title: Subjects with familial hypercholesterolemia are characterized by an inflammatory phenotype despite long-term intensive cholesterol lowering treatment.
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.
  
  
  CONCLUSIONS
  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.
authors: 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.
authors: Kirsten B
authors: KB
authors: Holven
authors: 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.
authors: Ingunn
authors: I
authors: Narverud
authors: 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.
authors: Henriette W
authors: HW
authors: Lindvig
authors: Faculty of Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors: Bente
authors: B
authors: Halvorsen
authors: The Lipid Clinic, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors: Gisle
authors: G
authors: Langslet
authors: The Lipid Clinic, Oslo University Hospital Rikshospitalet, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors: Marit S
authors: MS
authors: Nenseter
authors: Department of Health, Nutrition and Management, Faculty of Health Sciences, Oslo and Akershus University College of Applied Sciences, Oslo, Norway.
authors: Stine M
authors: SM
authors: Ulven
authors: Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway; The Lipid Clinic, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors: Leiv
authors: L
authors: Ose
authors: 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.
authors: Pål
authors: P
authors: Aukrust
authors: 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.
authors: Kjetil
authors: K
authors: Retterstøl
mesh_terms: D000328:Adult; D000368:Aged; D000886:Anthropometry; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001384:Azetidines / Q000008:administration & dosage / Q000627:therapeutic use; D015415:Biomarkers; D002478:Cells, Cultured; D008078:Cholesterol, LDL / Q000097:blood; D003470:Culture Media / Q000494:pharmacology; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D006938:Hyperlipoproteinemia Type II / Q000097:blood* / Q000188:drug therapy; D007249:Inflammation; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D044967:Serum; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000097:blood; D013997:Time Factors; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000097:blood*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D015415:Biomarkers; D008078:Cholesterol, LDL; D003470:Culture Media; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; D000069438:Ezetimibe
keywords: Atherosclerosis; Familial hypercholesterolemia; Inflammation; Statin treatment