IAS HDL Workshop, Whistler Research Highlights

Potential benefits of acute HDL therapy

 

Several posters highlighted the potential benefits of acute HDL infusion treatment on atherosclerosis.

 

A study by the Heart Research Institute, Sydney, Australia showed that short-term infusion of human lipid-free apolipoprotein A-IV, apo-IV (the third most abundant apolipoprotein in HDL) into mice stabilised atherosclerotic plaque. These effects were attributed to anti-inflammatory, antioxidant and anti-apoptotic properties of apoA-IV (1). In another study (2), acute infusion with reconstituted HDL effectively stabilised atherosclerotic lesions in a mouse model of hyperlipidemia (apoE deficient mice). Suppression of atherogenic apolipoprotein B accumulation and monocyte infiltration were thought to mediate this effect.

 

In an animal model of impaired chylomicron metabolism, consistent with the metabolic syndrome, acute reconstituted HDL infusion (0.4 mg/kg apoA-I-POPC) reduced cholesterol remnant deposition in the artery and the frequency of myocardial lesions, and partially corrected diastolic compliance. These effects suggest potential benefits on the vascular sequelae of the metabolic syndrome (3).

 

1. Geronimo F, Barter P, Rye K, Rodgers K. Intravenous injections of human lipid-free apolipoprotein A-IV reduced inflammation, oxidation and apoptosis and improved plaque stability in brachiocephalic artery atheromas in apoE-knockout mice. Poster P-019

2. Kim J, Kim K, Lee B et al. Reconstituted high density lipoprotein diminishes atherogenesis in hyperlipidemic apoE-/- mice. Poster P-020.

3. Borthwick F, Warnakula S, Mangat R et al. Acute HDL infusion reduces arterial cholesterol deposition and myocardial lesion frequency in the hyperlipidemic JCR:LA‑cp rat model of the metabolic syndrome. Poster P-018.

 

 

HDL and beta-cell function

 

Cholesterol may be detrimental to islet function, according to research (1) led by Michael Hayden, University Killam Professor, Department of Medical Genetics, UBC, Canada.

 

Islet cholesterol levels and beta-cell function were assessed in mice lacking the gene for the LDL receptor (LDLr‑/-) or apolipoprotein E (ApoE-/-), as well as in mice with beta-cell deficiency of ABCA1 crossed with LDLr--/- mice. Hypercholesterolemia led to increased islet cholesterol levels and decreased beta-cell function in ApoE-/- mice but not in LDLr--/- mice, suggesting that LDLr-mediated uptake of cholesterol influences beta-cell function. ABCA1-mediated cholesterol efflux compensated for this effect suggesting a role in regulating islet cholesterol levels in vivo.

 

1. Kruit J, Brunham L, Kremer P et al. Cholesterol efflux via ABCA1 and cholesterol uptake via the LDL receptor influence cholesterol-induced impairment of beta-cell function. Poster P-003.

 

 

Importance of ABCA1 (ATP-binding cassette transporter)

 

ABCA1 is a major regulator of cellular cholesterol and phospholipid homeostasis, mediating the efflux of cholesterol and phospholipid to lipid-poor apolipoproteins (such as apoA-I and apoE) which then form nascent HDL. Mutations in this gene have been associated with Tangier disease and familial HDL deficiency.

 

Research reported at the meeting underlines the importance of ABCA1 in preventing atherosclerosis. While ABCA1 is primarily anti-atherogenic due to its role in promoting cholesterol efflux from macrophages, a study (1) reported that ABCA1 also limits the influx of monocytes into the arterial wall, thereby protecting against atherosclerotic lesion development.

 

Another study showed the importance of both apoE and ABCA1 to atherosclerotic lesion development. ApoE, produced by macrophages, induces ABCA1-mediated cholesterol efflux. ABCA1 also promotes apoE secretion by macrophages. In mice deficient in the LDL receptor, transplantation of bone marrow from mice deficient in both ABCA1 and apoE decreased plasma HDL cholesterol levels and increased atherosclerotic lesion development compared with single knockout mice (either deficient in ABCA1 or ApoE genes) (2).

 

1. Ye D, Hildebrand R, Singaraja R et al. Dynamics of macrophage infiltration into the artery wall at different stages of atherosclerotic lesion development and dependency on macrophage ABCA1 expression. Poster P-013

2. Lammers B, Hildebrand R, Ye D et al. Combined deletion of macrophage ABCA1 and ApoE results in increased atherosclerotic lesion development in LDL receptor knockout mice. Poster P-007.

