Pre-beta High-density Lipoprotein Research Articles

Levels of Prebeta-1 High-Density Lipoprotein Are a Strong Independent Positive Risk Factor for Coronary Heart Disease and Myocardial Infarction: A Meta-Analysis.

BackgroundWe previously showed that levels of prebeta‐1 high‐density lipoprotein (HDL), the principal acceptor of cholesterol effluxed from cells, including artery wall macrophages, are positively associated with coronary heart disease (CHD) and myocardial infarction (MI) risk.Methods and ResultsIn a multiethnic follow‐up cohort of 1249 individuals from University of California–San Francisco clinics, we determined the degree to which prebeta‐1 HDL levels, both absolute and percentage of apolipoprotein AI, are associated with CHD and history of MI. Independent, strong, positive associations were found. Meta‐analysis revealed for the absolute prebeta‐1 HDL for the top tertile versus the lowest, unadjusted odds ratios of 1.90 (95% CI, 1.40–2.58) for CHD and 1.79 (95% CI, 1.35–2.36) for MI. For CHD, adjusting for established risk factors, the top versus bottom tertiles, quintiles, and deciles yielded sizable odds ratios of 2.37 (95% CI, 1.74–3.25, P<0.001), 3.20 (95% CI, 2.07–4.94, P<0.001), and 4.00 (95% CI, 2.11–7.58, P<0.001), respectively. Men and women were analyzed separately in a combined data set of 2507 individuals. The odds ratios for CHD and MI risk were similar. Higher levels of prebeta‐1 HDL were associated with all 5 metabolic syndrome features. Addition of prebeta‐1 HDL to these 5 features resulted in significant improvements in risk‐prediction models.ConclusionsAnalysis of 2507 subjects showed conclusively that levels of prebeta‐1 HDL are strongly associated with a history of CHD or MI, independently of traditional risk factors. Addition of prebeta‐1 HDL can significantly improve clinical assessment of risk of CHD and MI.

ApoE and apoC-III-defined HDL subtypes: a descriptive study of their lecithin cholesterol acyl transferase and cholesteryl ester transfer protein content and activity

BackgroundThe functionality of high-density lipoproteins (HDL) is a better cardiovascular risk predictor than HDL concentrations. One of the key elements of HDL functionality is its apolipoprotein composition. Lecithin-cholesterol acyl transferase (LCAT) and cholesterol-ester transfer protein (CETP) are enzymes involved in HDL-mediated reverse cholesterol transport. This study assessed the concentration and activity of LCAT and CETP in HDL subspecies defined by their content of apolipoproteins E (apoE) and C-III (apoC-III) in humans.MethodsEighteen adults (ten women and eight men, mean age 55.6, BMI 26.9 Kg/m2, HbA1c 5.4%) were studied. HDL from each participant were isolated and divided into four subspecies containing respectively: No apoE and no apoC-III (E-C-), apoE but not apoC-III (E + C-), apoC-III but no apoE (E-C+) and both apoE and apoC-III (E + C+). The concentration and enzymatic activity of LCAT and CETP were measured within each HDL subspecies using immunoenzymatic and fluorometric methods. Additionally, the size distribution of HDL in each apolipoprotein-defined fraction was determined using non-denaturing electrophoresis and anti-apoA-I western blotting.ResultsHDL without apoE or apoC-III was the predominant HDL subtype. The size distribution of HDL was very similar in all the four apolipoprotein-defined subtypes. LCAT was most abundant in E-C- HDL (3.58 mg/mL, 59.6% of plasma LCAT mass), while HDL with apoE or apoC-III had much less LCAT (19.8, 12.2 and 8.37% of plasma LCAT respectively for E + C-, E-C+ and E + C+). LCAT mass was lower in E + C- HDL relative to E-C- HDL, but LCAT activity was similar in both fractions, signaling a greater activity-to-mass ratio associated with the presence of apoE. Both CETP mass and CETP activity showed only slight variations across HDL subspecies. There was an inverse correlation between plasma LCAT activity and concentrations of both E-C+ pre-beta HDL (r = − 0.55, P = 0.017) and E-C- alpha 1 HDL (r = − 0.49, P = 0.041). Conversely, there was a direct correlation between plasma CETP activity and concentrations of E-C+ alpha 1 HDL (r = 0.52, P = 0.025).ConclusionsThe presence of apoE in small HDL is correlated with increased LCAT activity and esterification of plasma cholesterol. These results favor an interpretation that LCAT and apoE interact to enhance anti-atherogenic pathways of HDL.

