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Canadian Journal of Cardiology

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

      Abstract

      Background

      Among strategies to reduce the remaining risk of cardiovascular disease, interest has focused on using infusions of synthetic high-density lipoprotein (sHDL).

      Methods

      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.

      Results

      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).

      Conclusions

      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.

      Résumé

      Contexte

      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.

      Méthodologie

      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 de sang ont été prélevés pour les analyses biochimiques et l’évaluation de la capacité d’efflux du cholestérol.

      Résultats

      Dans les deux protocoles, le volume de l’athérome dans les groupes sous placebo a augmenté entre la première et la seconde évaluation par échographie intravasculaire. Par contre, dans les groupes ayant reçu les perfusions de TN-HDLs, une stabilisation ou une légère régression des plaques (p < 0,05 comparativement au placebo après perfusion) ont été observées par rapport aux valeurs initiales. Le traitement par TN-HDLs a été associé à une élévation marquée du taux plasmatique de cholestérol libre et à une augmentation significative de la capacité d’efflux du cholestérol total. Les analyses histologiques des plaques dans les carotides ont révélé une diminution de l’accumulation de macrophages chez les lapins ayant reçu des perfusions de TN-HDLs comparativement à ceux sous placebo (p < 0,05).

      Conclusions

      Nos résultats montrent que les traitements aigus et subaigus par TN-HDLs stabilisent efficacement les plaques d’athérosclérose dans un modèle de lapin. Cet effet semble lié à une accumulation moindre de cellules inflammatoires dans les plaques. Malgré des résultats récents n’ayant pas corroboré son efficacité, le traitement par les HDLs demeure une option thérapeutique fascinante dans la réduction du risque cardiovasculaire.
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