We measured plasma PCSK9 concentrations in healthy men with a PCSK9 (proprotein convertase subtilisin/kexin type 9) loss-of-function variant (p.R46L), in statin-treated patients with a clinical diagnosis of familial hypercholesterolemia (FH) and carrying a PCSK9 gain-of-function mutation (p.D374Y), and in statin-treated patients with FH due to different genetic causes.
Baseline disease rates were higher for patients treated with PCSK-9 inhibitors (n=390) compared with highest-intensity statins (n=26,306): ASCVD (68.5% vs 33.4%, respectively); FH (39.7% vs 15.5%); both <i>P</i><0.001.
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.
Molecular analysis of FH was performed using target exome sequencing in <i>LDLR</i> (low-density lipoprotein cholesterol receptor gene), <i>APOB</i> (apolipoprotein B gene), and <i>PCSK9</i> (proprotein convertase subtilisin/kexin type 9 gene).
The current scope of PCSK9 inhibitor therapy in preventive cardiology is limited to patients with familial hypercholesterolemia and/or established atherosclerotic cardiovascular disease.
In this study, DNA sequencing of the 12 exons of the PCSK9 gene has been performed in 51 Norwegian subjects with a clinical diagnosis of familial hypercholesterolemia where mutations in the low-density lipoprotein receptor gene and mutation R3500Q in the apolipoprotein B-100 gene had been excluded.
The study is organized in five stages: 1. selection of individuals with a clinical diagnosis of FH; 2. completion of a clinical questionnaire and declaration of informed consent; 3. collection of blood samples; 4. biochemical characterization; 5. molecular study of three genes associated with the FH phenotype: LDLR, apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9).
Methods The purpose of this commentary is to provide a brief update on recent data investigating several key aspects of FH in patients with acute coronary syndromes, including prevalence, risk of coronary artery disease, molecular diagnosis, cardiac imaging, as well as the efficacy of PCSK9 inhibition.
In 2016, the National Lipid Association conducted an online survey on PCSK9 inhibitor use and barriers to prescription among experienced healthcare workers who provide care to high-risk patients with ASCVD or familial hypercholesterolemia (FH).
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.
Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors lower low-density lipoprotein (LDL) cholesterol in the vast majority of patients with autosomal dominant familial hypercholesterolemia.
Genetic studies have confirmed that individuals with gain-of-function PCSK9 mutations have increased PCSK9 activity, elevated LDL-cholesterol levels and a severe form of familial hypercholesterolaemia.
Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are a novel class of medications for patients with familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease requiring additional lipid lowering beyond dietary measures and statin use.
Moreover, a substantial deficit was identified in the awareness of various clinical algorithms to diagnose patients with FH, cascade screening, specialist lipid services, and the existence of statin alternatives, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.
The potential market authorisation of novel therapeutic agents such as PCSK9 monoclonal inhibitors makes it essential to have a better screening programme to prioritise the candidates for treatment with the most severe form of FH and at higher risk of coronary events.
To facilitate genetic cascade screening for familial hypercholesterolemia (FH) in Europe, two versions (7 and 9) of a DNA microarray were developed to detect the most frequent point mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) genes.
Familial hypercholesterolemia (FH) is a disease implicated with defects in either, Low density lipoprotein receptor gene (LDLR), Apolipoprotein B-100 gene (APOB), the Proprotein convertase subtilisin/kexin type 9 gene (PCSK9) or other related genes of the lipid metabolism pathway.