Abstract 17265: Remnant Cholesterol as a Direct Mediator of Arterial and Cellular Inflammation in Humans
Introduction: Mendelian randomization studies validated a causal role for remnant cholesterol in cardiovascular disease. Remnant particles can enter the arterial wall, potentially propagating arterial inflammation. Also, they are proposed to accumulate in circulating immune cells and their progenitors, pushing them towards a pro-inflammatory phenotype. We evaluated the impact of elevated levels of remnant cholesterol on inflammatory activity of the arterial wall, phenotype of circulating monocytes, and bone marrow activity in familial dysbetalipoprotenemia subjects with remnant hyperlipidemia (RH).
Methods and Results: We included 15 RH patients (age 61±8, 64% male, FPLC measured remnant cholesterol: 3.5IQR[2-6]mmol/L) and 13 controls (age 58±6, 64% male, remnant cholesterol 0.4[0.2-0.5]mmol/L). Arterial inflammation, measured with 18F-FDG PET/CT, revealed a significant increase in RH patients (Aortic target-to-background ratio: 2.79±0.42(SD) vs 2.36±0.24 in controls, p=0.003). Monocytes from RH patients showed an increased number of lipid droplets per monocyte: 8±3(SD) vs 5±2 in controls, p=0.02), with concomitant higher expression of surface integrins (CD11b, CD11c, CD18), measured using flow cytometry. Also RH patients exhibited monocytosis and leukocytosis, with a concomitant 1.2-fold increase of 18F-FDG uptake in the bone marrow, representing progenitor cell activity. 18F-FDG uptake in the bone marrow correlated to circulating leukocyte levels (r=0.564). Finally, validating the relationship between plasma remnant cholesterol levels and hematopoietic activity, we found a strong correlation between remnant cholesterol levels and leukocyte counts in the Copenhagen General Population Study (n=103.953, p for trend=5*10-276).
Conclusion: Patients with RH have increased arterial wall inflammation and are characterized by an inflammatory phenotype of circulating monocytes. Moreover, our observational study as well as validation in a large cohort support a link between remnant cholesterol and bone marrow activity. These findings indicate an important inflammatory component to the atherogenicity of remnant cholesterol, contributing to its relationship with increased CVD risk.
Author Disclosures: S.J. Bernelot Moens: None. S.L. Verweij: None. J.G. Schnitzler: None. L.C. Stiekema: None. S. Bekkering: None. M. Bos: None. A. Langsted: None. B.G. Nordestgaard: None. E.S. Stroes: None. J. Kroon: None.
- © 2016 by American Heart Association, Inc.