PCSK9 is the last member of the proprotein convertases (PCs) family and its gene is mutated in ~ 2% to 3% of individuals with familial hypercholesterolemia (FH).
The new option of proprotein convertase subtilisin/kexin type 9 gene inhibitors in addition to other current optimal lipid-lowering strategies might help to further improve clinical outcome in patients with probable/definite FH.
In a span of approximately 15 years, PCSK9 has morphed from an esoteric and rare cause of familial hypercholesterolemia (FH) into the most efficient cholesterol-lowering target ever known, with the completion of two large scale cardiovascular outcome trials showing positive results.
Although therapeutic monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) are indicated for LDL-C reduction among adult patients with FH, placebo-controlled outcome data among FH patients are scant.
The current scope of PCSK9 inhibitor therapy in preventive cardiology is limited to patients with familial hypercholesterolemia and/or established atherosclerotic cardiovascular disease.
A total of 249 patients with molecularly and/or clinically (Dutch Lipid Clinic Network score > 6) defined familial hypercholesterolemia who had experienced a first cardiovascular event were consecutively included and plasma proprotein convertase subtilisin/kexin type 9 concentrations were measured by enzyme-linked immunosorbent assay.
Methods Out of 196 patients with clinically suspected FH (LDL-cholesterol [LDL-C] levels above 3.37 mmol/L, cholesterol level above 6.46 mmol/L in a first-degree relative or the presence of premature cardiovascular acute disease in a first/second-degree relative), we screened 164 index cases for mutations in the LDLR, APOB and PCSK9 genes.
We report the case of a 41-year-old woman with familial hypercholesterolaemia and premature cardiovascular disease, who was non-responsive to the action of PCSK9 inhibitor solely due to the incorrect subcutaneous injection technique.
Pharmacokinetic and pharmacodynamic assessment of alirocumab in patients with familial hypercholesterolemia associated with proprotein convertase subtilisin/kexin type 9 gain-of-function or apolipoprotein B loss-of-function mutations.
Evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, is safe and effective in reducing low-density lipoprotein cholesterol in adults with familial hypercholesterolemia.
We propose the following classification: familial hypercholesterolemia syndrome integrated by (1) heterozygous familial hypercholesterolemia: patients with clinically definite FH and a functional mutation in one allele of the LDLR, ApoB:100, and PCSK9 genes; (2) homozygous familial hypercholesterolemia: mutations affect both alleles; (3) polygenic familial hypercholesterolemia: patients with clinically definite FH but no mutations associated with FH are found (to be distinguished from non-familial, multifactorial hypercholesterolemia); (4) familial hypercholesterolemia combined with hypertriglyceridemia: a subgroup of familial combined hyperlipidaemia patients fulfilling clinically definite FH with associated hypertriglyceridemia.
The monogenic cause of FH includes apolipoprotein B (APOB), low-density lipoprotein receptor (LDLR), and proprotein convertase subtilisin/kexin 9 (PCSK9).
Since launching a new class of lipid-lowering agents, proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody and microsome triglyceride transfer protein inhibitors, the indication for lipoprotein apheresis in FH has been changing.
The incidence rates of low-density lipoprotein receptor (LDLR) and apolipoprotein B (APOB) mutations were 82% and 9%, and proprotein convertase subtilisin/kexin type 9 (PCSK9) mutations were rare in Chinese patients with FH.
Familial hypercholesterolemia (FH) is a monogenic dominant inherited disorder of lipid metabolism characterized by elevated low-density lipoprotein levels, and is mainly attributable to mutations in low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proportein convertase subtilisin/kexin type 9 (PCSK9) genes.
Motivated by the FH mutation data on PCSK9, we found that modeling the PCSK9/LDLR interface revealed extensive electron delocalization between and within the protein partners.
Patients with familial hypercholesterolaemia (FH) may require proprotein convertase subtilisin/kexin-type 9 (PCSK9) mAb as add-on therapy to achieve LDL-cholesterol (LDL-C) goals.