High-density Lipoprotein Infusions Research Articles

Dysfunctional High-Density Lipoprotein Cholesterol and Coronary Artery Disease: A Narrative Review.

High-density lipoprotein (HDL) cholesterol is traditionally viewed as protective against cardiovascular disease (CVD). However, emerging evidence reveals that dysfunctional HDL, characterized by impaired reverse cholesterol transport (RCT), reduced anti-inflammatory and antioxidant activities and increased endothelial dysfunction, which can contribute to coronary artery disease (CAD). Dysfunctional HDL, resulting from oxidative modifications of Apolipoprotein A-1 (Apo A-1) and enzyme inactivation, fails to effectively remove cholesterol from peripheral tissues and may promote inflammation and atherosclerosis. Genetic mutations affecting HDL metabolism further complicate its role in cardiovascular health. Studies have shown that conventional therapies aimed at raising HDL-C levels do not necessarily reduce cardiovascular events, highlighting the need for new approaches that improve HDL functionality. Therapeutic strategies such as Apo A-1 mimetic peptides, reconstituted HDL infusions, and drugs targeting specific HDL metabolic pathways are being explored. Additionally, weight loss, statin therapy, and niacin have shown potential in enhancing HDL function. The pathophysiology of dysfunctional HDL involves complex mechanisms, including oxidative stress, inflammation, and genetic mutations, which alter its structure and function, diminishing its cardioprotective effects. New functional assays, such as the cholesterol efflux capacity (CEC) and HDL inflammatory index, provide more accurate predictions of cardiovascular risk by assessing HDL quality rather than quantity. As research progresses, the focus is shifting towards therapeutic strategies that enhance HDL function and address the root causes of its dysfunction, offering a more effective approach to reducing cardiovascular risk and preventing CAD.

Beneficial effects of recombinant CER-001 high-density lipoprotein infusion in sepsis: results from a bench to bedside translational research project.

Sepsis is characterized by a dysregulated immune response and metabolic alterations, including decreased high-density lipoprotein cholesterol (HDL-C) levels. HDL exhibits beneficial properties, such as lipopolysaccharides (LPS) scavenging, exerting anti-inflammatory effects and providing endothelial protection. We investigated the effects of CER-001, an engineered HDL-mimetic, in a swine model of LPS-induced acute kidney injury (AKI) and a Phase 2a clinical trial, aiming to better understand its molecular basis in systemic inflammation and renal function. We carried out a translational approach to study the effects of HDL administration on sepsis. Sterile systemic inflammation was induced in pigs by LPS infusion. Animals were randomized into LPS (n = 6), CER20 (single dose of CER-001 20mg/kg; n = 6), and CER20 × 2 (two doses of CER-001 20mg/kg; n = 6) groups. Survival rate, endothelial dysfunction biomarkers, pro-inflammatory mediators, LPS, and apolipoprotein A-I (ApoA-I) levels were assessed. Renal and liver histology and biochemistry were analyzed. Subsequently, we performed an open-label, randomized, dose-ranging (Phase 2a) study included 20 patients with sepsis due to intra-abdominal infection or urosepsis, randomized into Group A (conventional treatment, n = 5), Group B (CER-001 5mg/kg BID, n = 5), Group C (CER-001 10mg/kg BID, n = 5), and Group D (CER-001 20mg/kg BID, n = 5). Primary outcomes were safety and efficacy in preventing AKI onset and severity; secondary outcomes include changes in inflammatory and endothelial dysfunction markers. CER-001 increased median survival, reduced inflammatory mediators, complement activation, and endothelial dysfunction in endotoxemic pigs. It enhanced LPS elimination through the bile and preserved liver and renal parenchyma. In the clinical study, CER-001 was well-tolerated with no serious adverse events related to study treatment. Rapid ApoA-I normalization was associated with enhanced LPS removal and immunomodulation with improvement of clinical outcomes, independently of the type and gravity of the sepsis. CER-001-treated patients had reduced risk for the onset and progression to severe AKI (stage 2 or 3) and, in a subset of critically ill patients, a reduced need for organ support and shorter ICU length of stay. CER-001 shows promise as a therapeutic strategy for sepsis management, improving outcomes and mitigating inflammation and organ damage. The study was approved by the Agenzia Italiana del Farmaco (AIFA) and by the Local Ethic Committee (N° EUDRACT 2020-004202-60, Protocol CER-001- SEP_AKI_01) and was added to the EU Clinical Trials Register on January 13, 2021.

