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CSL112 (Apolipoprotein A-I [Human]) Enhances Cholesterol Efflux Similarly in Healthy Individuals and Stable Atherosclerotic Disease Patients.

ABSTRACT: OBJECTIVE:CSL112 (apolipoprotein A-I [apoA-I; human]) is a novel formulation of apoA-I in development for reduction of early recurrent cardiovascular events after acute myocardial infarction. Cholesterol efflux capacity (CEC) is a marker of high-density lipoprotein (HDL) function that is strongly correlated with incident cardiovascular disease. Impaired CEC has been observed in patients with coronary heart disease. Here, we determined whether infused apoA-I improves CEC when administered to patients with stable atherosclerotic disease versus healthy volunteers. APPROACH AND RESULTS:Measurements of apoA-I, HDL unesterified cholesterol, HDL esterified cholesterol, pre-?1-HDL, and CEC were determined in samples from patients with stable atherosclerotic disease before and after intravenous administration of CSL112. These measures were compared with 2 prior studies in healthy volunteers for differences in CEC at baseline and after CSL112 infusion. Patients with stable atherosclerotic disease exhibited significantly lower ATP-binding cassette transporter 1-mediated CEC at baseline (P<0.0001) despite slightly higher apoA-I levels when compared with healthy individuals (2 phase 1 studies pooled; P?0.05), suggesting impaired HDL function. However, no differences were observed in apoA-I pharmacokinetics or in pre-?1-HDL (P=0.5) or CEC (P=0.1) after infusion of CSL112. Similar elevation in CEC was observed in patients with low or high baseline HDL function (based on tertiles of apoA-I-normalized CEC; P=0.1242). These observations were extended and confirmed using cholesterol esterification as an additional measure. CONCLUSIONS:CSL112 shows comparable, strong, and immediate effects on CEC despite underlying cardiovascular disease. CSL112 is, therefore, a promising novel therapy for lowering the burden of atherosclerosis and reducing the risk of recurrent cardiovascular events.

SUBMITTER: Gille A

PROVIDER: S-EPMC5895137 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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CSL112 (Apolipoprotein A-I [Human]) Enhances Cholesterol Efflux Similarly in Healthy Individuals and Stable Atherosclerotic Disease Patients.

Gille Andreas A D'Andrea Denise D Tortorici Michael A MA Hartel Gunter G Wright Samuel D SD

Arteriosclerosis, thrombosis, and vascular biology 20180208 4

<h4>Objective</h4>CSL112 (apolipoprotein A-I [apoA-I; human]) is a novel formulation of apoA-I in development for reduction of early recurrent cardiovascular events after acute myocardial infarction. Cholesterol efflux capacity (CEC) is a marker of high-density lipoprotein (HDL) function that is strongly correlated with incident cardiovascular disease. Impaired CEC has been observed in patients with coronary heart disease. Here, we determined whether infused apoA-I improves CEC when administered ...[more]

PMID: 29437574

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Project description:BackgroundObservational data associate lower levels of serum vitamin D with coronary artery calcification, cardiovascular events and mortality. However, there is little interventional evidence demonstrating that moderate vitamin D deficiency plays a causative role in cardiovascular disease. This study examined the cardiovascular effects of dietary vitamin D deficiency and of vitamin D receptor agonist (paricalcitol) administration in apolipoprotein E knockout mice.MethodsMice were fed atherogenic diets with normal vitamin D content (1.5 IU/kg) or without vitamin D. Paricalcitol, or matched vehicle, was administered 3× weekly by intraperitoneal injection. Following 20 weeks of these interventions cardiovascular phenotype was characterized by histological assessment of aortic sinus atheroma, soluble markers, blood pressure and echocardiography. To place the cardiovascular assessments in the context of intervention effects on bone, structural changes at the tibia were assessed by microtomography.ResultsVitamin D deficient diet induced significant reductions in plasma vitamin D (p<0.001), trabecular bone volume (p<0.01) and bone mineral density (p<0.005). These changes were accompanied by an increase in calcification density (number of calcifications per mm(2)) of von Kossa-stained aortic sinus atheroma (461 versus 200, p<0.01). Paricalcitol administration suppressed parathyroid hormone (p<0.001), elevated plasma calcium phosphate product (p<0.005) and induced an increase in calcification density (472 versus 200, p<0.005) similar to that seen with vitamin D deficiency. Atheroma burden, blood pressure, metabolic profile and measures of left ventricular hypertrophy were unaffected by the interventions.ConclusionVitamin D deficiency, as well as excess, increases atherosclerotic calcification. This phenotype is induced before other measures of cardiovascular pathology associated clinically with vitamin D deficiency. Thus, maintenance of an optimal range of vitamin D signalling may be important for prevention of atherosclerotic calcification.

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CSL112 (Apolipoprotein A-I [Human]) Enhances Cholesterol Efflux Similarly in Healthy Individuals and Stable Atherosclerotic Disease Patients.

Publications

CSL112 (Apolipoprotein A-I [Human]) Enhances Cholesterol Efflux Similarly in Healthy Individuals and Stable Atherosclerotic Disease Patients.

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