Remnant Cholesterol Elicits Arterial Wall Inflammation and a Multilevel Cellular Immune Response in Humans

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 37; no. 5; pp. 969 - 975
• Main Authors: Bernelot Moens, Sophie J, Verweij, Simone L, Schnitzler, Johan G, Stiekema, Lotte C.A, Bos, Merijn, Langsted, Anne, Kuijk, Carlijn, Bekkering, Siroon, Voermans, Carlijn, Verberne, Hein J, Nordestgaard, Børge G, Stroes, Erik S.G, Kroon, Jeffrey
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.05.2017
• Subjects: Aged; Arteries - diagnostic imaging; Arteries - immunology; Arteries - metabolism; Arteritis - blood; Arteritis - diagnostic imaging; Arteritis - immunology; Bone Marrow Cells - immunology; Bone Marrow Cells - metabolism; Case-Control Studies; Cells, Cultured; Cholesterol - blood; Cholesterol - immunology; Denmark; Female; Fluorodeoxyglucose F18; Hematopoietic Stem Cells - immunology; Hematopoietic Stem Cells - metabolism; Humans; Hyperlipoproteinemia Type III - blood; Hyperlipoproteinemia Type III - diagnostic imaging; Hyperlipoproteinemia Type III - immunology; Immunity, Cellular; Integrins - immunology; Integrins - metabolism; Lipoproteins - blood; Lipoproteins - immunology; Male; Middle Aged; Monocytes - immunology; Monocytes - metabolism; Phenotype; Positron Emission Tomography Computed Tomography; Radiopharmaceuticals; Signal Transduction; Triglycerides - blood; Triglycerides - immunology; atherosclerosis; cardiovascular disease; cholesterol; inflammation; bone marrow
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.116.308834

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 F-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 F-FDG uptake in the arterial wall in patients with FD (n=17, age 60±8 years, remnant cholesterol3.26 [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 monocytesPatients 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 F-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.