Levels of prebeta-1 high-density lipoprotein are elevated in 3 phenotypes of dyslipidemia

Prebeta-1 high-density lipoprotein (HDL) is a small subspecies of HDL that functions as the HDL quantum particle and is the principal acceptor of cholesterol effluxed from macrophages through the ATP-binding cassette transporter, ABCA1. High levels of prebeta-1 HDL are associated with increased risk of structural coronary artery disease and myocardial infarction. We aimed to compare prebeta-1 HDL levels in normal subjects and in 3 phenotypes of dyslipidemia. We studied 2435 individuals (1388 women; 1047 men). Of these, 2018 were not taking lipid-lowering medication when enrolled: 392 were normolipidemic controls; 713 had elevated levels of low-density lipoprotein cholesterol; 623 had combined hyperlipidemia; and 290 had hypertriglyceridemia. Relative to controls, prebeta-1 HDL levels were increased in all 3 dyslipidemic phenotypes, particularly the combined and hypertriglyceridemia groups. This increase possibly reflects increased acceptor capacity of apolipoprotein B-100 containing lipoproteins for entropically driven transfer of cholesteryl esters from HDL via cholesteryl ester transfer protein. Multiple regression analysis revealed that the main predictor variables significantly associated with prebeta-1 HDL levels were apolipoprotein A-I (apoA-1) (β=0.500), triglyceride (β=0.285), HDL-C (β=-0.237), and age (β=-0.169). There was an interaction between apoA-1 and sex (female vs male; β=-0.110). Among postmenopausal women, estrogenized subjects had a similar level of prebeta-1 HDL compared to those not receiving estrogens. Prebeta-1 HDL levels are elevated in the 3 most common types of hyperlipidemia and are most strongly influenced by the levels of apoA-1, triglyceride, and HDL-C.

CARAT: will infusing a pre-beta high-density lipoprotein mimetic (CER-001) regress coronary atherosclerosis?

Aim: While infusing reconstituted high-density lipoproteins (rHDL) has been demonstrated to have favorable effects on lipid transport, vascular function and plaque prior to the use of intensive statin therapy, the impact of CER-001, a pre-beta high-density lipoprotein (HDL) mimetic containing sphingomyelin and dipalmitoyl phosphatidlyglycerol is uncertain.

Self-Assembling Cyclic d,l-α-Peptides as Modulators of Plasma HDL Function. A Supramolecular Approach toward Antiatherosclerotic Agents.

There is great interest in developing new modes of therapy for atherosclerosis to treat coronary heart disease and stroke, particularly ones that involve modulation of high-density lipoproteins (HDLs). Here, we describe a new supramolecular chemotype for altering HDL morphology and function. Guided by rational design and SAR-driven peptide sequence enumerations, we have synthesized and determined the HDL remodeling activities of over 80 cyclic d,l-α-peptides. We have identified a few distinct sequence motifs that are effective in vitro in remodeling human and mouse plasma HDLs to increase the concentration of lipid-poor pre-beta HDLs, which are key initial acceptors of cholesterol in the reverse cholesterol transport (RCT) process, and concomitantly promote cholesterol efflux from macrophage cells. Functional assays with various control peptides, such as scrambled sequences, linear and enantiomeric cyclic peptide variants, and backbone-modified structures that limit peptide self-assembly, provide strong support for the supramolecular mode of action. Importantly, when the lead cyclic peptide c[wLwReQeR] was administered to mice (ip), it also promoted the formation of small, lipid-poor HDLs in vivo, displayed good plasma half-life (∼6 h), did not appear to have adverse side effects, and exerted potent anti-inflammatory effects in an acute in vivo inflammation assay. Given that previously reported HDL remodeling peptides have been based on α-helical apoA-I mimetic architectures, the present study, involving a new structural class, represents a promising step toward new potential therapeutics to combat atherosclerosis.

