Canadian Journal of Cardiology
Basic Research| Volume 35, ISSUE 10, P1400-1408, October 2019

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


      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).


      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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        • Olkkonen V.M.
        • Sinisalo J.
        • Jauhiainen M.
        New medications targeting triglyceride-rich lipoproteins: can inhibition of ANGPTL3 or apoC-III reduce the residual cardiovascular risk?.
        Atherosclerosis. 2018; 272: 27-32
        • Ladeiras-Lopes R.
        • Agewall S.
        • Tawakol A.
        • et al.
        Atherosclerosis: recent trials, new targets and future directions.
        Int J Cardiol. 2015; 192: 72-81
        • Toth P.P.
        • Barter P.J.
        • Rosenson R.S.
        • et al.
        High-density lipoproteins: a consensus statement from the National Lipid Association.
        J Clin Lipidol. 2013; 7: 484-525
        • Karathanasis S.K.
        • Freeman L.A.
        • Gordon S.M.
        • Remaley A.T.
        The changing face of HDL and the best way to measure it.
        Clin Chem. 2017; 63: 196-210
        • Talbot C.P.J.
        • Plat J.
        • Ritsch A.
        • Mensink R.P.
        Determinants of cholesterol efflux capacity in humans.
        Prog Lipid Res. 2018; 69: 21-32
        • Khera A.V.
        • Cuchel M.
        • de la Llera-Moya M.
        • et al.
        Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis.
        N Engl J Med. 2011; 364: 127-135
        • The AIM-HIGH Investigators
        Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
        N Engl J Med. 2011; 365: 2255-2267
        • Rader D.J.
        • Tall A.R.
        The not-so-simple HDL story: is it time to revise the HDL cholesterol hypothesis?.
        Nat Med. 2012; 18: 1344-1346
        • Voight B.F.
        • Peloso G.M.
        • Orho-Melander M.
        • et al.
        Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.
        Lancet. 2012; 380: 572-580
        • Mora S.
        • Glynn R.J.
        • Ridker P.M.
        High-density lipoprotein cholesterol, size, particle number, and residual vascular risk after potent statin therapy.
        Circulation. 2013; 128: 1189-1197
        • Calabresi L.
        • Baldassarre D.
        • Simonelli S.
        • et al.
        Plasma lecithin:cholesterol acyltransferase and carotid intima-media thickness in European individuals at high cardiovascular risk.
        J Lipid Res. 2011; 52: 1569-1574
        • Haase C.L.
        • Tybjaerg-Hansen A.
        • Qayyum A.A.
        • et al.
        LCAT, HDL cholesterol and ischemic cardiovascular disease: a Mendelian randomization study of HDL cholesterol in 54,500 individuals.
        J Clin Endocrinol Metab. 2012; 97: E248-E256
        • Calabresi L.
        • Gomaraschi M.
        • Simonelli S.
        • Bernini F.
        • Franceschini G.
        HDL and atherosclerosis: insights from inherited HDL disorders.
        Biochim Biophys Acta. 2015; 1851: 13-18
        • Murphy A.J.
        • Westerterp M.
        • Yvan-Charvet L.
        • Tall A.R.
        Anti-atherogenic mechanisms of high density lipoprotein: effects on myeloid cells.
        Biochim Biophys Acta. 2012; 1821: 513-521
        • Luscher T.F.
        • Landmesser U.
        • von Eckardstein A.
        • Fogelman A.M.
        High-density lipoprotein: vascular protective effects, dysfunction, and potential as therapeutic target.
        Circ Res. 2014; 114: 171-182
        • Pirillo A.
        • Catapano A.L.
        • Norata G.D.
        HDL in infectious diseases and sepsis.
        Handb Exp Pharmacol. 2015; 224: 483-508
        • Parolini C.
        • Marchesi M.
        • Lorenzon P.
        • et al.
        Dose-related effects of repeated ETC-216 (recombinant apolipoprotein A-I Milano/1-palmitoyl-2-oleoyl phosphatidylcholine complexes) administrations on rabbit lipid-rich soft plaques: in vivo assessment by intravascular ultrasound and magnetic resonance imaging.
        J Am Coll Cardiol. 2008; 51: 1098-1103
        • Parolini C.
        • Marchesi M.
        • Chiesa G.
        HDL therapy for the treatment of cardiovascular diseases.
        Curr Vasc Pharmacol. 2009; 7: 550-556
        • Takata K.
        • Di Bartolo B.A.
        • Nicholls S.J.
        High-density lipoprotein infusions.
        Cardiol Clin. 2018; 36: 311-315
        • Graversen J.H.
        • Laurberg J.M.
        • Andersen M.H.
        • et al.
        Trimerization of apolipoprotein A-I retards plasma clearance and preserves antiatherosclerotic properties.
        J Cardiovasc Pharmacol. 2008; 51: 170-177
        • Chiesa G.
        • Parolini C.
        • Sirtori C.R.