 

New evidence also suggested a role for ABCA1 in neuroinflammation and susceptibility to neuronal death.

 

Previous studies in animal models of Alzheimer’s disease have shown that ABCA1 affects apoE lipidation and reduces plaque deposition and neuroinflammation. These data suggested a role for ABCA1 as a potential emerging target in Alzheimer’s disease.

 

Research conducted by the University of British Columbia, Vancouver and Washington University, St Louis, USA (3) showed that mice specifically lacking brain ABCA1 had more pyknotic neurons, representative of dead neurons, than controls. ABCA1 appeared to be implicated in neuroinflammation and neurodegradation, by influencing microglia phagocytosis and astrocyte activation.

 

3. Karasinska J, De Haan W, Franciosi S et al. ABCA1 influences neuroinflammation and susceptibility to neuronal death. Poster P-006.

 

 

RVX-208: selective upregulation of apoA-I

 

RVX-208, an orally active small molecule, increases apoA-I production and has benefical effects on biomarkers of reverse cholesterol transport, the process by which cholesterol is transferred from peripheral tissues to the liver for excretion. These data suggest that RVX-208 may be anti-atherogenic.

 

Following up on this, studies in apoE deficient mice, a model of atherosclerosis, showed that administration of RVX-208 for 12 weeks raised HDL cholesterol levels and reduced atherosclerotic plaque numbers. Additionally, in early clinical trials, administration of RVX-208 for up to 28 days raised HDL cholesterol and apoA-I plasma levels, with more pronounced effects in individuals with low HDL cholesterol (<40 mg/dL) (1). These encouraging data provide a basis for continuing development of this unique molecule.

 

1. R Jahagirdar, A Gordon, S Azhar et al. RVX-208 an orally active small molecule raises apoA-I/HDL in human clinical trials and reduces plaque numbers in an apoE null mouse model of atherosclerosis. Poster P-022.

 

 

Epidemiology of low HDL cholesterol

 

High prevalence of isolated low plasma HDL cholesterol in the Philippines.

 

Data from the Philippine National Nutrition and Health Survey 2003 (n=4,502) showed that 70% of Filipinos had low HDL cholesterol, either as an isolated or mixed dyslipidemia; however, only 8% of individuals also had elevated triglycerides. The authors concluded that this high prevalence of isolated low HDL cholesterol among Filipinos may be attributable to a genetic or racial predisposition (1).

 

Genetics of familial low HDL cholesterol

 

A study from the Academic Medical Center, University of Amsterdam, The Netherlands showed that mutations in the ABCA1, LCAT and apoA-I genes account for more than one-third of familial low HDL cholesterol (43.6%), higher than rates observed in the general population (~17.2%) (2,3). These data highlight the importance of knowledge of HDL cholesterol trait heritability for identifying molecular defects that cause low HDL cholesterol.

 

Carriers of LCAT mutations at increased atherosclerotic risk

 

Carriers of mutations in LCAT (lecithin:cholesterol acyltransferase) exhibit atherogenic lipid profile characterised by low plasma levels of HDL cholesterol (34 mg/dL versus 55 mg/dL in controls) and moderately elevated triglycerides (median, interquartile range: 96, 57-136 mg/dL vs. 66, 38-95 mg/dL).  These individuals also had evidence of increased atherosclerosis, as characterised by increased carotid mean wall area (18.2 vs. 14.2 mm2, p=0.01) and normalised wall index (0.34 vs. 0.31, p=0.01), measured by magnetic resonance imaging. Multivariate analysis showed that heterozygosity for LCAT was predictive of increased atherosclerosis and risk for cardiovascular disease (4).

 

1. Cruz-Anacleto M, Sy R, Soria M et al. Translating the pattern of HDL-C among Filipinos to the rest of the world. Poster P-048.

2. Tiethen I, Singaraja R, Kuivenhoven J et al. More than one-third of extreme low HDLc cases in families can be explained by mutations in three genes. Poster P-055.

3. Cohen JC, Kiss RS, Pertsemlidis A et al. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 2004;305:869.

4. Holleboom A, Duivenvoorden R, van den Bogaard B et al. Carriers of LCAT gene mutations have increased atherosclerosis: a 3.0 Tesla MRI study. Poster P-093.

