Impact of lipoprotein apheresis with dextran‐sulfate adsorption on the expression of genes involved in cardiovascular health in the blood of patients with homozygous familial hypercholesterolemia

Abstract

Lipoprotein apheresis (LA) with dextran sulfate adsorption (DSA) is a reliable method to decrease LDL-cholesterol (C) concentrations in patients with homozygous familial hypercholesterolemia (HoFH). The objective of the present study was to investigate the impact of LA with DSA on the mRNA expression of genes associated with cardiovascular health in the whole blood of HoFH patients. Blood samples were collected before and after LA treatment with DSA in 9 HoFH patients. Microarray analyses were performed to measure the whole blood expression of >30 000 annotated genes pre-and post-LA. Concomitant reductions in LDL-C (median 273.8%, range: 255.9 to 282.0, P 5 .0001) and lipoprotein (a) concentrations (median 274.1%, range 265.6 to 284.1, P 5 .003) were induced with LA treatment. LA with DSA did not impact the whole blood mRNA expression of most key genes involved in cardiovascular health, including those associated with cholesterol, fatty acid and lipoprotein metabolism. However, LA with DSA significantly upregulated the whole blood expression of early growth response protein (EGR)1 (1.94-fold, P 5 .02), EGR3 (1.56-fold, P 5 .0008) and B-cell lymphoma 3-encoded protein (BCL3; 1.25-fold, P 5 .03).In conclusion, this study demonstrated that a single LA treatment with DSA has very limited impact on the whole blood expression of a broad spectrum of genes associated with cardiovascular health. Our results suggest that contact between blood cells and the primary membrane or extracorporeal circulation could upregulate the expression of EGR1, EGR3, BCL3, and MMP9 in blood cells. K E Y W O R D Shomozygous familial hypercholesterolemia, lipoprotein apheresis, microarray analysis | I NT ROD UCTI ONHomozygous familial hypercholesterolemia (HoFH) is caused, in most cases, by mutations in both alleles of the LDL receptor (LDLR) gene. Clinical features of HoFH include markedly high LDL-cholesterol (C) concentrations, tendon and skin xanthomas, extensive atherosclerosis, and extreme coronary artery disease (CAD) risk.1 If untreated, CAD occurs during childhood or adolescence in HoFH patients. 1Repetitive long-term lipoprotein apheresis (LA) remains the gold-standard therapy for HoFH as it has been demonstrated to increase life expectancy in these patients.

Comparison of cytokine changes in three different lipoprotein apheresis systems in an ex vivo whole blood model

“…This may indicate that lipoprotein apheresis affects expression of IP‐10 differently in an in vivo and an ex vivo setting. Recently, Stefanutti et al demonstrated an impact on the messenger RNA of IL‐1α, IL‐6, and TNF in patients undergoing lipoprotein apheresis, indicating a possible regulatory effect on the expression of precursors in the chain of production of inflammatory mediators . This could contribute to explaining the observed differences between in effect on IP‐10 in in vivo and ex vivo studies.…”