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.

Moderate statin treatment reduces prebeta-1 high-density lipoprotein levels in dyslipidemic patients

Elevated plasma levels of prebeta-1 high-density lipoprotein (HDL), the principal acceptor of cholesterol effluxed from macrophages, are associated with increased risk of atherosclerotic coronary heart disease and myocardial infarction. The objective of the study was to assess the effects on prebeta-1 HDL levels of 6-week moderate-dose statin treatment. We studied 101 patients (mean age 52.7years; 53.5% female; 63 with primary hypercholesterolemia; 38 with combined hyperlipidemia) before and after treatment with statins. Mean atorvastatin potency equivalence was 23.6mg/d. Prebeta-1 HDL plasma levels were measured by immunofixation of agarose gels using anti-apolipoprotein A-1 antibody. We observed a 42.0% reduction of low-density lipoprotein cholesterol (181±56 vs 105mg/dL, P<.001). Triglyceride (TG) levels decreased by 22.3% (157 vs 122mg/dL, P<.001), HDL cholesterol levels remained similar (56.0 vs 57.1, P= NS). Levels of prebeta-1 HDL were significantly reduced by 17.9% after statin treatment (mean 11.4 vs 9.4mg apoA-1/dL, P<.001). The magnitude of this decrease was similar with each of 3 statins (atorvastatin, simvastatin, and rosuvastatin). The decrease in prebeta-1 HDL was strongly associated with the decline in TG, but not with the decline in low-density lipoprotein cholesterol. The association of high prebeta-1 HDL with coronary heart disease identifies it as an inferential measure of the rate of cholesterol efflux from the artery wall. Our observations demonstrate a reduction of prebeta-1 HDL with statin therapy, partially reflecting the reduced TGs, and probably reflecting a direct beneficial impact on cholesterol efflux.

Effect of serial infusions of reconstituted high-density lipoprotein (CER-001) on coronary atherosclerosis: rationale and design of the CARAT study

High-density lipoprotein (HDL) is believed to have atheroprotective properties, but an effective HDL-based therapy remains elusive. Early studies have suggested that infusion of reconstituted HDL promotes reverse cholesterol transport and vascular reactivity. The CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial (CARAT) is investigating the impact of infusing an engineered pre-beta HDL mimetic containing sphingomyelin (SM) and dipalmitoyl phosphatidlyglycerol (CER-001) on coronary atheroma volume in patients with a recent acute coronary syndrome (ACS). The CARAT is a phase 2, multicenter trial in which 292 patients with an ACS undergoing intracoronary ultrasonography and showing percent atheroma volume (PAV) greater than 30% are randomly assigned to treatment with ten infusions of CER-001 3 mg/kg or matching placebo, administered at weekly intervals. Intracoronary ultrasonography is repeated at the end of the treatment period. The primary endpoint is the nominal change in PAV. Safety and tolerability will also be evaluated. CARAT will establish whether serial 3 mg/kg infusions of an engineered pre-beta HDL mimetic containing SM and dipalmitoyl phosphatidlyglycerol (CER-001) will regress atherosclerotic plaque in patients with a recent ACS.

