Increased inflammatory activation in patients with familial dysbetalipoproteinaemia
Remnant Cholesterol Elicits Arterial Wall Inflammation and a Multilevel Cellular Immune Response in Humans
A causal association between high remnant cholesterol and elevated c-reactive protein (CRP) levels, as well as between remnant cholesterol and ischaemic heart disease was reported recently by Mendelian randomisation studies [1-3]. However, the possible mechanisms by which remnant cholesterol particles cause inflammatory changes are unclear.
In this study, the impact of elevated levels of remnant cholesterol on multi-level inflammatory activation was evaluated in 17 patients with familial dysbetalipoproteinaemia (FD) and 17 healthy controls. Arterial wall inflammation and bone marrow activity were assessed with 18F-FDG PET/CT, monocyte phenotype was tested with flow cytometry and the association between remnant cholesterol levels and blood leukocyte counts was validated in the Copenhagen General Population Study (CGPS).
- Patients with FD had significantly higher levels of remnant cholesterol (FD patients 3.26 mmol/L, 95% CI: 2.07–5.71, controls 0.29 mmol/L, 95% CI: 0.27–0.4, P<0.001).
- FD patients had a 1.2-fold higher uptake of 18F-FDG in the arterial wall of the aorta and the carotid arteries (target-to-background ratio [TBR]max aorta: FD patients 2.83±0.42 vs control 2.33±0.22, P<0.001, TBRmax carotid: FD patients 2.02±0.35 vs control 1.63±0.27, P=0.001).
- 18F-FDG uptake in the most diseased segment (MDS) revealed a similar pattern (TBR MDS aorta: FD patients 2.93±0.45 vs control 2.41±0.25, P<0.001, TBRMDS carotid: FD patients 2.11±0.37 vs control 1.73±0.29, P=0.002). These differences did not change after adjusting for SBP and BMI.
- In patients with FD, the expression of integrins CD11b and CD18 was significantly increased in the classical (CD14++, CD16-¬¬) and intermediate (CD14++, CD16+) monocyte subset.
- The percentage of monocytes containing lipids was significantly increased in patients with FD 92% (95% CI: 86–95) vs 76% (95% CI: 66–81) in controls (P=0.001), with a concomitant increase in the number of lipid droplets per positive monocyte.
- There was a 1.2-fold higher uptake of 18F-FDG in the bone marrow of patients with FD compared with controls (standard uptake value [SUV]mean in FD patients 1.83±0.3 vs 1.56±0.2 in controls, P=0.051 and SUVmax patients with FD 2.79±0.6 vs controls 2.33±0.3, P=0.041).
- In patients with FD the increased FDG uptake in the bone marrow correlated significantly to leukocyte counts (SUVmean r=0.577; r2=0.33, P=0.015, SUVmax r=0.506, r2=0.25, P=0.038).
- In the CGPS cohort, there was a significant dose-dependent relationship between remnant cholesterol and circulating leukocyte counts ranging from 6.8×10−9/L (95% CI: 5.8–7.9) in individuals with remnant cholesterol <0.5 mmol/L to 7.4 ×10−9/L (95% CI: 6.4–8.9) in those with remnant cholesterol ≥2 mmol/L.
Patients with FD have increased arterial wall and cellular inflammation, as well as increased bone marrow activation. These findings suggest that additional pathophysiological processes lead to the atherogenicity of remnant cholesterol that contributes to the increased cardiovascular disease risk in these patients.