Editorial introductions.

Current Opinion in Lipidology was launched in 1990. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of lipidology is divided into six sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editor for this issue. SECTION EDITOR Erik StroesErik StroesErik S. G. Stroes is Chair of the Department of Vascular Medicine at the Academic Medical Center, Amsterdam, The Netherlands. After gaining his Doctor of Medicine degree from Erasmus University, Rotterdam, The Netherlands, he then specialized in internal medicine at University Medical Center, Utrecht, The Netherlands, and later in vascular medicine at the Academic Medical Center, Amsterdam. Professor Stroes’ research interests include the role of the vessel wall in atherosclerosis development and lipid disorders in relation to atherogenesis. He has been an investigator in numerous lipid-lowering trials using various surrogate markers, such as intima-media thickness and flow-mediated dilation, and more recently 3T magnetic resonance imaging as a surrogate marker for vascular disease progression. He has also been involved in the development of novel therapeutic moieties for dyslipidemia, such as lipoprotein lipase gene therapy, antisense oligonucleotide inhibition of apolipoprotein B synthesis, and reconstituted high-density lipoprotein infusion. He has been the recipient of numerous research grants and several awards. Professor Stroes is Chair of the Dutch Atherosclerosis Society, member of the Vascular Biology Working Group, member of the American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology, and former Chair of the Dutch Internist Vascular Society. He has published more than 300 papers in various peer-reviewed journals and authored several book chapters in the field. Gerald F WattsGerald F WattsGerald F Watts (DSc DM PhD FRCP FRACP) trained at Imperial College (St Mary's Hospital) and King's College (St Thomas’ Hospital) in the University of London. He is a consultant physician, specializing in lipid disorders and cardiovascular medicine, within the department of cardiology at Royal Perth Hospital, as well as Winthrop Professor of Cardiometabolic Medicine in the University of Western Australia. He is Chair of The Familial Hypercholesterolaemia (FH)-Australasia Network and executive board member of the International Atherosclerosis Society. His research interests include lipid disorders and cardiovascular prevention, with clinical interest focusing on delivering improved health care for patients and families with FH. Professor Watts is actively involved in undergraduate medical education and supervisors PhD students and post-doctoral fellows. He has authored over 500 published works, including scientific articles, reviews, book chapters and monographs, and is associate editor of Atherosclerosis, Journal Clinical Lipidology and Metabolism.

Beneficial effects of high-density lipoprotein (HDL) on stent biocompatibility and the potential value of HDL infusion therapy following percutaneous coronary intervention.

Several epidemiological studies have shown a clear inverse relationship between serum levels of high-density lipoprotein cholesterol (HDL-C) and the risk of atherosclerotic cardiovascular disease (ASCVD), even at low-density lipoprotein cholesterol levels below 70 mg/dL. There is much evidence from basic and clinical studies that higher HDL-C levels are beneficial, whereas lower HDL-C levels are detrimental. Thus, HDL is widely recognized as an essential anti-atherogenic factor that plays a protective role against the development of ASCVD. Percutaneous coronary intervention is an increasingly common treatment choice to improve myocardial perfusion in patients with ASCVD. Although drug-eluting stents have substantially overcome the limitations of conventional bare-metal stents, there are still problems with stent biocompatibility, including delayed re-endothelialization and neoatherosclerosis, which cause stent thrombosis and in-stent restenosis. According to numerous studies, HDL not only protects against the development of atherosclerosis, but also has many anti-inflammatory and vasoprotective properties. Therefore, the use of HDL as a therapeutic target has been met with great interest. Although oral medications have not shown promise, the developed HDL infusions have been tested in clinical trials and have demonstrated viability and reproducibility in increasing the cholesterol efflux capacity and decreasing plasma markers of inflammation. The aim of the present study was to review the effect of HDL on stent biocompatibility in ASCVD patients following implantation and discuss a novel therapeutic direction of HDL infusion therapy that may be a promising candidate as an adjunctive therapy to improve stent biocompatibility following percutaneous coronary intervention.

Synergetic Effect of rHDL and LXR Agonist on Reduction of Atherosclerosis in Mice.

