Infusions of Large Synthetic HDL Containing Trimeric apoA-I Stabilize Atherosclerotic Plaques in Hypercholesterolemic Rabbits

Among strategies to reduce the remaining risk of cardiovascular disease, interest has focused on using infusions of synthetic high-density lipoprotein (sHDL). New Zealand rabbits underwent a perivascular injury at both carotids and were randomly allocated into 2 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 4 groups of rabbits were treated 5 times with Placebo or TN-sHDL at different doses (8, 40, 100 mg/kg). Plaque changes were analysed in vivo by intravascular ultrasound. Blood was drawn from rabbits for biochemical analyses and cholesterol efflux capacity evaluation. In both protocols, atheroma volume in the Placebo groups increased between the first and the second intravascular ultrasound evaluation. A stabilization or a slight regression was instead observed vs baseline in the TN-sHDL-treated groups (P < 0.005 vs Placebo after infusion). TN-sHDL treatment caused a sharp rise of plasma-free cholesterol levels and a significant increase of total cholesterol efflux capacity. Histologic analysis of carotid plaques showed a reduced macrophage accumulation in TN-sHDL-treated rabbits compared with Placebo (P < 0.05). Our results demonstrate that acute and subacute treatments with TN-sHDL are effective in stabilizing atherosclerotic plaques in a rabbit model. This effect appears to be related to a reduced intraplaque accumulation of inflammatory cells. Besides recent failures in proving its efficacy, sHDL treatment remains a fascinating therapeutic option for the reduction of cardiovascular risk. Parmi les stratégies visant à réduire le risque résiduel de maladie cardiovasculaire, la perfusion de lipoprotéines de haute densité synthétiques (HDLs) suscite un grand intérêt. Des lapins de Nouvelle-Zélande ont subi une lésion périvasculaire aux deux carotides et ont été répartis de façon aléatoire dans deux protocoles : (1) une étude portant sur une seule dose, au cours de laquelle les lapins ont reçu une seule perfusion de HDLs renfermant une forme trimère d’apoA1 humaine (TN-HDLs, 200 mg/kg) ou un placebo; ou (2) une étude portant sur diverses doses, au cours de laquelle 4 groupes de lapins ont été traités à 5 reprises par un placebo ou par des perfusions de TN-HDLs à différentes doses (8, 40, 100 mg/kg). L’évolution des plaques a été analysée in vivo par échographie intravasculaire. Des échantillons d