Effects of the cholesteryl ester transfer protein inhibitor, TA-8995, on cholesterol efflux capacity and high-density lipoprotein particle subclasses

TA-8995 is a potent inhibitor of cholesteryl ester transfer protein (CETP) with beneficial effects on lipids and lipoproteins. The effect of TA-8995 on cholesterol efflux capacity (CEC), a measure of high-density lipoprotein (HDL) function, and HDL subparticle distribution is largely unknown. To assess the effect of the CETP inhibitor TA-8995 on ABCA1- and non-ABCA1-driven CEC and on HDL particle distribution. Total, non-ABCA1-, and ABCA1-specific CEC from J774cells and HDL subclass distribution assessed by two-dimensional gel electrophoresis were measured at baseline and after 12-week treatment in 187 mild-dyslipidemic patients randomized to placebo, 1mg, 5mg, 10mg TA-8995, or 10mg TA-8995 combined with 10mg rosuvastatin (NCT01970215). Compared with placebo, total, non-ABCA1-, and ABCA1-specific CEC were increased dose dependently by up to 38%, 72%, and 28%, respectively, in patients randomized to 10mg of TA-8995. PreBeta-1 HDL, the primary acceptor for ABCA1-driven cholesterol efflux, was increased by 36%. This increase in preBeta-1 HDL correlated significantly with the total and the ABCA1-driven CEC increase, whereas the high-density lipoprotein cholesterol (HDL-C) increase did not. TA-8995 dose dependently increased not only total and non-ABCA1-specific CEC but also ABCA1-specific CEC and preBeta-1 HDL particle levels. These findings suggest that TA-8995 not only increases HDL-C levels but also promotes functional properties of HDL particles. This CETP inhibitor-driven preBeta-1 HDL increase is an important predictor of both ABCA1 and total CEC increase, independent of HDL-C increase. Whether these changes in HDL particle composition and functionality have a beneficial effect on cardiovascular outcome requires formal testing in a cardiovascular outcome trial.

Abstract 29: Alpha-1-antitrypsin Protects High Density Lipoprotein From Functional Inactivation by Elastase

High density lipoproteins (HDL) are complexes of lipid and protein with several known atheroprotective functions. These functions are driven by specific lipids and proteins contained on the HDL particle and include reverse cholesterol transport, suppression of inflammation, and modulation of endothelial function. These activities are most important within atherosclerotic plaque, a harsh environment where HDL interact with macrophage foam cells, activated neutrophils, and dysfunctional endothelial cells. Neutrophils and macrophages secrete proteases, such as elastase, which damage structural components and soluble proteins and propagate inflammatory signaling. It has been suggested that, in plaque, HDL become damaged and dysfunctional. We recently characterized a subspecies of HDL that carries the protein alpha-1-antitrypsin (A1AT), an abundant plasma serine protease inhibitor. In the current study, we tested the hypothesis that A1AT enriched HDL are protected from proteolytic damage and functional inactivation by elastase, the main protease inhibited by A1AT. Human HDL was isolated by ultracentrifugation and was enriched with A1AT by co-incubation and unbound A1AT was removed. Treatment of native HDL with elastase resulted in significant proteolytic degradation of both apoA-I and apoA-II, visualized by coomassie stained SDS-PAGE. Analysis of lipoprotein size by one dimensional native gel electrophoresis revealed that pre-beta HDL were completely degraded by elastase. Compared to native HDL, A1AT enriched HDL samples were protected from protein and pre-beta particle degradation by elastase. We next tested the effect of elastase treatment on HDL function. In native HDL, elastase had damaging effects on ABCA1 mediated cholesterol efflux (-32%; p&lt;0.0001) and the ability to esterify free cholesterol (-14%; p&lt;0.02). A1AT enriched HDL displayed no loss of functionality upon treatment with elastase. Both of these activities are required for HDL to perform what is thought to be its most important function, reverse cholesterol transport. In conclusion, the data presented indicate that HDL particles which contain A1AT may represent a functionally important species of HDL, which have an advantage in the protease-rich plaque environment.

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.

Cholesteryl ester transfer protein: ace of spades, queen of hearts, or the joker?

Cholesteryl ester transfer protein: ace of spades, queen of hearts, or the joker?