High-density lipoproteins (HDLs) are unique in that they play an important role in the reverse cholesterol transport process. However, reconstituted HDL (rHDL) infusions have demonstrated limited beneficial effect in clinical practice. This is perhaps a consequence of the limited cholesterol efflux abilities of atheroma macrophages due to decreased expression of cholesterol transporters in advanced atheromas and following rHDL infusion treatment. Thus, we propose that a combination therapy of rHDL and a liver X receptor (LXR) agonist could maximize the therapeutic benefit of rHDL by upregulating ATP-binding cassette transporters A-1 (ABCA1) and ATP-binding cassette transporter G-1 (ABCG1), and enhancing cholesterol efflux to rHDL. In macrophages, rHDL downregulated the expression of ABCA1/G1 in a dose- and rHDL composition-dependent manner. Although LXR agonist, T0901317 (T1317), upregulated the expression of ABCA1 and ABCG1, the drug itself did not have any effect on cholesterol efflux (6.6 ± 0.5%) while the combination of rHDL and T1317 exhibited enhanced cholesterol efflux from [3H]-cholesterol loaded J774A.1 macrophages (23.3 ± 1.3%). Treatment with rHDL + T1317 significantly reduced the area of aortic plaque in ApoE−/− mice compared to PBS treated control animals (24.16 ± 1.42% vs. 31.59 ± 1.93%, p < 0.001), while neither rHDL nor T1317 treatment alone had a significant effect. Together, we show that rHDL paired with an LXR agonist can induce a synergetic effect in reducing atheroma burden. This synergy could lead to lower overall effective dose for both drugs, potentially overcoming the existing barriers in clinical development and renewing pharmaceutical interest in these two drug classes.

Editorial introductions

Current Opinion in Lipidology was launched in 1990. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of lipidology is divided into six sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Erik S.G. StroesErik S.G. StroesErik S.G. Stroes is Chair of the Department of Vascular Medicine at the Academic Medical Center, Amsterdam, The Netherlands. After gaining his Doctor of Medicine degree from Erasmus University, Rotterdam, The Netherlands, he then specialized in internal medicine at University Medical Center, Utrecht, The Netherlands, and later in vascular medicine at the Academic Medical Center, Amsterdam. Professor Stroes’ research interests include the role of the vessel wall in atherosclerosis development and lipid disorders in relation to atherogenesis. He has been an investigator in numerous lipid-lowering trials using various surrogate markers, such as intima-media thickness and flow-mediated dilation, and more recently 3T magnetic resonance imaging as a surrogate marker for vascular disease progression. He has also been involved in the development of novel therapeutic moieties for dyslipidemia, such as lipoprotein lipase gene therapy, antisense oligonucleotide inhibition of apolipoprotein B synthesis, and reconstituted high-density lipoprotein infusion. He has been the recipient of numerous research grants and several awards. Professor Stroes is Chair of the Dutch Atherosclerosis Society, member of the Vascular Biology Working Group, member of the American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology, and former Chair of the Dutch Internist Vascular Society. He has published more than 300 papers in various peer-reviewed journals and authored several book chapters in the field. Gerald F. WattsGerald F. WattsGerald F. Watts (DSc DM PhD FRCP FRACP) trained at Imperial College (St Mary's Hospital) and King's College (St Thomas’ Hospital) in the University of London. He is a consultant physician, specializing in lipid disorders and cardiovascular medicine, within the department of cardiology at Royal Perth Hospital, as well as Winthrop Professor of Cardiometabolic Medicine in the University of Western Australia. He is Chair of The Familial Hypercholesterolaemia (FH)-Australasia Network and executive board member of the International Atherosclerosis Society. His research interests include lipid disorders and cardiovascular prevention, with clinical interest focusing on delivering improved health care for patients and families with FH. Professor Watts is actively involved in undergraduate medical education and supervisors PhD students and post-doctoral fellows. He has authored over 500 published works, including scientific articles, reviews, book chapters and monographs, and is associate editor of Atherosclerosis, Journal Clinical Lipidology and Metabolism.

HDL (High-Density Lipoprotein) Remodeling and Magnetic Resonance Imaging-Assessed Atherosclerotic Plaque Burden: Study in a Preclinical Experimental Model.

