Innate immune cell function in statin-treated patients with severe hypercholesterolemia is comparable to normocholesterolemic individuals: A cross-sectional study.

BACKGROUND AND AIMS: Hypercholesterolemia is a major risk factor for atherosclerotic cardiovascular disease. Innate immune cells, including monocytes and neutrophils, play important roles in the pathophysiology of atherosclerosis. We previously reported that monocytes from patients with severely elevated low-density lipoprotein (LDL) cholesterol (LDL-c > 4.9 mmol/l) have a hyperresponsive phenotype, which persists even after three months statin treatment. This long-term hyperresponsive innate immune phenotype is termed trained immunity (innate immune memory), and is mediated by persistent enrichment of activating histone modifications leading to higher chromatin accessibility. In this study we investigated the monocyte and neutrophil phenotype of patients with severe hypercholesterolemia treated for 12 months with statins, compared to normocholesterolemic controls.

METHODS

In a multicentric cross-sectional study, treatment-naïve patients with severe hypercholesterolemia (defined as LDL-cholesterol >4.9 mmol/L) requiring statin treatment were included. Blood was drawn after 12 months of lipid lowering therapy with statins (n = 15) and compared to healthy normocholesterolemic controls (LDL-c<3.5 mmol/l; n = 18).We assessed monocyte phenotype with flow cytometry, cytokine production capacity of PBMCs, and H3K4me3 expression on the TNFA promotor. In addition, we assessed the neutrophil phenotype and function.

RESULTS

Treatment lowered LDL-c from 5.8 to 2.7 mmol/L. PBMC cytokine production capacity, as well as the expression of H3K4me3 histone mark on the TNFA promotor did not differ from the controls (LDL-c 2.6 mmol/L). Although neutrophil CD11b, CD66b, and CD62L expression was the same, production of several granular proteins was lower in patients.

CONCLUSIONS

Previous studies reported hyperresponsive monocytes in treatment-naïve patients with LDL-c > 4.9 mmol/l. We now demonstrate that in an independent cohort of patients with LDL-c > 4.9 who are treated for 12 months with lipid-lowering drugs, the monocyte phenotype and function was similar to that of normocholesterolemic controls. In addition, neutrophils phenotype was similar, while the secretion of several granular proteins was lower in the patients.