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



Arterial wall inflammation and bone marrow activity were measured using18F-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 of18F-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 of18F-FDG uptake in bone marrow. In addition, we found a strong correlation between remnant levels and leukocyte counts in the CGPS (n=103 953,Pfor trend 5×10-276). In vitro experiments substantiated that remnant cholesterol accumulates in human hematopoietic stem and progenitor cells coinciding with myeloid skewing.



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.
From the Departments of Vascular Medicine (S.J.B.M., S.L.V., L.C.A.S., M.B., S.B., E.S.G.S., J.K.), Experimental Vascular Medicine (J.G.S.), and Nuclear Medicine (H.J.V.), AMC, Amsterdam, The Netherlands; The Copenhagen General Population Study (A.L., B.G.N.) and Department of Clinical Biochemistry (A.L., B.G.N.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; and Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, The Netherlands (C.K., C.V.).
Sophie J
SJ
Bernelot Moens
From the Departments of Vascular Medicine (S.J.B.M., S.L.V., L.C.A.S., M.B., S.B., E.S.G.S., J.K.), Experimental Vascular Medicine (J.G.S.), and Nuclear Medicine (H.J.V.), AMC, Amsterdam, The Netherlands; The Copenhagen General Population Study (A.L., B.G.N.) and Department of Clinical Biochemistry (A.L., B.G.N.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; and Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, The Netherlands (C.K., C.V.).
Simone L
SL
Verweij
From the Departments of Vascular Medicine (S.J.B.M., S.L.V., L.C.A.S., M.B., S.B., E.S.G.S., J.K.), Experimental Vascular Medicine (J.G.S.), and Nuclear Medicine (H.J.V.), AMC, Amsterdam, The Netherlands; The Copenhagen General Population Study (A.L., B.G.N.) and Department of Clinical Biochemistry (A.L., B.G.N.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; and Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, The Netherlands (C.K., C.V.).
Johan G
JG
Schnitzler
From the Departments of Vascular Medicine (S.J.B.M., S.L.V., L.C.A.S., M.B., S.B., E.S.G.S., J.K.), Experimental Vascular Medicine (J.G.S.), and Nuclear Medicine (H.J.V.), AMC, Amsterdam, The Netherlands; The Copenhagen General Population Study (A.L., B.G.N.) and Department of Clinical Biochemistry (A.L., B.G.N.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; and Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, The Netherlands (C.K., C.V.).
Lotte C A
LCA
Stiekema
From the Departments of Vascular Medicine (S.J.B.M., S.L.V., L.C.A.S., M.B., S.B., E.S.G.S., J.K.), Experimental Vascular Medicine (J.G.S.), and Nuclear Medicine (H.J.V.), AMC, Amsterdam, The Netherlands; The Copenhagen General Population Study (A.L., B.G.N.) and Department of Clinical Biochemistry (A.L., B.G.N.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; and Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, The Netherlands (C.K., C.V.).
Merijn
M
Bos
From the Departments of Vascular Medicine (S.J.B.M., S.L.V., L.C.A.S., M.B., S.B., E.S.G.S., J.K.), Experimental Vascular Medicine (J.G.S.), and Nuclear Medicine (H.J.V.), AMC, Amsterdam, The Netherlands; The Copenhagen General Population Study (A.L., B.G.N.) and Department of Clinical Biochemistry (A.L., B.G.N.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; and Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, The Netherlands (C.K., C.V.).
Anne
A
Langsted
From the Departments of Vascular Medicine (S.J.B.M., S.L.V., L.C.A.S., M.B., S.B., E.S.G.S., J.K.), Experimental Vascular Medicine (J.G.S.), and Nuclear Medicine (H.J.V.), AMC, Amsterdam, The Netherlands; The Copenhagen General Population Study (A.L., B.G.N.) and Department of Clinical Biochemistry (A.L., B.G.N.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; and Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, The Netherlands (C.K., C.V.).
