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
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.).
Arterioscler Thromb Vasc Biol. 2017 May;37(5):969-975. doi: 10.1161/ATVBAHA.116.308834. Epub 2017 Mar 23.
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 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 cholesterol: 3.26 [2.07-5.71]) compared with controls (n=17, age 61±8 years, remnant cholesterol 0.29 [0.27-0.40]; <0.001). Monocytes from patients with FD showed increased lipid accumulation (lipid-positive monocytes: Patients with FD 92% [86-95], controls 76% [66-81], =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, for 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.
孟德尔随机化研究揭示了残余胆固醇在心血管疾病中的因果作用。残余颗粒在动脉壁中积聚，可能会引发局部和全身炎症。我们评估了残余胆固醇对家族性异常β脂蛋白血症（FD）患者动脉壁炎症、循环单核细胞和骨髓的影响。
使用F-FDG PET/CT测量动脉壁炎症和骨髓活性。通过流式细胞术评估单核细胞表型。在哥本哈根普通人群研究（CGPS）中验证了残余水平与造血活性之间的相关性。我们发现，与对照组（n = 17，年龄61±8岁，残余胆固醇0.29 [0.27 - 0.40]；P<0.001）相比，FD患者（n = 17，年龄60±8岁，残余胆固醇：3.26 [2.07 - 5.71]）动脉壁中F-FDG摄取增加了1.2倍。FD患者的单核细胞显示脂质积累增加（脂质阳性单核细胞：FD患者为92% [86 - 95]，对照组为76% [66 - 81]，P = 0.001，每个单核细胞中的脂滴增加），以及表面整合素（CD11b、CD11c和CD18）的表达更高。FD患者还表现出单核细胞增多和白细胞增多，同时骨髓中F-FDG摄取增加了1.2倍。此外，我们在CGPS（n = 103 953，趋势P = 5×10-276）中发现残余水平与白细胞计数之间存在强相关性。体外实验证实，残余胆固醇在人类造血干细胞和祖细胞中积累，同时伴有髓系偏向。
FD患者的动脉壁和细胞炎症增加。这些发现表明残余胆固醇的致动脉粥样硬化性中存在重要的炎症成分，这导致FD患者心血管疾病风险增加。
