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

Sophie J Bernelot Moens; Simone L Verweij; Johan G Schnitzler; Lotte C A Stiekema; Merijn Bos; Anne Langsted; Carlijn Kuijk; Siroon Bekkering; Carlijn Voermans; Hein J Verberne; Børge G Nordestgaard; Erik S G Stroes; Jeffrey Kroon

doi:10.1161/atvbaha.116.308834

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

Sophie J Bernelot Moens, Simone L Verweij, Johan G Schnitzler, Lotte C A Stiekema, Merijn Bos, Anne Langsted, Carlijn Kuijk, Siroon Bekkering, Carlijn Voermans, Hein J Verberne, Børge G Nordestgaard, Erik S G Stroes, Jeffrey Kroon

Institut for Klinisk Medicin

29 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Arteriosclerosis, Thrombosis, and Vascular Biology
Vol/bind	37
Udgave nummer	5
Sider (fra-til)	969-975
ISSN	1079-5642
DOI	https://doi.org/10.1161/atvbaha.116.308834
Status	Udgivet - 1 maj 2017

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10.1161/atvbaha.116.308834

ATVBAHA.116.308834Forlagets udgivne version, 1,14 MB

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Bernelot Moens, S. J., Verweij, S. L., Schnitzler, J. G., Stiekema, L. C. A., Bos, M., Langsted, A., Kuijk, C., Bekkering, S., Voermans, C., Verberne, H. J., Nordestgaard, B. G., Stroes, E. S. G., & Kroon, J. (2017). Remnant Cholesterol Elicits Arterial Wall Inflammation and a Multilevel Cellular Immune Response in Humans. Arteriosclerosis, Thrombosis, and Vascular Biology, 37(5), 969-975. https://doi.org/10.1161/atvbaha.116.308834

Bernelot Moens, SJ, Verweij, SL, Schnitzler, JG, Stiekema, LCA, Bos, M, Langsted, A, Kuijk, C, Bekkering, S, Voermans, C, Verberne, HJ, Nordestgaard, BG, Stroes, ESG & Kroon, J 2017, 'Remnant Cholesterol Elicits Arterial Wall Inflammation and a Multilevel Cellular Immune Response in Humans', Arteriosclerosis, Thrombosis, and Vascular Biology, bind 37, nr. 5, s. 969-975. https://doi.org/10.1161/atvbaha.116.308834

@article{97cc8ab25473495188019d77eb4e9449,

title = "Remnant Cholesterol Elicits Arterial Wall Inflammation and a Multilevel Cellular Immune Response in Humans",

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.",

keywords = "Aged, Arteries, Arteritis, Bone Marrow Cells, Case-Control Studies, Cells, Cultured, Cholesterol, Denmark, Female, Fluorodeoxyglucose F18, Hematopoietic Stem Cells, Humans, Hyperlipoproteinemia Type III, Immunity, Cellular, Integrins, Lipoproteins, Male, Middle Aged, Monocytes, Phenotype, Positron Emission Tomography Computed Tomography, Radiopharmaceuticals, Signal Transduction, Triglycerides, Journal Article, Observational Study, Validation Studies",

author = "{Bernelot Moens}, {Sophie J} and Verweij, {Simone L} and Schnitzler, {Johan G} and Stiekema, {Lotte C A} and Merijn Bos and Anne Langsted and Carlijn Kuijk and Siroon Bekkering and Carlijn Voermans and Verberne, {Hein J} and Nordestgaard, {B{\o}rge G} and Stroes, {Erik S G} and Jeffrey Kroon",

note = "{\textcopyright} 2017 American Heart Association, Inc.",

year = "2017",

month = may,

day = "1",

doi = "10.1161/atvbaha.116.308834",

language = "English",

volume = "37",

pages = "969--975",

journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",

issn = "1079-5642",

publisher = "Lippincott Williams & Wilkins",

number = "5",

}

TY - JOUR

T1 - Remnant Cholesterol Elicits Arterial Wall Inflammation and a Multilevel Cellular Immune Response in Humans

AU - Bernelot Moens, Sophie J

AU - Verweij, Simone L

AU - Schnitzler, Johan G

AU - Stiekema, Lotte C A

AU - Bos, Merijn

AU - Langsted, Anne

AU - Kuijk, Carlijn

AU - Bekkering, Siroon

AU - Voermans, Carlijn

AU - Verberne, Hein J

AU - Nordestgaard, Børge G

AU - Stroes, Erik S G

AU - Kroon, Jeffrey

PY - 2017/5/1

Y1 - 2017/5/1

N2 - 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.

AB - 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.

KW - Aged

KW - Arteries

KW - Arteritis

KW - Bone Marrow Cells

KW - Case-Control Studies

KW - Cells, Cultured

KW - Cholesterol

KW - Denmark

KW - Female

KW - Fluorodeoxyglucose F18

KW - Hematopoietic Stem Cells

KW - Humans

KW - Hyperlipoproteinemia Type III

KW - Immunity, Cellular

KW - Integrins

KW - Lipoproteins

KW - Male

KW - Middle Aged

KW - Monocytes

KW - Phenotype

KW - Positron Emission Tomography Computed Tomography

KW - Radiopharmaceuticals

KW - Signal Transduction

KW - Triglycerides

KW - Journal Article

KW - Observational Study

KW - Validation Studies

U2 - 10.1161/atvbaha.116.308834

DO - 10.1161/atvbaha.116.308834

M3 - Journal article

C2 - 28336558

SN - 1079-5642

VL - 37

SP - 969

EP - 975

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

IS - 5

ER -

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

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