HDL (high-density lipoprotein) role in atherosclerosis is controversial. Clinical trials with CETP (cholesterylester transfer protein)-inhibitors have not provided benefit. We have shown that HDL remodeling in hypercholesterolemia reduces HDL cardioprotective potential. We aimed to assess whether hypercholesterolemia affects HDL-induced atherosclerotic plaque regression. Approach and Results: Atherosclerosis was induced in New Zealand White rabbits for 3-months by combining a high-fat-diet and double-balloon aortic denudation. Then, animals underwent magnetic resonance imaging (basal plaque) and randomized to receive 4 IV infusions (1 infusion/wk) of HDL isolated from normocholesterolemic (NC-HDL; 75 mg/kg; n=10), hypercholesterolemic (HC-HDL; 75 mg/Kg; n=10), or vehicle (n=10) rabbits. Then, animals underwent a second magnetic resonance imaging (end plaque). Blood, aorta, and liver samples were obtained for analyses. Follow-up magnetic resonance imaging revealed that NC-HDL administration regressed atherosclerotic lesions by 4.3%, whereas, conversely, the administration of HC-HDLs induced a further 6.5% progression (P<0.05 versus basal). Plaque characterization showed that HC-HDL administered animals had a 2-fold higher lipid and cholesterol content versus those infused NC-HDL and vehicle (P<0.05). No differences were observed among groups in CD31 levels, nor in infiltrated macrophages or smooth muscle cells. Plaques from HC-HDL administered animals exhibited higher Casp3 (caspase 3) content (P<0.05 versus vehicle and NC-HDL) whereas plaques from NC-HDL infused animals showed lower expression of Casp3, Cox1 (cyclooxygenase 1), inducible nitric oxide synthase, and MMP (metalloproteinase) activity (P<0.05 versus HC-HDL and vehicle). HDLs isolated from animals administered HC-HDL displayed lower antioxidant potential and cholesterol efflux capacity as compared with HDLs isolated from NC-HDL-infused animal and vehicle or donor HDL (P<0.05). There were no differences in HDL-ApoA1 content, ABCA1 (ATP-binding cassette transporter A1) vascular expression, and SRB1 (scavenger receptor B1) and ABCA1 liver expression. HDL particles isolated from a hypercholesterolemic milieu lose their ability to regress and stabilize atherosclerotic lesions. Our data suggest that HDL remodeling in patients with co-morbidities may lead to the loss of HDL atheroprotective functions.

Anti-Inflammatory Effects of HDL (High-Density Lipoprotein) in Macrophages Predominate Over Proinflammatory Effects in Atherosclerotic Plaques.

HDL (high-density lipoprotein) infusion reduces atherosclerosis in animal models and is being evaluated as a treatment in humans. Studies have shown either anti- or proinflammatory effects of HDL in macrophages, and there is no consensus on the underlying mechanisms. Here, we interrogate the effects of HDL on inflammatory gene expression in macrophages. Approach and Results: We cultured bone marrow-derived macrophages, treated them with reconstituted HDL or HDL isolated from APOA1Tg;Ldlr-/- mice, and challenged them with lipopolysaccharide. Transcriptional profiling showed that HDL exerts a broad anti-inflammatory effect on lipopolysaccharide-induced genes and proinflammatory effect in a subset of genes enriched for chemokines. Cholesterol removal by POPC (1-palmitoyl-2-oleoyl-glycero-3-phosphocholine) liposomes or β-methylcyclodextrin mimicked both pro- and anti-inflammatory effects of HDL, whereas cholesterol loading by POPC/cholesterol-liposomes or acetylated LDL (low-density lipoprotein) before HDL attenuated these effects, indicating that these responses are mediated by cholesterol efflux. While early anti-inflammatory effects reflect reduced TLR (Toll-like receptor) 4 levels, late anti-inflammatory effects are due to reduced IFN (interferon) receptor signaling. Proinflammatory effects occur late and represent a modified endoplasmic reticulum stress response, mediated by IRE1a (inositol-requiring enzyme 1a)/ASK1 (apoptosis signal-regulating kinase 1)/p38 MAPK (p38 mitogen-activated protein kinase) signaling, that occurs under conditions of extreme cholesterol depletion. To investigate the effects of HDL on inflammatory gene expression in myeloid cells in atherosclerotic lesions, we injected reconstituted HDL into Apoe-/- or Ldlr-/- mice fed a Western-type diet. Reconstituted HDL infusions produced anti-inflammatory effects in lesion macrophages without any evidence of proinflammatory effects. Reconstituted HDL infusions in hypercholesterolemic atherosclerotic mice produced anti-inflammatory effects in lesion macrophages suggesting a beneficial therapeutic effect of HDL in vivo.

