MyNgan Duong

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

BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.

HDL function and subclinical atherosclerosis in juvenile idiopathic arthritis

BACKGROUND Increasing evidence suggests that inflammation adversely impacts the protective properties of high-density lipoproteins (HDL) and progression of atherosclerosis. The impact of early chronic inflammatory conditions on HDL function and vascular risk has not been well investigated. METHODS We compared measures of HDL particle distribution and functionality, in addition to measures of carotid intima-medial thickness (cIMT) in patients with juvenile idiopathic arthritis (JIA) and age matched controls. RESULTS JIA patients demonstrated lower levels of HDL cholesterol [47.0 (40.0, 56.0) vs. 56.0 (53.0, 61.0) mg/dL, P=0.04], total HDL [29.5 (27.9, 32.3) vs. 32.9 (31.6, 36.3) mg/dL, P=0.05] and large HDL [5.1 (3.7, 7.3) vs. 8.0 (6.7, 9.7) mg/dL, P=0.04] particles. In association JIA patients demonstrated greater cholesterol efflux mediated via ATP binding cassette A1 (ABCA1) [17.3% (12.8, 19.7) vs. 10.0% (5.8, 16.0), P=0.05] and less efflux mediated via ATP binding cassette G-1 (ABCG1) [3.2% (2.0, 3.9) vs. 4.8% (3.5, 5.8), P=0.01] and SR-B1 [6.9% (6.0, 8.4) vs. 9.1% (8.6, 10.2), P=0.002] compared with controls. Exposure of macrophages to serum from JIA patients resulted in a smaller increase in mRNA expression of ABCA1 (2.0±0.95 vs. 7.1±5.7 fold increase, P=0.01) and greater increases in expression of ABCG1 [1.4 (0.9, 1.5) vs. 0.8 (0.7, 1.1) fold increase, P=0.04] and SR-B1 (1.3±0.47 vs. 0.7±0.3 fold increase, P=0.001) compared with controls. Arylesterase (128.9±27.6 vs. 152.0±45.2 umoles/min/mL, P=0.04) activity and endothelial cell migration (491.2±68.9 vs. 634.2±227.4 cells/field, P=0.01) were less in JIA patients. No differences in cIMT were observed between JIA patients and controls. CONCLUSIONS The presence of JIA was associated with alterations in HDL particle distribution, cholesterol efflux and non-lipid transporting activities. The ultimate implication of these findings for cardiovascular risk requires further investigation.

Controversies on HDL: Should it be a Target Biomarker in Patients with Lipid Disorders?

Low-density lipoprotein (LDL) cholesterol lowering with statins have had a profound impact on cardiovascular (CV) event rates and accordingly have become an integral component of strategies designed to reduce CV risk. The finding of a residual clinical risk, despite LDL cholesterol lowering, supports the need to develop additional therapeutic strategies for CV prevention. Numerous lines of evidence suggest that targeting the protective properties of high-density lipoproteins (HDL) may be beneficial. Disappointing results from recent reports of HDL genetics and raising agents and clinical events has fueled considerable debate as to whether attempts to target HDL will be of clinical benefit or futility. This review will reflect on challenges faced in developing new effective HDL targeted therapies.

Effect of lipid-modifying therapies on the functional quality of high-density lipoproteins: implications for drug development.

Background: Increasing interest has focused on the development of therapeutic strategies to promote the biological activity of high-density lipoproteins (HDL) to achieve more effective prevention of cardiovascular disease. The highly publicized failure of raising HDL cholesterol with the cholesteryl ester transfer protein inhibitor, torcetrapib, has fueled immense discussion with regard to the potential impact of lipid modifying therapies on the functional quality of HDL particles. Objective/method: To review the literature that has investigated the role of HDL functionality in protection against cardiovascular disease. Conclusion: It remains to be unequivocally demonstrated that therapies that directly target HDL are cardioprotective in humans. Increasing attention on the functional quality of HDL will be essentinal for developing new biomarkers and medical therapies.

Lipidomics: Opportunities to Identify New Causal Mechanisms and Therapeutics for Atherosclerosis

A systems biology approach toward biosample analysis has the potential to play an important role in the identification of novel mechanisms of disease. Lipids are fundamental in atherogenesis, and therefore ‘lipidomics’ is likely to become increasingly utilized for biomarker discovery. These biomarkers can be tested for their ability to predict clinical events, superior to current risk prediction algorithms. These biochemical footprints will also serve as potential therapeutic targets for the next generation of anti-atherosclerotic therapies. In a similar fashion, lipidomics will also serve as a future technique for identifying molecular signatures of drug toxicity, and treatment efficacy, much prior to the advent of clinical events. A major challenge for this field is the need for statistical and bioinformatic platforms to evolve in parallel, in order to effectively handle the enormous amount of biochemical data yielded from the high-throughput analysis. Such advances will lead us closer to a more a personalized approach to medical diagnosis and treatment.

HYPERGLYCEMIA AND OXIDATION IMPAIRS THE IMPACT OF HIGH-DENSITY LIPOPROTEINS ON ENDOTHELIAL CELL GROWTH AND MIGRATION.

Methods: Human umbilical vein endothelial cells (HUVECs) were co-incubated with increasing concentrations of native and reconstituted HDL (5-40 μg/mL) and their major apolipoproteins. The extent of HUVEC growth was evaluated using a 96-hour proliferation assay and migration using 12-hour wound healing model. These effects were further evaluated in the setting of dextrose (20 mM) and oxidative modification of HDL.