Subjects with familial hypercholesterolemia are characterized by an inflammatory phenotype despite long-term intensive cholesterol lowering treatment

Kirsten B Holven; Ingunn Narverud; Henriette W Lindvig; Bente Halvorsen; Gisle Langslet; Marit S Nenseter; Stine M Ulven; Leiv Ose; Pål Aukrust; Kjetil Retterstøl

doi:10.1016/j.atherosclerosis.2014.01.022

Subjects with familial hypercholesterolemia are characterized by an inflammatory phenotype despite long-term intensive cholesterol lowering treatment

Atherosclerosis. 2014 Apr;233(2):561-567. doi: 10.1016/j.atherosclerosis.2014.01.022. Epub 2014 Jan 24.

Authors

Affiliations

¹ Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address: kirsten.holven@medisin.uio.no.
² Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway; The Lipid Clinic, Oslo University Hospital Rikshospitalet, Oslo, Norway; Department of Health, Nutrition and Management, Faculty of Health Sciences, Oslo and Akershus University College of Applied Sciences, Oslo, Norway.
³ Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway; The Lipid Clinic, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁴ Faculty of Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁵ The Lipid Clinic, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁶ The Lipid Clinic, Oslo University Hospital Rikshospitalet, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁷ Department of Health, Nutrition and Management, Faculty of Health Sciences, Oslo and Akershus University College of Applied Sciences, Oslo, Norway.
⁸ Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway; The Lipid Clinic, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁹ Faculty of Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.

PMID: 24530965
DOI: 10.1016/j.atherosclerosis.2014.01.022

Abstract

Objective: The atherosclerotic process is driven by elevated Low-density lipoprotein (LDL)-cholesterol in combination with enhanced inflammatory responses. Several mediators participate in this complex inflammatory network including members of the tumour necrosis factor (receptor) superfamily. Familial hypercholesterolemia (FH) is associated with increased risk of developing premature atherosclerosis. Statin treatment may normalize LDL-cholesterol levels, but it is not known if the inflammatory responses are normalized in statin-treated FH patients.

Methods: In long-term statin-treated FH subjects (n=33) and healthy controls (n=10) the expression of tumour necrosis factor (receptor) superfamily related genes in peripheral blood mononuclear cells (PBMC) were analyzed by real-time quantitative RT-PCR. TNFα release was measured in PBMC from patients and controls by immunoassay.

Results: In FH patients with normal LDL-cholesterol, after a median of 17 years of statin treatment, our major findings were: (i) Gene expression of CD137, LIGHT (lymphotoxins inducible expression, competes with HSV glycoprotein D for HVEM, a receptor expressed on T-lymphocytes), HVEM (Herpesvirus entry mediator), the two TNFα Receptors (TNFR1 and TNFR2), TNF related apoptosis inducing ligand (TRAIL) and CD40 were increased in PBMC from FH patients compared to controls. (ii) The release of TNFα in PBMC from FH patients, in response to LPS was increased compared to controls. (iii) PBMC from FH patients had enhanced spontaneous release of TNFα when incubated in the presence of control serum and in particular in the presence of FH serum.

Conclusion: Despite long-term statin therapy, an increased expression of several TNF related genes in PBMC isolated from FH patients was observed. Our findings may implicate a pathogenic role for inflammation and TNF related molecules in FH, and these findings suggest the possibility that novel treatment modalities beyond that of statins and lipid lowering drugs may be useful in FH subjects.

Keywords: Atherosclerosis; Familial hypercholesterolemia; Inflammation; Statin treatment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Anthropometry
Anticholesteremic Agents / administration & dosage
Anticholesteremic Agents / therapeutic use*
Azetidines / administration & dosage
Azetidines / therapeutic use
Biomarkers
Cells, Cultured
Cholesterol, LDL / blood
Culture Media / pharmacology
Drug Therapy, Combination
Ezetimibe
Female
Gene Expression Profiling
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage
Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
Hyperlipoproteinemia Type II / blood*
Hyperlipoproteinemia Type II / drug therapy
Inflammation
Leukocytes, Mononuclear / chemistry
Leukocytes, Mononuclear / metabolism
Male
Middle Aged
Phenotype
Serum
TNF-Related Apoptosis-Inducing Ligand / blood
Time Factors
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / blood*
Tumor Necrosis Factor-alpha / analysis
Tumor Necrosis Factor-alpha / metabolism

Substances

Anticholesteremic Agents
Azetidines
Biomarkers
Cholesterol, LDL
Culture Media
Hydroxymethylglutaryl-CoA Reductase Inhibitors
TNF-Related Apoptosis-Inducing Ligand
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
Tumor Necrosis Factor-alpha
Ezetimibe