† Investigating Hepatocyte Cholesterol Uptake Ex Vivo Following CSL112 (Apolipoprotein A-I [Human]) Infusion in Post Myocardial Infarction Patients.

Cholesterol efflux capacity (CEC) is an important measure of high-density lipoprotein (HDL) function and is used as a measure of the ability of HDL to promote cholesterol efflux from macrophages, the first step in reverse cholesterol transport. CEC is inversely related to incident cardiovascular (CV) events and is a predictor of CV disease. CSL112 (apoA-I [human]) is a novel therapy designed to reduce the risk of recurrent CV events following acute myocardial infarction (AMI). CSL112 infusion rapidly and robustly increases CEC when infused in patients post-AMI. It is unknown whether this effect on CEC translates to increased hepatocyte cholesterol uptake, the subsequent step in reverse cholesterol transport. To evaluate whether infusion of CSL112 increases cholesterol uptake by hepatocytes when administered to patients post-AMI. Patients from the AEGIS-I (ApoA-I Event Reducing in Ischemic Syndromes I) study received either placebo, 2 g or 6 g CSL112 post-AMI. Serum samples from a subset of individuals (n=15 per group) were studied ex vivo. Firstly, CEC was assessed using J774 macrophages loaded with labelled [3H] cholesterol tracer. Cholesterol uptake media (200 μL) was then collected and applied to Fu5AH hepatocytes for assessment of labelled cholesterol uptake. A dose-dependent increase in hepatocyte cholesterol uptake was observed following CSL112 infusion, with the 6 g dose inducing a 2.1-fold increase at the end of infusion (2 hours), and sustained elevation above baseline at 24 to 48 hours post-infusion. Hepatocyte cholesterol uptake across all dose groups and timepoints was strongly correlated with total CEC (r=0.949; p<0.001) and plasma apoA-I (r=0.746; p<0.001). A rapid and robust increase in CEC following CSL112 infusion is associated with increased cholesterol uptake into hepatocytes, an important subsequent step in reverse cholesterol transport which precedes cholesterol excretion in bile. The efficacy and safety of CSL112 is currently being investigated in an ongoing Phase 3 study (AEGIS-II; NCT03473223). Yes The study was sponsored by CSL Behring. [ABSTRACT FROM AUTHOR]