Modification of lipoprotein and glucose metabolism, vascular inflammatory biomarkers and neuropathy after weight loss following bariatric surgery

Modification of lipoprotein and glucose metabolism, vascular inflammatory biomarkers and neuropathy after weight loss following bariatric surgery

Inhibition of cholesteryl ester transfer protein increases cholesteryl ester content of large HDL independently of HDL-to-HDL homotypic transfer: In vitro vs in vivo comparison using anacetrapib and dalcetrapib

The increase in high density lipoprotein (HDL)-cholesterol observed with cholesteryl ester transfer protein (CETP) inhibition is commonly attributed to blockade of cholesteryl ester (CE) transfer from HDL to low density lipoprotein particles. In vitro, it has been observed that CETP can mediate transfer of CE between HDL particles (“homotypic transfer”), and it is postulated that this contributes to HDL remodeling and generation of anti-atherogenic pre-beta HDL. Inhibition of CETP could limit this beneficial remodeling and reduce pre-beta HDL levels. We observed that anacetrapib does not reduce pre-beta HDL in vivo, but the role of HDL homotypic transfer was not examined. This study evaluated the effects of anacetrapib on homotypic transfer from HDL3 to HDL2 in vivo using deuterium-labeled HDL3, and compared this to in vitro settings, where homotypic transfer was previously described. In vitro, both anacetrapib and dalcetrapib inhibited transfer of CE from HDL3 to HDL2 particles. In CETP transgenic mice, anacetrapib did not inhibit the appearance of labeled CE derived from HDL3 in HDL2 particles, but rather promoted the appearance of labeled CE in HDL2. We concluded that inhibition of CETP by anacetrapib promoted HDL particle remodeling, and does not impair the flux of cholesterol ester into larger HDL particles when studied in vivo, which is not consistent with in vitro observations. We further conclude, therefore, that the in vitro conditions used to examine HDL-to-HDL homotypic transfer may not recapitulate the in vivo condition, where multiple mechanisms contribute to cholesteryl ester flux into and out of the HDL pool.

STATIN TREATMENT REDUCES PEBETA-1 HDL LEVELS IN DYSLIPIDEMIC PATIENTS

Prebeta-1 HDL is a small molecular species of high-density lipoprotein (HDL) that is the principal acceptor of cholesterol effluxed from macrophages. High prebeta-1 HDL levels are associated with increased risk of structural coronary artery disease (CAD) and myocardial infarction. Prebeta-1 HDL

Incubation of MDCO-216 (ApoA-IMilano/POPC) with Human Serum Potentiates ABCA1-Mediated Cholesterol Efflux Capacity, Generates New Prebeta-1 HDL, and Causes an Increase in HDL Size.

MDCO-216 is a complex of dimeric ApoA-IMilano and palmitoyl oleoyl phosphatidylcholine (POPC), previously shown to reduce atherosclerotic plaque burden. Here we studied the effect of incubation of human plasma or serum with MDCO-216 on cholesterol efflux capacity from J774 cells, on prebeta-1 high density lipoprotein (prebeta-1 HDL) and on HDL size assessed by proton nuclear magnetic resonance (1H-NMR). MDCO-216 incubated in buffer containing 4% human serum albumin stimulated both ABCA1-mediated efflux and ABCA1-independent cholesterol efflux from J774 macrophages. When incubated with human serum a dose- and time-dependent synergistic increase of the ABCA1-mediated efflux capacity were observed. Using a commercially available ELISA for prebeta-1 HDL, MDCO-216 as such was poorly detected (12–15% of nominal amount of protein). Prebeta-1 HDL was rapidly lost when human plasma alone is incubated at 37°C. In contrast, incubation of human plasma with MDCO-216 at 37°C produced a large amount of new prebeta-1 HDL. Native 2D electrophoresis followed by immunoblotting with an apoA-I antibody, which also detects ApoA-I Milano, confirmed the increase in prebeta-1 HDL upon incubation at 37°C. With the increase of prebeta-1 HDL, the concomitant disappearance of the small alpha-3 and alpha-4 HDL and MDCO-216 and an increase in the large alpha-1 and alpha-2 HDL were observed. Immunoblotting with Mab 17F3 specific for ApoA-I Milano showed the appearance of ApoA-I Milano in alpha-1 and alpha-2, but not in prebeta-1 HDL. 1H-NMR analysis of plasma incubated with MDCO-216 confirmed rapid disappearance of small-sized HDL particles and increase of medium- and large-sized HDL particles accompanied with a decrease in total HDL particle number. In conclusion, incubation of human plasma or serum with MDCO-216 strongly enhanced ABCA1-mediated cholesterol efflux, caused a strong increase of prebeta-1 HDL, and drastically changed the distribution of HDL subpopulations. Overall, the results are in line with the hypothesis that MDCO-216 fuses with small alpha-migrating HDL particles forming larger particles containing both apoA-I WT and ApoA-I Milano, meanwhile liberating the endogenous wild-type apoA-I which enriches prebeta-1 HDL subpopulation.

