Expression of LDLRs (Low-Density Lipoprotein Receptors), Dyslipidemia Severity, and Response to PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Inhibition in Homozygous Familial Hypercholesterolemia
| Autor: | Raul D. Santos |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
medicine.medical_specialty
Apolipoprotein B Familial hypercholesterolemia 030204 cardiovascular system & hematology FÁRMACOS DO SANGUE E SISTEMA HEMATOPOÉTICO Antibodies Monoclonal Humanized Compound heterozygosity Article Hyperlipoproteinemia Type II 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Ezetimibe Internal medicine medicine Humans Subtilisins 030212 general & internal medicine biology business.industry PCSK9 Antibodies Monoclonal medicine.disease Lipoproteins LDL Endocrinology Receptors LDL chemistry Low-density lipoprotein Mutation LDL receptor biology.protein Kexin lipids (amino acids peptides and proteins) Proprotein Convertase 9 Cardiology and Cardiovascular Medicine business medicine.drug |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| ISSN: | 1524-4636 1079-5642 |
| DOI: | 10.1161/atvbaha.117.310675 |
| Popis: | OBJECTIVES: Evolocumab, a PCSK9 neutralizing antibody, lowers low-density lipoprotein cholesterol (LDL-C) in Homozygous Familial Hypercholesterolemic (HoFH) patients with reduced LDL receptor (LDLR) function. However, their individual responses are highly variable, even among carriers of identical LDLR genetic defects. We aimed to elucidate why HoFH patients variably respond to PCSK9 inhibition. APPROACH AND RESULTS: Lymphocytes were isolated from 22 HoFH patients enrolled in the TAUSSIG trial. Ten patients were true homozygotes (FH1/FH1) and five identical compound heterozygotes (FH1/FH2). Lymphocytes were plated with or without mevastatin, recombinant PCSK9 (rPCSK9), or a PCSK9 neutralizing antibody. Cell surface LDLR expression was analyzed by flow cytometry. All HoFH lymphocytes had reduced cell surface LDLR expression compared with non-FH lymphocytes, for each treatment modality. Lymphocytes from FH1/FH2 patients (LDLR defective/negative) displayed the lowest LDLR expression levels followed by lymphocytes from FH1/FH1 patients (defective/defective). Mevastatin increased whereas rPCSK9 reduced LDLR expression. The PCSK9 neutralizing antibody restored LDLR expression. Lymphocytes displaying higher LDLR expression levels were those isolated from patients presenting with lowest levels of LDL-C and apolipoprotein B, prior and after 24 weeks of evolocumab treatment. These negative correlations remained significant in FH1/FH1 patients, and appeared more pronounced when patients with apolipoprotein E3/E3 genotypes were analyzed separately. Significant positive correlations were found between the levels of LDLR expression and the percentage reduction in LDL-C upon evolocumab treatment. CONCLUSIONS: Residual LDLR expression in HoFH is a major determinant of LDL-C levels and appears to drive their individual response to evolocumab. |
| Databáze: | OpenAIRE |
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