ABSTRACT
OBJECTIVE: Mendelian randomization studies revealed a causal role for remnant cholesterol in cardiovascular disease. Remnant particles accumulate in the arterial wall, potentially propagating local and systemic inflammation. We evaluated the impact of remnant cholesterol on arterial wall inflammation, circulating monocytes, and bone marrow in patients with familial dysbetalipoproteinemia (FD). APPROACH AND RESULTS: Arterial wall inflammation and bone marrow activity were measured using 18F-FDG PET/CT. Monocyte phenotype was assessed with flow cytometry. The correlation between remnant levels and hematopoietic activity was validated in the CGPS (Copenhagen General Population Study). We found a 1.2-fold increase of 18F-FDG uptake in the arterial wall in patients with FD (n=17, age 60±8 years, remnant cholesterol: 3.26 [2.07-5.71]) compared with controls (n=17, age 61±8 years, remnant cholesterol 0.29 [0.27-0.40]; P<0.001). Monocytes from patients with FD showed increased lipid accumulation (lipid-positive monocytes: Patients with FD 92% [86-95], controls 76% [66-81], P=0.001, with an increase in lipid droplets per monocyte), and a higher expression of surface integrins (CD11b, CD11c, and CD18). Patients with FD also exhibited monocytosis and leukocytosis, accompanied by a 1.2-fold increase of 18F-FDG uptake in bone marrow. In addition, we found a strong correlation between remnant levels and leukocyte counts in the CGPS (n=103 953, P for trend 5×10-276). In vitro experiments substantiated that remnant cholesterol accumulates in human hematopoietic stem and progenitor cells coinciding with myeloid skewing. CONCLUSIONS: Patients with FD have increased arterial wall and cellular inflammation. These findings imply an important inflammatory component to the atherogenicity of remnant cholesterol, contributing to the increased cardiovascular disease risk in patients with FD.
Subject(s)
Arteries/immunology , Arteritis/immunology , Cholesterol/immunology , Hyperlipoproteinemia Type III/immunology , Immunity, Cellular , Lipoproteins/immunology , Triglycerides/immunology , Aged , Arteries/diagnostic imaging , Arteries/metabolism , Arteritis/blood , Arteritis/diagnostic imaging , Bone Marrow Cells/immunology , Bone Marrow Cells/metabolism , Case-Control Studies , Cells, Cultured , Cholesterol/blood , Denmark , Female , Fluorodeoxyglucose F18 , Hematopoietic Stem Cells/immunology , Hematopoietic Stem Cells/metabolism , Humans , Hyperlipoproteinemia Type III/blood , Hyperlipoproteinemia Type III/diagnostic imaging , Integrins/immunology , Integrins/metabolism , Lipoproteins/blood , Male , Middle Aged , Monocytes/immunology , Monocytes/metabolism , Phenotype , Positron Emission Tomography Computed Tomography , Radiopharmaceuticals , Signal Transduction , Triglycerides/bloodABSTRACT
Intraosseous xanthoma associated with hyperlipoproteinemia, a rare disorder, was observed in the entire distal femur of a 52-year-old man. Initial radiographs suggested a primary bone neoplasm; however, an open biopsy established a diagnosis of intraosseous xanthoma. Histologically, the lesion was characterized by replacement of normal bone and marrow with xanthoma cells and extracellular cholesterol clefts. The hyperlipidemia was classified as Type III hyperlipoproteinemia and was successfully controlled by dietary lipid restriction alone. The disability was effectively treated and ambulation was possible with the aid of a cane.