Carlijn
C
Kuijk
From the Departments of Vascular Medicine (S.J.B.M., S.L.V., L.C.A.S., M.B., S.B., E.S.G.S., J.K.), Experimental Vascular Medicine (J.G.S.), and Nuclear Medicine (H.J.V.), AMC, Amsterdam, The Netherlands; The Copenhagen General Population Study (A.L., B.G.N.) and Department of Clinical Biochemistry (A.L., B.G.N.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; and Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, The Netherlands (C.K., C.V.).
Siroon
S
Bekkering
From the Departments of Vascular Medicine (S.J.B.M., S.L.V., L.C.A.S., M.B., S.B., E.S.G.S., J.K.), Experimental Vascular Medicine (J.G.S.), and Nuclear Medicine (H.J.V.), AMC, Amsterdam, The Netherlands; The Copenhagen General Population Study (A.L., B.G.N.) and Department of Clinical Biochemistry (A.L., B.G.N.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; and Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, The Netherlands (C.K., C.V.).
Carlijn
C
Voermans
From the Departments of Vascular Medicine (S.J.B.M., S.L.V., L.C.A.S., M.B., S.B., E.S.G.S., J.K.), Experimental Vascular Medicine (J.G.S.), and Nuclear Medicine (H.J.V.), AMC, Amsterdam, The Netherlands; The Copenhagen General Population Study (A.L., B.G.N.) and Department of Clinical Biochemistry (A.L., B.G.N.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; and Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, The Netherlands (C.K., C.V.).
Hein J
HJ
Verberne
From the Departments of Vascular Medicine (S.J.B.M., S.L.V., L.C.A.S., M.B., S.B., E.S.G.S., J.K.), Experimental Vascular Medicine (J.G.S.), and Nuclear Medicine (H.J.V.), AMC, Amsterdam, The Netherlands; The Copenhagen General Population Study (A.L., B.G.N.) and Department of Clinical Biochemistry (A.L., B.G.N.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; and Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, The Netherlands (C.K., C.V.).
Børge G
BG
Nordestgaard
From the Departments of Vascular Medicine (S.J.B.M., S.L.V., L.C.A.S., M.B., S.B., E.S.G.S., J.K.), Experimental Vascular Medicine (J.G.S.), and Nuclear Medicine (H.J.V.), AMC, Amsterdam, The Netherlands; The Copenhagen General Population Study (A.L., B.G.N.) and Department of Clinical Biochemistry (A.L., B.G.N.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; and Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, The Netherlands (C.K., C.V.).
Erik S G
ESG
Stroes
From the Departments of Vascular Medicine (S.J.B.M., S.L.V., L.C.A.S., M.B., S.B., E.S.G.S., J.K.), Experimental Vascular Medicine (J.G.S.), and Nuclear Medicine (H.J.V.), AMC, Amsterdam, The Netherlands; The Copenhagen General Population Study (A.L., B.G.N.) and Department of Clinical Biochemistry (A.L., B.G.N.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; and Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, The Netherlands (C.K., C.V.). j.kroon@amc.uva.nl.
Jeffrey
J
Kroon
D000368:Aged; D001158:Arteries / Q000000981:diagnostic imaging / Q000276:immunology* / Q000378:metabolism; D001167:Arteritis / Q000097:blood / Q000000981:diagnostic imaging / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood / Q000276:immunology*; D003718:Denmark; D005260:Female; D019788:Fluorodeoxyglucose F18; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006952:Hyperlipoproteinemia Type III / Q000097:blood / Q000000981:diagnostic imaging / Q000276:immunology*; D007111:Immunity, Cellular; D016023:Integrins / Q000276:immunology / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D000072078:Positron Emission Tomography Computed Tomography; D019275:Radiopharmaceuticals; D015398:Signal Transduction; D014280:Triglycerides / Q000097:blood / Q000276:immunology*
D016023:Integrins; D008074:Lipoproteins; D019275:Radiopharmaceuticals; D014280:Triglycerides; C112017:remnant-like particle cholesterol; D019788:Fluorodeoxyglucose F18; D002784:Cholesterol
atherosclerosis; bone marrow; cardiovascular disease; cholesterol; inflammation