 

 

HDL cholesterol and residual cardiovascular risk

 

Low HDL cholesterol is a contributor to residual cardiovascular risk

 

Researchers from Tel Aviv University provided further evidence that low HDL cholesterol is predictive of cardiovascular disease morbidity in statin-treated patients at goal for LDL cholesterol (<100 mg/dL). In 1440 patients with pre-existing cardiovascular disease, the rate of revascularisation procedures increased with decreasing plasma HDL cholesterol levels, from 25% in patients with plasma HDL cholesterol levels in the highest quartile (mean 51 ± 9 mg/dL) to 58% in those in the lowest quartile (25 ± 4 mg/dL), p<0.001 (1).

 

In another study (2), plasma HDL cholesterol was a significant and inverse predictor of major cardiac events in statin-treated patients undergoing coronary stenting. At 6 months, every 10 mg/dL increase in HDL cholesterol was associated with 40% (95% CI 9-61%, p=0.016) reduction in major cardiac events.

 

1. Elis A, Lishner M, Hermoni D. The association between HDL-C levels and cardiovascular morbidity in statin treated cardiovascular disease patients within target LDL-C levels. Poster P-037.

2. Choo E, Koh Y, Park CS et al. Level of HDL-cholesterol after six-month statin therapy could predict clinical outcomes after coronary intervention. Poster P-045.

 

 

HDL and inflammation

 

Increasing evidence for a link between HDL cholesterol and inflammation

 

Individuals with low HDL cholesterol are more susceptible to an inflammatory challenge than those with high HDL cholesterol levels. However, this finding cannot be explained by differences in the HDL proteome (protein constituents of HDL) between these two groups, according to a study jointly undertaken by the Academic Medical Center, Amsterdam, The Netherlands, the University of Ličge, Belgium and the Department of Molecular and Clinical Medicine, Linköping, Sweden (1).

 

A report from the VYTELD study (Vytorin in the Elderly Study) (2)showed that plasma levels of HDL cholesterol were negatively and more consistently correlated with high-sensitivity C-reactive protein (hs-CRP) than LDL cholesterol, non-HDL cholesterol or apoB, in older patients (≥65 years) treated with lipid-modifying therapy (ezetimibe plus simvastatin, or atorvastatin). Changes in plasma HDL cholesterol and hs-CRP levels with each regimen at 12 weeks were significantly and inversely associated. 

 

1. Levels J, Geurts P, Karlsson H et al. Subjects with low and high high-density lipoprotein cholesterol levels differ in their response to challenge with LPS but this is not related to the HDL proteome dynamics. Poster P-071.

2. Brown WV, Foody J, Zieve F et al. Inverse relationship between HDL-C raising and hsCRP reduction in older patients treated with lipid-lowering therapy in the VYTELD study. Poster P-075.

 

 

Neuroprotective role for HDL

 

Previous studies have reported that plasma levels of HDL cholesterol are inversely associated with stroke incidence (1), suggesting a protective effect. In this study using an animal model of embolic stroke, administration of HDL (10 mg/kg) within 3 hours of stroke reduced the cerebral infarct volume (by up to 74%), and decreased neurological deficit at 24 hours by 40% versus saline-treated controls. These effects were attributed to the ability of HDL to protect the blood-brain barrier and limit neutrophil recruitment (2).

 

1. Amarenco P, Goldstein LB, Messig M et al; SPARCL Investigators. Relative and cumulative effects of lipid and blood pressure control in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels trial. Stroke 2009;40:2486-92.

2. Meilhac O, Lapergue B, Moreno J et al. Protective effect of high density lipoprotein-based therapy in a model of embolic stroke. Poster P-101.

 

 

Impact of pioglitazone on HDL cholesterol

 

Chronic administration of pioglitazone to type 2 diabetes patients produced favourable effects on the lipid profile, increasing HDL cholesterol by 11% and lowering triglycerides by 15% and small dense LDL particles by 28%, compared with baseline (pre-treatment) values. Pioglitazone treatment also increased expression of genes associated with reverse cholesterol transport (ABCA1, ABCG1 and apoA-I), suggesting the potential for benefit on plaque stabilisation (1).

1. Funada J, Takata Y, Morioka N et al. Effects of pioglitazone on lipid metabolism in patients with type 2 diabetes. Poster P-038.


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