Rapid Change in Plaque Size, Composition, and Molecular Footprint After Recombinant Apolipoprotein A-IMilano (ETC-216) Administration

Ibáñez, Borja; Vilahur, Gemma; Cimmino, Giovanni; Speidl, Walter S.; Piñero, Antonio; Choi, Brian G.; Zafar, M. Urooj; Santos‐Gallego, Carlos G.; Krause, Brian R.; Badimón, Lina; Fuster, Valentín; Badimón, Juan J.

doi:10.1016/j.jacc.2007.09.071

Cited by 117 publications

(79 citation statements)

References 24 publications

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“…10,11 Animal studies have shown that increases in HDL acutely change plaque composition. [12][13][14] Although there have been studies showing that plaque characteristics, as assessed with IVUS, change in the coronary circulation after HDL infusions, histological changes have not been studied. The primary goal of this study was to determine the effects of reconstituted HDL (rHDL) on serum markers of inflammation and on atherosclerotic plaque composition.…”

mentioning

confidence: 99%

Infusion of Reconstituted High-Density Lipoprotein Leads to Acute Changes in Human Atherosclerotic Plaque

Shaw

Bobik

Murphy

et al. 2008

Circulation Research

254

197

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Abstract-Studies have shown a reduction in plaque volume and change in plaque ultrasound characteristics after 4 infusions of reconstituted high-density lipoprotein (rHDL). Whether rHDL infusion leads to acute changes in plaque characteristics in humans is not known. Patients with claudication scheduled for percutaneous superficial femoral artery revascularization were randomized to receive 1 intravenous infusion of either placebo or rHDL (80 mg/kg given over 4 hours). Five to 7 days following the infusion, patients returned and revascularization was performed including atherectomy to excise plaque from the superficial femoral artery. Twenty patients (17 males) average age, 68Ϯ10 years (meanϮSD) were recruited. Eleven patients had a history of documented coronary artery disease, all patients were on aspirin, and 18 were on statins. Ten of the patients received rHDL and 10 placebo. There was significantly less vascular cell adhesion molecule-1 expression (28Ϯ3% versus 50Ϯ3%; PϽ0.05) and a reduction in lipid content in the plaque of HDL-treated subjects compared to placebo. The level of HDL cholesterol increased by 20% after infusion of rHDL and the capacity of apolipoprotein B-depleted plasma to support cholesterol efflux increased. Intravenous infusion of a single dose of reconstituted HDL led to acute changes in plaque characteristics with a reduction in lipid content, macrophage size, and measures of inflammation. These changes may contribute to the cardioprotective effects of HDL.

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mentioning

confidence: 99%

Infusion of Reconstituted High-Density Lipoprotein Leads to Acute Changes in Human Atherosclerotic Plaque

Shaw

Bobik

Murphy

et al. 2008

Circulation Research

254

197

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“…Despite a lipid profile that is usually associated with a high risk of premature cardiovascular disease, apoA-I M carriers display no increase in cardiovascular disease or events (10,14,15). This has led to speculation that apoA-I M is a gainof-function mutation that has enhanced cardio-protective effects (16)(17)(18)(19)(20)(21)(22), while others believe that wild-type (WT) apoA-I and apoA-I M are functionally equivalent (23,24). A clinical trial of repeated intravenous infusions of apoA-I M -phospholipid complexes demonstrated regression of existing atheromas after five weekly treatments (25,26).…”

mentioning

confidence: 99%

Structural and functional consequences of the Milano mutation (R173C) in human apolipoprotein A-I

Alexander

Tanaka

Kono

et al. 2009

Journal of Lipid Research

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Carriers of the apolipoprotein A-I Milano (apoA-I M ) variant, R173C, have reduced levels of plasma HDL but no increase in cardiovascular disease. Despite intensive study, it is not clear whether the removal of the arginine or the introduction of the cysteine is responsible for this altered functionality. We investigated this question using two engineered variations of the apoA-I M mutation: R173S apoA-I, similar to apoA-I M but incapable of forming a disulfide bond, and R173K apoA-I, a conservative mutation. Characterization of the lipid-free proteins showed that the order of stability was wild type≈R173K.R173S.R173C. Compared with wildtype apoA-I, apoA-I M had a lower affinity for lipids, while R173S apoA-I displayed intermediate affinity. The in vivo effects of the apoA-I variants were measured by injecting apoA-I-expressing adeno-associated virus into apoA-I-null mice. Mice that expressed the R173S variant again showed an intermediate phenotype. Thus, both the loss of the arginine and its replacement by a cysteine contribute to the altered properties of apoA-I M . The arginine is potentially involved in an intrahelical salt bridge with E169 that is disrupted by the loss of the positively charged arginine and repelled by the cysteine, destabilizing the helix bundle domain in the apoA-I molecule and modifying its lipid binding

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“…It offered the opportunity to assess the short-and long-term effects of repeat administrations of MDCO-216 on plasma lipid and lipoprotein levels, and the effect of treatment on the exvivo serum cholesterol effl ux capacity via currently known effl ux mechanisms. The opportunity had additional relevance since little information has been published on the effects of exogenous apoA-1M administration on lipids and lipoproteins in animals fed a normal diet; previous animal studies were focused on the effect of apoA-IM administration on lipid levels and atherosclerosis in cholesterol-fed animals (16)(17)(18)(19)(20).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, administration of the predecessor compound ETC-216 was shown to reduce atherosclerotic plaque size and volume in mice and rabbit models (16)(17)(18)(19)(20) and in patients with acute coronary syndromes ( 21 ). However, no studies have been reported describing the effects of repeated administration of this product candidate on lipid and lipoprotein levels, either in animals or in man.…”

Section: Methodsmentioning

confidence: 99%

Effect of repeated apoA-IMilano/POPC infusion on lipids, (apo)lipoproteins, and serum cholesterol efflux capacity in cynomolgus monkeys

Kempen¹,

Gomaraschi

Bellibas

et al. 2013

Journal of Lipid Research

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Rapid Change in Plaque Size, Composition, and Molecular Footprint After Recombinant Apolipoprotein A-IMilano (ETC-216) Administration

Abstract: Acute plaque regression observed after short-term apoA-I(Milano) administration was associated with a significant reduction in suspected makers of plaque vulnerability in an experimental model of atherosclerosis.

Cited by 117 publications

References 24 publications

Infusion of Reconstituted High-Density Lipoprotein Leads to Acute Changes in Human Atherosclerotic Plaque

Infusion of Reconstituted High-Density Lipoprotein Leads to Acute Changes in Human Atherosclerotic Plaque

Structural and functional consequences of the Milano mutation (R173C) in human apolipoprotein A-I

Effect of repeated apoA-IMilano/POPC infusion on lipids, (apo)lipoproteins, and serum cholesterol efflux capacity in cynomolgus monkeys

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