        Acute effects of high-density lipoproteins: biochemical basis and clinical findings.
        Curr Opin Cardiol. 2008; 23: 379-385
        • Marchesi M.
        • Parolini C.
        • Valetti C.
        • et al.
        The intracellular quality control system down-regulates the secretion of amyloidogenic apolipoprotein A-I variants: a possible impact on the natural history of the disease.
        Biochim Biophys Acta. 2011; 1812: 87-93
        • Ohnsorg P.M.
        • Mary J.L.
        • Rohrer L.
        • et al.
        Trimerized apolipoprotein A-I (TripA) forms lipoproteins, activates lecithin: cholesterol acyltransferase, elicits lipid efflux, and is transported through aortic endothelial cells.
        Biochim Biophys Acta. 2011; 1811: 1115-1123
        • Murphy A.J.
        • Hoang A.
        • Aprico A.
        • Sviridov D.
        • Chin-Dusting J.
        Anti-inflammatory functions of apolipoprotein A-I and high-density lipoprotein are preserved in trimeric apolipoprotein A-I.
        J Pharmacol Exp Ther. 2013; 344: 41-49
        • Jonas A.
        Reconstitution of high-density lipoproteins.
        Methods Enzymol. 1986; 128: 553-582
        • Chiesa G.
        • Di Mario C.
        • Colombo N.
        • et al.
        Development of a lipid-rich, soft plaque in rabbits, monitored by histology and intravascular ultrasound.
        Atherosclerosis. 2001; 156: 277-287
        • Chiesa G.
        • Rigamonti E.
        • Monteggia E.
        • et al.
        Evaluation of a soft atherosclerotic lesion in the rabbit aorta by an invasive IVUS method versus a non-invasive MRI technology.
        Atherosclerosis. 2004; 174: 25-33
        • Marchesi M.
        • Parolini C.
        • Caligari S.
        • et al.
        Rosuvastatin does not affect human apolipoprotein A-I expression in genetically modified mice: a clue to the disputed effect of statins on HDL.
        Br J Pharmacol. 2011; 164: 1460-1468
        • Parolini C.
        • Rigamonti E.
        • Marchesi M.
        • et al.
        Cholesterol-lowering effect of dietary lupinus angustifolius proteins in adult rats through regulation of genes involved in cholesterol homeostasis.
        Food Chem. 2012; 132: 1475-1479
        • Parolini C.
        • Manzini S.
        • Busnelli M.
        • et al.
        Effect of the combinations between pea proteins and soluble fibres on cholesterolaemia and cholesterol metabolism in rats.
        Br J Nutr. 2013; 110: 1394-1401
        • Parolini C.
        • Vik R.
        • Busnelli M.
        • et al.
        A salmon protein hydrolysate exerts lipid-independent anti-atherosclerotic activity in ApoE-deficient mice.
        PLoS One. 2014; 9e97598
        • Parolini C.
        • Busnelli M.
        • Ganzetti G.S.
        • et al.
        Magnetic resonance imaging visualization of vulnerable atherosclerotic plaques at the brachiocephalic artery of apolipoprotein E knockout mice by the blood-pool contrast agent B22956/1.
        Mol Imaging. 2014; 13: 1-9
        • Busnelli M.
        • Manzini S.
        • Hilvo M.
        • et al.
        Liver-specific deletion of the Plpp3 gene alters plasma lipid composition and worsens atherosclerosis in apoE(-/-) mice.
        Sci Rep. 2017; 7: 44503
        • Caligari S.
        • Chiesa G.
        • Johnson S.K.
        • et al.
        Lupin (Lupinus albus) protein isolate has adequate nutritional value and reduces large intestinal weight in rats after restricted and ad libitum feeding.
        Ann Nutr Metab. 2006; 50: 528-537
        • de la Llera-Moya M.
        • Drazul-Schrader D.
        • Asztalos B.F.
        • et al.
        The ability to promote efflux via ABCA1 determines the capacity of serum specimens with similar high-density lipoprotein cholesterol to remove cholesterol from macrophages.
        Arterioscler Thromb Vasc Biol. 2010; 30: 796-801
        • Favari E.
        • Ronda N.
        • Adorni M.P.
        • et al.
        ABCA1-dependent serum cholesterol efflux capacity inversely correlates with pulse wave velocity in healthy subjects.
        J Lipid Res. 2013; 54: 238-243
        • Chiesa G.
        • Monteggia E.
        • Marchesi M.
        • et al.
        Recombinant apolipoprotein A-I(Milano) infusion into rabbit carotid artery rapidly removes lipid from fatty streaks.
        Circ Res. 2002; 90: 974-980
        • Nissen S.E.
        • Tsunoda T.
        • Tuzcu E.M.
        • et al.
        Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial.
        JAMA. 2003; 290: 2292-2300
        • Jensen L.O.
        • Thayssen P.
        • Pedersen K.E.
        • Stender S.
        • Haghfelt T.
        Regression of coronary atherosclerosis by simvastatin: a serial intravascular ultrasound study.