Editorial introductions

Current Opinion in Lipidology was launched in 1990. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of lipidology is divided into six sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Erik S.G. StroesErik S.G. Stroes is Chair of the Department of Vascular Medicine at the Academic Medical Center, Amsterdam, The Netherlands. After gaining his Doctor of Medicine degree from Erasmus University, Rotterdam, The Netherlands, he then specialized in internal medicine at University Medical Center, Utrecht, The Netherlands, and later in vascular medicine at the Academic Medical Center, Amsterdam. Professor Stroes’ research interests include the role of the vessel wall in atherosclerosis development and lipid disorders in relation to atherogenesis. He has been an investigator in numerous lipid-lowering trials using various surrogate markers, such as intima-media thickness and flow-mediated dilation, and more recently 3T magnetic resonance imaging as a surrogate marker for vascular disease progression. He has also been involved in the development of novel therapeutic moieties for dyslipidemia, such as lipoprotein lipase gene therapy, antisense oligonucleotide inhibition of apolipoprotein B synthesis, and reconstituted high-density lipoprotein infusion. He has been the recipient of numerous research grants and several awards. Professor Stroes is Chair of the Dutch Atherosclerosis Society, member of the Vascular Biology Working Group, member of the American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology, and former Chair of the Dutch Internist Vascular Society. He has published more than 300 papers in various peer-reviewed journals and authored several book chapters in the field. Gerald F. WattsGerald F. Watts (DSc, DM, PhD, FRCP, FRACP) trained at Imperial College (St Mary's Hospital) and King's College (St Thomas’ Hospital) in the University of London. He is a consultant physician, specializing in lipid disorders and cardiovascular medicine, within the department of cardiology at Royal Perth Hospital, as well as Winthrop Professor of Cardiometabolic Medicine in the University of Western Australia. He is Chair of The Familial Hypercholesterolaemia (FH)-Australasia Network and executive board member of the International Atherosclerosis Society. His research interests include lipid disorders and cardiovascular prevention, with clinical interest focusing on delivering improved health care for patients and families with FH. Professor Watts is actively involved in undergraduate medical education and supervisors PhD students and post-doctoral fellows. He has authored over 500 published works, including scientific articles, reviews, book chapters and monographs, and is associate editor of Atherosclerosis, Journal Clinical Lipidology and Metabolism.

Abstract 164: Synthetic High-Density Lipoprotein Cholesterol Scavengers for the Treatment of Niemann-Pick C Disease

Background: Niemann-Pick C disease (NPC) is genetic disorder caused by an accumulation of unesterified cholesterol in late endosomes and lysosomes due to defects in NPC genes. The levels of ABCA1 gene expression and concentration of high-density lipoproteins (HDL) are significantly decreased in NPC patients. Infusion of synthetic HDL (sHDL) in patients with atherosclerosis has been previously found safe (up to 100 mg/kg) and effective at reducing cholesterol in atheroma. The objective of this study is to identify sHDL composition capable of rescuing cholesterol storage in NPC. Materials and Methods: A panel of sHDL formulations was prepared by lyophilization method using commercially available Apolipoprotein A-I mimetic peptide, 5A, complexed in various ratios with phospholipids such as sphingomyelin (SM), palmitoyl-oleoyl phosphatidylcholine (POPC), or dimyristoyl phosphatidylcholine (DMPC). The efficacy of 5A alone and sHDLs was determined in primary patient NPC and wild type fibroblast cells using fluorescent filipin staining and cholesterol efflux assay. Trafficking of sHDL in NPC fibroblasts was assessed by confocal microscopy using fluorescently-labeled sHDL. Finally, in vivo study was executed to examine effects of our best sHDL formulation 5A-SM in NPC1 I1061T homozygotes and littermate controls treated with vehicle or sHDL (100 mg/kg, i.p., 3x/wk) for 4 weeks, starting at 7 wks of age. Neurological correction was accessed by the balance beam tests and body weight changes were tracked. Results: Treatment of NPC fibroblasts with sHDL resulted in a dose- and time-dependent rescue of lipid storage (5A-POPC&lt;5A-SM&lt;5A-DMPC). Cellular toxicity was observed only for 5A-DMPC (~30%). HDL trafficking studies revealed that sHDLs got endocytosed into cells and co-localized with LAMP1. Additionally, administration of 100 mg/kg 5A-SM resulted in a significant rescue of body weight (p&lt;0.01) in the NPC mice with no toxicity to animals. However, neuro-correction after sHDL treatment in adult mice was not detected. The absence of neuro-correction observed in adult NPC mice suggest that the alternative delivery routes, treatment durations, or sHDL compositions are still needed.

High-Density Lipoprotein Infusions.

