: a 100 ng/mL increase in PCSK9 will lead to an increase in LDL-C of 0·20–0·25 mmol/L in controls and HeFH alike, irrespective of their LDLR mutation. This explains why non-FH and HeFH patients respond equally well to monoclonal antibodies targeting PCSK9.