Abstract 403: Generation of PreBeta1 High Density Lipoprotein by CSL112 in Human Plasma

The ability of apoA-I to remove cholesterol from atherosclerotic plaque is thought to underlie its inverse correlation with cardiovascular risk. CSL112 was designed as an infusible formulation of human apoA-I to rapidly remove plaque cholesterol and reduce risk after an ACS. We have recently shown that infusion of CSL112 into rabbits caused a strong and immediate increase in the ABCA1-dependent efflux capacity of plasma, an increase in plasma unesterified cholesterol and rapid subsequent esterification of the cholesterol. In the presence of human plasma, CSL112 was significantly more potent than human HDL 3 at enhancing cholesterol efflux, and the efflux elevation was predominantly via the ABCA1 transporter. Consistent with this observation, addition of CSL112 to plasma led to generation of high levels of PreBeta1-HDL, a favorable substrate for ABCA1. Phase 1 studies of CSL112 have confirmed the elevation of efflux capacity in humans and the rapid generation of PreBeta1. Here we examine the steps leading to formation of PreBeta1-HDL. Plasma spiked with 0.8 mg/mL CSL112 and held at 0[[Unable to Display Character: &amp;#8304;]]C did not increase PreBeta1-HDL levels. However, incubation at 37[[Unable to Display Character: &amp;#8304;]]C caused the generation of PreBeta1 that reached half-maximal levels at 15-20 min and maximal levels at 2 h (7-fold over baseline). By contrast, addition of HDL 3 to plasma caused minimal generation of PreBeta1-HDL at any time point. Native gradient gel electrophoresis showed that formation of PreBeta1 was accompanied by elevation in the size and protein content of HDL 3 and HDL 2 . These data suggest that the remarkable ability of CSL112 to elevate efflux and PreBeta1 derives from engaging plasma proteins in a process of lipoprotein remodeling.

Increased plasma visfatin concentration is a marker of an atherogenic metabolic profile

Background and aimsVisfatin is associated with atherosclerosis-related diseases. We assessed in non-diabetic individuals the association of plasma visfatin levels with cardiovascular disease (CVD) risk and the atherosclerosis-related metabolic variables. Methods and resultsWhen study population (n = 179, age 49 ± 11 years) was divided according to visfatin tertiles, the 10-year CVD Framingham risk scores were significantly increased in the top visfatin tertile. We observed a positive association between visfatin tertiles with waist circumference and blood pressure, as well as with total cholesterol and triglyceride levels, but not with apolipoprotein C-III, fibrinogen or pre-beta1 high density lipoprotein (HDL). The percentage of large HDL subclasses was significantly lower and the percentage of small HDL subclasses over the HDL-C concentration was significantly higher in the top visfatin tertile compared with the other tertiles. The atherogenic small dense low density lipoprotein subclasses (sdLDL-C) were significantly increased in the top visfatin tertile compared with the lower tertiles. High sensitivity C-reactive protein (hsCRP) concentration was significantly increased in the top visfatin tertile compared with the lower tertiles. Although age and sex distribution did not differ between visfatin tertiles, the simultaneous adjustment for these parameters attenuated the significance of the differences observed in sdLDL-C and hsCRP levels. Similarly, after adjustment for hsCRP or waist circumference, only triglycerides and blood pressure levels, as well as the distribution of HDL subclasses, remained significantly different between visfatin tertiles. ConclusionsOur results support a role for visfatin in the detection of subjects with many metabolic abnormalities, which result in increased CVD risk.