High-density lipoproteins (HDLs) have presented an attractive target for development of new therapies for cardiovascular prevention on the basis of epidemiology and preclinical studies demonstrating their protective properties. Development of HDL mimetics provides an opportunity to administer functional HDL. However, clinical trials have produced variable results, with no evidence to date that they reduce cardiovascular events. This article reviews development programs of HDL mimetics.

Synthetic High-Density Lipoprotein-Mediated Targeted Delivery of Liver X Receptors Agonist Promotes Atherosclerosis Regression

Targeting at enhancing reverse cholesterol transport (RCT) is apromising strategy for treating atherosclerosis via infusion of reconstitute high density lipoprotein (HDL) as cholesterol acceptors or increase of cholesterol efflux by activation of macrophage liver X receptors (LXRs). However, systemic activation of LXRs triggers excessive lipogenesis in the liver and infusion of HDL downregulates cholesterol efflux from macrophages. Here we describe an enlightened strategy using phospholipid reconstituted apoA-I peptide (22A)-derived synthetic HDL (sHDL) to deliver LXR agonists to the atheroma and examine their effect on atherosclerosis regression in vivo. A synthetic LXR agonist, T0901317 (T1317) was encapsulated in sHDL nanoparticles (sHDL-T1317). Similar to the T1317 compound, the sHDL-T1317 nanoparticles upregulated the expression of ATP-binding cassette transporters and increased cholesterol efflux in macrophages in vitro and in vivo. The sHDL nanoparticles accumulated in the atherosclerotic plaques of ApoE-deficient mice. Moreover, a 6-week low-dose LXR agonist-sHDL treatment induced atherosclerosis regression while avoiding lipid accumulation in the liver. These findings identify LXR agonist loaded sHDL nanoparticles as a promising therapeutic approach to treat atherosclerosis by targeting RCT in a multifaceted manner: sHDL itself serving as both a drug carrier and cholesterol acceptor and the LXR agonist mediating upregulation of ABC transporters in the aorta.

Regression of coronary atherosclerosis with infusions of the high-density lipoprotein mimetic CER-001 in patients with more extensive plaque burden.

CER-001 is an engineered pre-beta high-density lipoprotein (HDL) mimetic, which rapidly mobilizes cholesterol. Infusion of CER-001 3 mg/kg exhibited a potentially favorable effect on plaque burden in the CHI-SQUARE (Can HDL Infusions Significantly Quicken Atherosclerosis Regression) study. Since baseline atheroma burden has been shown as a determinant for the efficacy of HDL infusions, the degree of baseline atheroma burden might influence the effect of CER-001. CHI-SQUARE compared the effect of 6 weekly infusions of CER-001 (3, 6 and 12 mg/kg) vs. placebo on coronary atherosclerosis in 369 patients with acute coronary syndrome (ACS) using serial intravascular ultrasound (IVUS). Baseline percent atheroma volume (B-PAV) cutoff associated with atheroma regression following CER-001 infusions was determined by receiver-operating characteristics curve analysis. 369 subjects were stratified according to the cutoff. The effect of CER-001 at different doses was compared to placebo in each group. A B-PAV ≥30% was the optimal cutoff associated with PAV regression following CER-001 infusions. CER-001 induced PAV regression in patients with B-PAV ≥30% but not in those with B-PAV <30% (-0.45%±2.65% vs. +0.34%±1.69%, P=0.01). Compared to placebo, the greatest PAV regression was observed with CER-001 3mg/kg in patients with B-PAV ≥30% (-0.96%±0.34% vs. -0.25%±0.31%, P=0.01), whereas there were no differences between placebo (+0.09%±0.36%) versus CER-001 in patients with B-PAV <30% (3 mg/kg; +0.41%±0.32%, P=0.39; 6 mg/kg; +0.27%±0.36%, P=0.76; 12 mg/kg; +0.32%±0.37%, P=0.97). Infusions of CER-001 3 mg/kg induced the greatest atheroma regression in ACS patients with higher B-PAV. These findings identify ACS patients with more extensive disease as most likely to benefit from HDL mimetic therapy.

High-Density Lipoprotein Infusion Therapy and Atherosclerosis: Current Research and Future Directions.

