Elevated HDL Cholesterol is Functionally Ineffective in Cardiac Transplant Recipients: Evidence for Impaired Reverse Cholesterol Transport

Abstract-Studies have shown a reduction in plaque volume and change in plaque ultrasound characteristics after 4 infusions of reconstituted high-density lipoprotein (rHDL). Whether rHDL infusion leads to acute changes in plaque characteristics in humans is not known. Patients with claudication scheduled for percutaneous superficial femoral artery revascularization were randomized to receive 1 intravenous infusion of either placebo or rHDL (80 mg/kg given over 4 hours). Five to 7 days following the infusion, patients returned and revascularization was performed including atherectomy to excise plaque from the superficial femoral artery. Twenty patients (17 males) average age, 68Ϯ10 years (meanϮSD) were recruited. Eleven patients had a history of documented coronary artery disease, all patients were on aspirin, and 18 were on statins. Ten of the patients received rHDL and 10 placebo. There was significantly less vascular cell adhesion molecule-1 expression (28Ϯ3% versus 50Ϯ3%; PϽ0.05) and a reduction in lipid content in the plaque of HDL-treated subjects compared to placebo. The level of HDL cholesterol increased by 20% after infusion of rHDL and the capacity of apolipoprotein B-depleted plasma to support cholesterol efflux increased. Intravenous infusion of a single dose of reconstituted HDL led to acute changes in plaque characteristics with a reduction in lipid content, macrophage size, and measures of inflammation. These changes may contribute to the cardioprotective effects of HDL.

show abstract

“…24 No difference in HDL size distribution was found between the groups or between pre-and postinfusion plasma samples (data not shown).…”

Section: Cholesterol Effluxmentioning

confidence: 97%

Infusion of Reconstituted High-Density Lipoprotein Leads to Acute Changes in Human Atherosclerotic Plaque

Shaw

Bobik

Murphy

et al. 2008

Circulation Research

Self Cite

254

197

View full text Add to dashboard Cite

show abstract

“…This might be of physiopathological relevance in the initial steps of atherogenesis, in which monocytes are arrested on the surface of endothelial cells. Recently, it was shown that hyperalphalipoproteinemia in cardiac transplant recipients is associated with the formation of partially dysfunctional HDL (46). Other studies showed that average HDL size and CE content increase as a result of low CETP activity (47)(48)(49)(50).…”

Section: Discussionmentioning

confidence: 99%

Atherogenic, enlarged, and dysfunctional HDL in human PLTP/apoA-I double transgenic mice

