Abstract-Apolipoprotein A-I Milano (AIM), a natural variant of human apolipoprotein A-I, confers to carriers a significant protection against vascular disease. In previous studies, administration of recombinant AIM-phospholipid (AIM-PL) complexes to hypercholesterolemic rabbits markedly inhibited neointimal formation after arterial injury; moreover, repeated injections of AIM-PL in apoE-deficient mice significantly reduced atherosclerosis progression. The objective of the present study was to determine if a single localized infusion of AIM-PL complexes administered directly to atheromatous lesions could promote plaque regression. Lipid-rich, atheromatous plaques were generated at both common carotid arteries of 25 rabbits by applying a perivascular electric injury, followed by 1.5% cholesterol diet for 90 days. Rabbits were infused with either saline, phospholipid vesicles, or 3 different AIM-PL doses (250, 500, or 1000 mg of protein) delivered through an intravascular ultrasound (IVUS) catheter positioned at the origin of the right carotid. The lesions at the left carotid artery were therefore exposed to the agents systemically. Infusion of AIM-PL at the 2 highest doses caused reduction of right carotid artery plaque area by the end a 90-minute infusion as assessed by IVUS analysis. Plaque area regression was confirmed by histology in carotid arteries receiving direct (500 and 1000 mg doses) and systemic (500 mg dose) delivery, 72 hours after the start of the treatment. Plaque lipid content was associated with significant and similar decreases in Oil Red O staining in both arteries. These results suggest AIM-PL complexes enhanced lipid removal from arteries is the mechanism responsible for the observed plaque changes.

These results confirm the efficacy of ETC-216 for atherosclerosis treatment and provide guidance for dose selection and frequency to obtain a significant reduction of plaque volume.

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Background: Among strategies to reduce the remaining risk of cardiovascular disease, interest has focused on using infusions of synthetic HDL (sHDL). Methods: New Zealand rabbits underwent a perivascular injury at both carotids and were randomly allocated into two protocols: 1) a single dose study, where rabbits were treated with a single infusion of sHDL containing a trimeric form of human apoA-I (TN-sHDL, 200 mg/kg) or with Placebo; 2) a multiple dose study, where four groups of rabbits were treated five times with Placebo or TN-sHDL at different doses (8, 40, 100 mg/kg). Plaque changes were analysed in vivo by IntraVascular UltraSound (IVUS). Blood was drawn from rabbits for biochemical analyses and cholesterol efflux capacity (CEC) evaluation. Results: In both protocols, atheroma volume in the Placebo groups increased between the first and the second IVUS evaluation. A stabilization or a slight regression was instead observed vs baseline in the TN-sHDL treated groups (p<0.005 vs Placebo post-infusion). TN-sHDL treatment caused a sharp rise of plasma free cholesterol levels and a significant increase of total CEC. Histological analysis of carotid plaques showed a reduced macrophage accumulation in TN-sHDL treated rabbits compared to Placebo (p<0.05). Conclusions: Our results demonstrate that acute and sub-acute treatments with TN-sHDL are effective in stabilizing atherosclerotic plaques in a rabbit model. This effect appears to be related to a reduced intra-plaque accumulation of inflammatory cells. Besides recent failures in proving its efficacy, sHDL treatment remains a fascinating therapeutic option for reduction of cardiovascular risk.