Persistent changes in lipoprotein lipids after a single infusion of ascending doses of MDCO-216 (apoA-IMilano/POPC) in healthy volunteers and stable coronary artery disease patients. (December 2016)

• Record Type: Journal Article
• Authors: Kempen, Herman J.; Gomaraschi, Monica; Simonelli, Sara; Calabresi, Laura; Moerland, Matthijs; Otvos, James; Jeyarajah, Elias; Kallend, David; Wijngaard, Peter L.J.
• Is Part Of: Atherosclerosis. Volume 255(2016)
• Page Start: 17
• Page End: 24
• Publication Date: 2016-12
• Subjects: Clinical trials -- Drug therapy -- Lipoproteins -- Lipids -- Atherosclerosis -- HDL; CAD coronary artery disease -- CE esterified cholesterol -- CER cholesterol esterification rate -- FC free cholesterol -- PL phospholipids -- TC total cholesterol; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2016.10.042
• Languages: English
• ISSNs: 0021-9150

Abstract

Abstract: Background and aims: Effects of single ascending doses of MDCO-216 on plasma lipid and lipoprotein levels were assessed in human healthy volunteers and in patients with stable coronary artery disease (CAD). Methods: MDCO-216 was infused at a single dose of 5, 10, 20, 30 or 40 mg/kg over 2 h and blood was collected at 2, 4, 8, 24, 48, 168 and 720 h after start of infusion (ASOI). Lipoprotein lipids were assessed by FLPC and by 1H NMR. Results: Plasma concentrations of free cholesterol (FC) displayed a rapid and dose-dependent rise, peaking at 8 h, but remaining above baseline until 48 h ASOI, whereas levels of esterified cholesterol (CE) increased at lower doses but not at higher doses, and even decreased below baseline at the highest dose. Plasma cholesterol esterification rate (CER) decreased with a first nadir between 4 and 8 h and a second nadir at 48 h ASOI. Taken over all subjects receiving MDCO-216, the increase in FC at 8 h correlated inversely with the drop in CER at 4 h but positively with the increase in basal and scavenger receptor class B type I (SR-BI)-mediated cholesterol efflux capacities at 2 h ASOI. Upon FPLC analysis, FC was found to increase first in high density lipoproteins (HDL) and very low density lipoproteins (VLDL) and later (at 48 or 168 h ASOI) in low density lipoproteins (LDL). CE initially decreased in LDL and HDL but after 24 h started to increase in VLDL and LDL whereas HDL-CE was still below baseline at 48 h. Phospholipids (PL) showed the same pattern as FC. Triglycerides (TG) also rose rapidly, most prominently in VLDL, but also in LDL and HDL. Apolipoprotein E (Apo-E) in VLDL increased at 4–8 h but returned to baseline at 24 h ASOI. 1H NMR analysis showed a rapid and dose-dependent increase in HDL particle size, peaking at 2 h and returning to baseline at 24 h, and a small increase in HDL particle concentration. After infusion of the 40 mg/kg dose, LDL and VLDL-particles also increased in number and size. Conclusions: A single administration of MDCO-216 caused rapid changes in lipid levels and lipoprotein composition, some of which persisted for at least 7 days. Highlights: Infusion of a rec-HDL containing apoA-IMilano leads to prompt increases of FC level in plasma, whereas CE level does not rise and at higher doses even decreases. This rise is more pronounced and longer sustained in cardiovascular disease (CAD) patients as compared to healthy volunteers. The increase of free cholesterol correlates strongly with basal and SR-B1-mediated cholesterol efflux capacity, and also inversely with endogenous cholesterol esterification rate. FC increases in all lipoproteins, the rise is short-lived in HDL and longer-lived in VLDL and LDL.