        Circulation. 2004; 110: 265-270
        • Tardif J.C.
        • Gregoire J.
        • L'Allier P.L.
        • et al.
        Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial.
        JAMA. 2007; 297: 1675-1682
        • Stegman B.
        • Shao M.
        • Nicholls S.J.
        • et al.
        Coronary atheroma progression rates in men and women following high-intensity statin therapy: a pooled analysis of REVERSAL, ASTEROID and SATURN.
        Atherosclerosis. 2016; 254: 78-84
        • Braschi S.
        • Neville T.A.
        • Maugeais C.
        • et al.
        Role of the kidney in regulating the metabolism of HDL in rabbits: evidence that iodination alters the catabolism of apolipoprotein A-I by the kidney.
        Biochemistry. 2000; 39: 5441-5449
        • Miyazaki A.
        • Sakuma S.
        • Morikawa W.
        • et al.
        Intravenous injection of rabbit apolipoprotein A-I inhibits the progression of atherosclerosis in cholesterol-fed rabbits.
        Arter Thromb Vasc Biol. 1995; 15: 1882-1888
        • Regenass-Lechner F.
        • Staack R.F.
        • Mary J.L.
        • et al.
        Immunogenicity, inflammation, and lipid accumulation in cynomolgus monkeys infused with a lipidated tetranectin-apoA-I fusion protein.
        Toxicol Sci. 2016; 150: 378-389
        • Kataoka Y.
        • Andrews J.
        • Duong M.
        • et al.
        Regression of coronary atherosclerosis with infusions of the high-density lipoprotein mimetic CER-001 in patients with more extensive plaque burden.
        Cardiovasc Diagn Ther. 2017; 7: 252-263
        • Karalis I.
        • Jukema J.W.
        HDL mimetics infusion and regression of atherosclerosis: is it still considered a valid therapeutic option?.
        Curr Cardiol Rep. 2018; 20: 66
        • Westerterp M.
        • Bochem A.E.
        • Yvan-Charvet L.
        • et al.
        ATP-binding cassette transporters, atherosclerosis, and inflammation.
        Circ Res. 2014; 114: 157-170
        • Brownell N.
        • Rohatgi A.
        Modulating cholesterol efflux capacity to improve cardiovascular disease.
        Curr Opin Lipidol. 2016; 27: 398-407
        • Kempen H.J.
        • Gomaraschi M.
        • Simonelli S.
        • et al.
        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.
        Atherosclerosis. 2016; 255: 17-24
        • Gille A.
        • D'Andrea D.
        • Tortorici M.A.
        • Hartel G.
        • Wright S.D.
        CSL112 (apolipoprotein A-I [human]) enhances cholesterol efflux similarly in healthy individuals and stable atherosclerotic disease patients.
        Arter Thromb Vasc Biol. 2018; 38: 953-963
        • Favari E.
        • Calabresi L.
        • Adorni M.P.
        • et al.
        Small discoidal pre-beta1 HDL particles are efficient acceptors of cell cholesterol via ABCA1 and ABCG1.
        Biochemistry. 2009; 48: 11067-11074
        • Rothblat G.H.
        • de la Llera-Moya M.
        • Atger V.
        • et al.
        Cell cholesterol efflux: integration of old and new observations provides new insights.
        J Lipid Res. 1999; 40: 781-796
        • Phillips M.C.
        Molecular mechanisms of cellular cholesterol efflux.
        J Biol Chem. 2014; 289: 24020-24029
        • Ronsein G.E.
        • Hutchins P.M.
        • Isquith D.
        • et al.
        Niacin therapy increases high-density lipoprotein particles and total cholesterol efflux capacity but not ABCA1-specific cholesterol efflux in statin-treated subjects.
        Arter Thromb Vasc Biol. 2016; 36: 404-411
        • Group H.T.C.
        • Landray M.J.
        • Haynes R.
        • et al.
        Effects of extended-release niacin with laropiprant in high-risk patients.
        N Engl J Med. 2014; 371: 203-212
        • Patel S.
        • Di Bartolo B.A.
        • Nakhla S.
        • et al.
        Anti-inflammatory effects of apolipoprotein A-I in the rabbit.
        Atherosclerosis. 2010; 212: 392-397
        • Giannarelli C.
        • Cimmino G.
        • Ibanez B.
        • et al.
        Acute ApoA-I Milano administration induces plaque regression and stabilisation in the long term.
        Thromb Haemost. 2012; 108: 1246-1248
        • Adorni M.P.
        • Favari E.
        • Ronda N.
        • et al.
        Free cholesterol alters macrophage morphology and mobility by an ABCA1 dependent mechanism.
        Atherosclerosis. 2011; 215: 70-76
        • Moore K.J.
        • Sheedy F.J.
        • Fisher E.A.
        • et al.
        Macrophages in atherosclerosis: a dynamic balance.
        Nat Rev Immunol. 2013; 13: 709-721