Relation of Increased Prebeta-1 High-Density Lipoprotein Levels to Risk of Coronary Heart Disease

Preβ-1 high-density lipoprotein (HDL) plays a key role in reverse cholesterol transport by promoting cholesterol efflux. Our aims were (1) to test previous associations between preβ-1 HDL and coronary heart disease (CHD) and (2) to investigate whether preβ-1 HDL levels also are associated with risk of myocardial infarction (MI). Plasma preβ-1 HDL was measured by an ultrafiltration-isotope dilution technique in 1,255 subjects recruited from the University of California-San Francisco Lipid and Cardiovascular Clinics and collaborating cardiologists. Preβ-1 HDL was significantly and positively associated with CHD and MI even after adjustment for established risk factors. Inclusion of preβ-1 HDL in a multivariable model for CHD led to a modest improvement in reclassification of subjects (net reclassification index 0.15, p = 0.01; integrated discrimination improvement 0.003, p = 0.2). In contrast, incorporation of preβ-1 HDL into a risk model of MI alone significantly improved reclassification of subjects (net reclassification index 0.21, p = 0.008; integrated discrimination improvement 0.01, p = 0.02), suggesting that preβ-1 HDL has more discriminatory power for MI than for CHD in our study population. In conclusion, these results confirm previous associations between preβ-1 HDL and CHD in a large well-characterized clinical cohort. Also, this is the first study in which preβ-1 HDL was identified as a novel and independent predictor of MI above and beyond traditional CHD risk factors.

Apolipoprotein A-I Mimetic Peptides

The beneficial effects of high-density lipoprotein (HDL) on atherosclerosis have largely been attributed to its major protein, apolipoprotein A-I (apoA-I). Used as a therapeutic intervention, apoA-I is a large protein that requires venous administration, and is both difficult and expensive to manufacture. Because of these problems with apoA-I, the generation of smaller, easier to manufacture apoA-I mimetic peptides has become a target for pharmacologic development in the therapeutic management of human atherosclerosis. A potent apoA-I mimetic peptide, 4F, was found to have significant activity in various inflammatory states in both mice and monkeys. The anti-inflammatory and antiatherogenic effects of 4F include increased pre-beta HDL formation, increased cholesterol efflux, the conversion of pro-inflammatory HDL to anti-inflammatory HDL, and reduced lipoprotein oxidation. In addition, improved arterial vasoreactivity is another important function of 4F. In a rat model of diabetes, D-4F increased arterial concentrations of heme oxygenase-1 (HO-1) and superoxide dismutase, decreased superoxide levels, reduced levels of circulating endothelial cells, decreased endothelial cell fragmentation, and restored arterial vasoreactivity to normal. In a mouse model of systemic sclerosis, D-4F functioned to improve vasodilation and angiogenic potential, while reducing myocardial inflammation and oxidative stress. With respect to mouse models of heart transplant-associated atherosclerosis, D-4F induced HO-1. In addition, D-4F was shown to improve cognitive performance in low-density lipoprotein-receptor null mice with Western diet-induced cognitive decline. D-4F also reduced the kidney content of oxidized phospholipids in a mouse model of hyperlipidemia-induced renal inflammation. In early human studies in patients with significant cardiovascular risk, a single dose of oral D-4F was found to safely improve the anti-inflammatory index of HDL. L-4F is also being studied in clinical trials as a potential treatment modality for obesity and the metabolic syndrome.