Atherosclerosis is the leading cause of heart disease, contributing to hundreds of thousands of deaths annually. The use of long-term antilipid therapy has decreased low-density lipoprotein as a target, but high-density lipoprotein (HDL) has many properties which can protect against the formation of atherosclerotic plaque and decrease plaque burden. Numerous studies have shown an inverse correlation with HDL level and the future risk of heart disease. HDL has the unique property of playing a key role in reverse cholesterol transport, essentially bringing cholesterol from the periphery back to the liver for excretion in bile. In addition, HDL has many anti-inflammatory and vasoprotective properties. Recently, the idea of using HDL as a target of therapy has been met with great interest. Although oral medications have not shown promise, newly developed HDL infusions are currently being tested in clinical trials to determine their effect on the amount of plaque, the composition of the plaque, and the general state of inflammation. HDL infusions achieve stable levels rapidly in the plasma, making them most suitable in the post-acute coronary syndrome stage when most ischemic events are likely to recur. These infusion therapies have repeatedly demonstrated viability and reproducibility in increasing the amount of circulating HDL, decreasing the plaque burden, and decreasing markers of inflammation in plasma. However, none thus far have demonstrated a mortality benefit, possibly reflecting the complexity of the relationship among HDL, inflammation, and atherosclerosis. This remains a viable and promising avenue for continued research.

Infusional high-density lipoproteins therapies as a novel strategy for treating atherosclerosis.

High-density lipoproteins (HDL) have received considerable interest as a target for the development of novel anti-atherosclerotic agents beyond conventional approaches to lipid lowering. While a number of approaches have focused on modifying remodeling and expression pathways implicated in the regulation of HDL levels, an additional approach involves simply infusions of delipidated HDL. Several groups have advanced HDL infusions to clinical development with intriguing signs suggesting potentially favorable impacts at the level of the artery wall. The findings of early studies of infusional HDL therapies will be reviewed.

High-Density Lipoproteins Rescue Diabetes-Impaired Angiogenesis via Scavenger Receptor Class B Type I

Disordered neovascularization and impaired wound healing are important contributors to diabetic vascular complications. We recently showed that high-density lipoproteins (HDLs) enhance ischemia-mediated neovascularization, and mounting evidence suggests HDL have antidiabetic properties. We therefore hypothesized that HDL rescue diabetes-impaired neovascularization. Streptozotocin-induced diabetic mice had reduced blood flow recovery and neovessel formation in a hindlimb ischemia model compared with nondiabetic mice. Reconstituted HDL (rHDL) infusions in diabetic mice restored blood flow recovery and capillary density to nondiabetic levels. Topical rHDL application rescued diabetes-impaired wound closure, wound angiogenesis, and capillary density. In vitro, rHDL increased key mediators involved in hypoxia-inducible factor-1α (HIF-1α) stabilization, including the phosphoinositide 3-kinase/Akt pathway, Siah1, and Siah2, and suppressed the prolyl hydroxylases (PHD) 2 and PHD3. rHDL rescued high glucose-induced impairment of tubulogenesis and vascular endothelial growth factor (VEGF) A protein production, a finding associated with enhanced phosphorylation of proangiogenic mediators VEGF receptor 2 and endothelial nitric oxide synthase. Siah1/2 small interfering RNA knockdown confirmed the importance of HIF-1α stability in mediating rHDL action. Lentiviral short hairpin RNA knockdown of scavenger receptor class B type I (SR-BI) in vitro and SR-BI(-/-) diabetic mice in vivo attenuated rHDL rescue of diabetes-impaired angiogenesis, indicating a key role for SR-BI. These findings provide a greater understanding of the vascular biological effects of HDL, with potential therapeutic implications for diabetic vascular complications.

Future of the Prevention and Treatment of Coronary Artery Disease

With ongoing progress in the prevention and treatment of coronary artery disease (CAD), a continued decrease in prevalence and lethality is expected in high-income countries. Prevention will include lipid-lowering, antithrombotic and anti-inflammatory therapies. With respect to the former, potent, safe and prolonged drugs (such as generic forms of PCSK9 inhibitors relying on monoclonal antibodies or miRNA) should result in a decreased incidence of acute coronary syndromes. Another key aspect will be the ability to identify genetic predictors of CAD and therefore implement targeted personalized prevention early in life. Curative treatment will involve a short course of potent and reversible antithrombotics, but long-term therapy will rely on the ability to stabilize or even regress plaque (eg, using PCSK9 inhibition or modified high-density lipoprotein infusions or anti-inflammatory therapies). Antithrombotic therapy will rely on highly reversible agents (or agents with specific titratable antagonists), and on personalized therapies in which the doses, combinations and duration of therapy will be determined differentially for each patient on the basis of clinical characteristics, genetic profiling and biomarkers. Finally, the need for revascularization in stable CAD will be rare, given the expected progress in prevention. The main challenge, 20 years from now, is likely to be the provision of such effective care at acceptable costs in low- and middle-income countries. (Circ J 2016; 80: 1067-1072).