Moerland

Samyn

Gent

et al. 2007

Journal of Lipid Research

View full text Add to dashboard Cite

In low density lipoprotein receptor (LDLR)-deficient mice, overexpression of human plasma phospholipid transfer protein (PLTP) results in increased atherosclerosis. PLTP strongly decreases HDL levels and might alter the antiatherogenic properties of HDL particles. To study the potential interaction between human PLTP and apolipoprotein A-I (apoA-I), double transgenic animals (hPLTPtg/ hApoAItg) were compared with hApoAItg mice. PLTP activity was increased 4.5-fold. Plasma total cholesterol and phospholipid were decreased. Average HDL size (analyzed by gel filtration) increased strongly, hPLTPtg/hApoAItg mice having very large, LDL-sized, HDL particles. Also, after density gradient ultracentrifugation, a substantial part of the apoA-I-containing lipoproteins in hPLTPtg/hApoAItg mice was found in the LDL density range. In cholesterol efflux studies from macrophages, HDL isolated from hPLTPtg/ hApoAItg mice was less efficient than HDL isolated from hApoAItg mice. Furthermore, it was found that the largest subfraction of the HDL particles present in hPLTPtg/hApoAItg mice was markedly inferior as a cholesterol acceptor, as no labeled cholesterol was transferred to this fraction. In an LDLR-deficient background, the human PLTP-expressing mouse line showed a 2.2-fold increased atherosclerotic lesion area. These data demonstrate that the action of human PLTP in the presence of human apoA-I results in the formation of a dysfunctional HDL subfraction, which is less efficient in the uptake of cholesterol from cholesterol-laden macrophages.-Moerland, M., H. Samyn, T. van Gent, M. Jauhiainen, J. Metso, R. The incidence of coronary heart disease shows a strong inverse relationship with the concentration of plasma HDL (1). Therefore, HDL is believed to have antiatherogenic properties, which are attributed to its effects on endothelial cells, its antioxidant activity, and its role in reverse cholesterol transport, a pathway in which peripheral cellular cholesterol is transported to the liver (2-4). One important determinant of the plasma HDL concentration is phospholipid transfer protein (PLTP) activity. During lipolysis, PLTP transfers phospholipids from apolipoprotein Bcontaining lipoproteins to HDL (5). Furthermore, PLTP acts as an HDL conversion factor by remodeling HDL to produce large particles and small lipid-poor particles, known as preb-HDL (6-9). The latter HDL subfraction is a very efficient acceptor of cellular cholesterol. In this way, PLTP plays an important role in the early steps of reverse cholesterol transport (10-12).Although the involvement of PLTP in the cellular efflux of cholesterol and phospholipids is potentially antiatherogenic, different in vivo studies showed that an increase in plasma PLTP activity is associated with decreased HDL cholesterol levels (9, 13, 14) and increased atherosclerotic lesion development (15-17). The PLTP-dependent decrease in HDL levels was explained by an accelerated HDL catabolism (13). In addition to its effect on HDL cholesterol levels, PLTP may alter the antiathe...

show abstract

“…40,41 Dysfunctional HDL in cardiovascular disease is not limited to CAD and acute coronary syndrome (ACS). Also in other cardiovascular diseases, such as heart failure, 42 ischaemic cardiomyopathy, 43 heart transplantion, 44,45 as well as in many conditions that are known to increase cardiovascular risk such as diabetes, CKD, acute and chronic inflammatory diseases, or familial hypercholesterolemia, [46][47][48] HDL has been found to lose its atheroprotective characteristics.…”

Section: Dysfunctional Hdl In Cardiovascular Diseasementioning

confidence: 99%

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Annema

Eckardstein

2016

Translational Research

View full text Add to dashboard Cite

Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary heart disease. HDL mediates cholesterol efflux from macrophages for reverse transport to the liver and elicits many anti-inflammatory and anti-oxidative activities which are potentially antiatherogenic. Nevertheless, HDL has not been successfully targeted by drugs for prevention or treatment of cardiovascular diseases. One potential reason is the targeting of HDL cholesterol which does not capture the structural and functional complexity of HDL particles. Hundreds of lipid species and dozens of proteins as well as several microRNAs have been identified in HDL. This physiological heterogeneity is further increased in pathologic conditions due to additional quantitative and qualitative molecular changes of HDL components which have been associated with both loss of physiological function and gain of pathologic dysfunction. This structural and functional complexity of HDL has prevented clear assignments of molecules to the functions of normal HDL and dysfunctions of pathologic HDL. Systematic analyses of structure-function relationships of HDL-associated molecules and their modifications are needed to test the different components and functions of HDL for their relative contribution in the pathogenesis of atherosclerosis. The derived biomarkers and targets may eventually help to exploit HDL for treatment and diagnostics of cardiovascular diseases.

show abstract

Elevated HDL Cholesterol is Functionally Ineffective in Cardiac Transplant Recipients: Evidence for Impaired Reverse Cholesterol Transport

Abstract: Hyperalphalipoproteinaemia in cardiac transplant recipients is associated with the formation of partially dysfunctional HDL. We conclude that high levels of HDL may not confer cardioprotection in this group of patients.

Cited by 28 publications

References 52 publications

Infusion of Reconstituted High-Density Lipoprotein Leads to Acute Changes in Human Atherosclerotic Plaque

Infusion of Reconstituted High-Density Lipoprotein Leads to Acute Changes in Human Atherosclerotic Plaque

Atherogenic, enlarged, and dysfunctional HDL in human PLTP/apoA-I double transgenic mice

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Contact Info

Product

Resources

About