Abstract 12156: Greater Regression of Coronary Atherosclerosis With the Pre-Beta High-Density Lipoprotein Mimetic CER-001 in Patients With More Extensive Plaque Burden

Introduction: Infusing high-density lipoprotein (HDL) has been shown to promote plaque regression in patients with acute coronary syndrome (ACS). The factors associated with a greater propensity to regression have not been elucidated. We hypothesized greater plaque regression with HDL infusion would be observed in patients with greater baseline plaque burden. Methods: The CHI-SQUARE study compared the effect of infusing the pre-beta HDL mimetic CER-001 (3 to 12 mg/kg) versus placebo weekly for 5 weeks in patients with a recent ACS on plaque burden using serial intravascular ultrasound. Receiver operating characteristics curve analysis determined that a baseline percent atheroma volume (PAV) ≥30% optimally associated with greater regression. Clinical and imaging characteristics were compared in patients with baseline PAV &lt;30% (n=74) or ≥30% (n=271). Results: There were no differences between the groups apart from greater use of statin in patients with baseline PAV ≥30% (100 v. 90%, p=0.01). Patients with a greater baseline PAV were more likely to demonstrate echolucency (20 v. 9%, p=0.02) and ultrasound attenuation (21 v. 7%, p=0.01), consistent with lipidic and inflammatory material. On serial evaluation, PAV decreased with CER-001 infusion in patients with baseline PAV ≥30% by -0.27% (p=0.01 v. baseline), but not in those with baseline PAV &lt;30% (+0.43%, p=0.15 v. baseline, p=0.01 between plaque burden groups). The greatest PAV regression was observed with infusing CER-001 3 mg/kg in patients with baseline PAV ≥30% by 0.96% (p=0.04 v. baseline, p=0.02 v. placebo) (Table), but not in those patients with baseline PAV &lt;30% (+0.08%, p=0.55 v. baseline, p=0.004 for comparison between plaque burden groups). Conclusions: Greater plaque regression with CER-001 3 mg/kg was observed in ACS patients with greater atheroma burden and more vulnerable features. The findings identify ACS patients with high-risk plaque features most likely to benefit from HDL mimetic therapy.

HDL and glucose metabolism: current evidence and therapeutic potential.

High-density lipoprotein (HDL) and its principal apolipoprotein A-I (ApoA-I) have now been convincingly shown to influence glucose metabolism through multiple mechanisms. The key clinically relevant observations are that both acute HDL elevation via short-term reconstituted HDL (rHDL) infusion and chronically raising HDL via a cholesteryl ester transfer protein (CETP) inhibitor reduce blood glucose in individuals with type 2 diabetes mellitus (T2DM). HDL may mediate effects on glucose metabolism through actions in multiple organs (e.g., pancreas, skeletal muscle, heart, adipose, liver, brain) by three distinct mechanisms: (i) Insulin secretion from pancreatic beta cells, (ii) Insulin-independent glucose uptake, (iii) Insulin sensitivity. The molecular mechanisms appear to involve both direct HDL signaling actions as well as effects secondary to lipid removal from cells. The implications of glucoregulatory mechanisms linked to HDL extend from glycemic control to potential anti-ischemic actions via increased tissue glucose uptake and utilization. Such effects not only have implications for the prevention and management of diabetes, but also for ischemic vascular diseases including angina pectoris, intermittent claudication, cerebral ischemia and even some forms of dementia. This review will discuss the growing evidence for a role of HDL in glucose metabolism and outline related potential for HDL therapies.

Cholesterol, inflammation and innate immunity.

Hypercholesterolaemia leads to cholesterol accumulation in macrophages and other immune cells, which promotes inflammatory responses, including augmentation of Toll-like receptor (TLR) signalling, inflammasome activation, and the production of monocytes and neutrophils in the bone marrow and spleen. On a cellular level, activation of TLR signalling leads to decreased cholesterol efflux, which results in further cholesterol accumulation and the amplification of inflammatory responses. Although cholesterol accumulation through the promotion of inflammatory responses probably has beneficial effects in the response to infections, it worsens diseases that are associated with chronic metabolic inflammation, including atherosclerosis and obesity. Therapeutic interventions such as increased production or infusion of high-density lipoproteins may sever the links between cholesterol accumulation and inflammation, and have beneficial effects in patients with metabolic diseases.