Dysfunctional HDL and atherosclerotic cardiovascular disease.

High-density lipoproteins (HDLs) protect against atherosclerosis by removing excess cholesterol from macrophages through the ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) pathways involved in reverse cholesterol transport. Factors that impair the availability of functional apolipoproteins or the activities of ABCA1 and ABCG1 could, therefore, strongly influence atherogenesis. HDL also inhibits lipid oxidation, restores endothelial function, exerts anti-inflammatory and antiapoptotic actions, and exerts anti-inflammatory actions in animal models.

JCL roundtable: HDL in the primary care setting.

One of the most difficult and confusing issues for clinical lipidologists and physicians in general has been the management of low concentrations of high-density lipoprotein cholesterol. We know this to be a very powerful predictor of risk in scores of community-based and clinical trial cohorts. Raising this number in many patients would seem to provide a great therapeutic opportunity, but so far this concept has been very difficult to prove.

A review of trials evaluating nonstatin lipid-lowering therapies.

Recently reported clinical trials raise doubts on the effectiveness of nonstatin lipid-lowering therapies in reducing the residual risk of cardiovascular events after statin monotherapy. Addition of -torcetrapib to statin therapy increased overall mortality in coronary patients despite a marked increase in high-density lipoprotein cholesterol. Combining ezetimibe with statin therapy neither further reduces carotid atherosclerosis nor slows aortic stenosis, and it has not been shown to be superior to statin monotherapy in reducing cardiovascular events.

Altered lipoprotein metabolism in chronic inflammatory states: proinflammatory high-density lipoprotein and accelerated atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis.

In this review, the authors discuss the formation and structure of high-density lipoproteins (HDLs) and how those particles are altered in inflammatory or stress states to lose their capacity for reverse cholesterol transport and for antioxidant activity. In addition, abnormal HDLs can become proinflammatory (piHDLs) and actually contribute to oxidative damage. The assay by which piHDLs are identified involves studying the ability of test HDLs to prevent oxidation of low-density lipoproteins.

Not getting to goal: the clinical costs of noncompliance.

Background: Cardiovascular disease is characterized by significant prevalence and cost in the managed care setting. Despite overwhelming evidence in favor of statin use for lowering low-density lipoprotein cholesterol (LDL-C), medication compliance to these agents remains suboptimal, as it does in other disease states.

Objective: To establish the benefits of statin therapy in cardiovascular disease, demonstrate the current lack of compliance to lipid-lowering agents, and present potential interventions to improve medication compliance.

Targeting the anti-inflammatory effects of high-density lipoprotein.

The effects of systemic inflammation can impair the anti-inflammatory functions of high-density lipoprotein (HDL) particles. In patients with atherosclerosis and/or inflammatory conditions, HDLs can be modified such that they paradoxically increase the recruitment and activation of macrophages, upregulate the expression of endothelial cell adhesion molecules, and participate in the oxidation of low-density lipoproteins (LDLs). Statins, apolipoprotein A-I mimetic peptides, and therapeutic lifestyle changes appear to mitigate these proinflammatory features of HDLs.

The two faces of the 'good' cholesterol.

Although a low level of high-density lipoprotein (HDL) cholesterol is a useful clinical predictor of coronary heart disease, raising the HDL cholesterol level does not necessarily lower this risk. Part of the explanation for this paradox may be that, under certain conditions, HDL either can be less functional as an antioxidant or can even enhance the oxidation and inflammation associated with atherosclerotic plaque. Thus, the functional properties of HDL--not simply the level--may need to be considered and optimized.

High-density lipoprotein as a therapeutic target: a systematic review.

Context: High-density lipoprotein cholesterol (HDL-C) is a cardiovascular risk factor that is gaining substantial interest as a therapeutic target.

Objectives: To review the current and emerging strategies that modify high-density lipoproteins (HDLs).

Data Sources: Systematic search of English-language literature (1965-May 2007) in MEDLINE and the Cochrane database, using the key words HDL-C and apolipoprotein A-I and the subheadings reverse cholesterol transport, CVD [cardiovascular disease] prevention and control, drug therapy, and therapy; review of presentations made at major cardiovascular meetings from 2003-2007; and review of ongoing trials from ClinicalTrials.

The paradox of dysfunctional high-density lipoprotein.

Purpose Of Review: This review addresses how, in atherosclerosis or systemic inflammation, HDL can lose its usual atheroprotective characteristics and even paradoxically assume proinflammatory properties.

Recent Findings: Specific chemical and structural changes within HDL particles can impede reverse cholesterol transport, enhance oxidation of LDL, and increase vascular inflammation. HDL may be viewed as a shuttle that can be either anti-inflammatory or proinflammatory, depending on its cargo of proteins, enzymes, and lipids.

Effects of high-dose atorvastatin on antiinflammatory properties of high density lipoprotein in patients with rheumatoid arthritis: a pilot study.

Objective: Patients with rheumatoid arthritis (RA) have a 2-3-fold increased risk of myocardial infarction. Recent work suggests that plasma high density lipoproteins (HDL) from patients with RA are more proinflammatory than HDL from controls. We examined the effects of atorvastatin 80 mg daily on the inflammatory properties of HDL and clinical disease activity in RA.

HDL function as a target of lipid-modifying therapy.

High-density lipoprotein (HDL) is conventionally believed to possess many features that protect against atherosclerosis. However, these lipoproteins may be modified in certain individuals and/or circumstances to become pro-inflammatory. The ability of HDL to inhibit or paradoxically to enhance vascular inflammation, lipid oxidation, plaque growth, and thrombosis reflects changes in specific enzyme and protein components.

The potential for CETP inhibition to reduce cardiovascular disease risk.

Background: Although reductions in cardiovascular risk can be achieved by lowering low-density lipoprotein cholesterol, treated patients remain at substantial risk. Epidemiological studies have established that higher levels of high-density lipoprotein cholesterol (HDL-C) are strongly associated with reduced cardiovascular risk, and therefore raising levels of HDL-C may be beneficial. The activity of cholesteryl ester transfer protein (CETP) appears to be inversely correlated with HDL-C levels and thus CETP is an attractive target for intervention to raise levels of HDL-C and potentially reduce residual cardiovascular risk.

Modifying the anti-inflammatory effects of high-density lipoprotein.

The anti-inflammatory effects of high-density lipoproteins (HDL) are well documented and include inhibition of low-density lipoprotein (LDL) oxidation, reduction of inflammatory cytokines and vascular leukocyte adhesion molecules, and participation in innate immunity. However, certain conditions, including coronary disease, diabetes mellitus, systemic inflammation, and a diet high in saturated fat, are associated with modification of HDL such that it paradoxically enhances LDL oxidation and/or vascular inflammation. Treatment with statins and/or apolipoprotein A1 mimetic peptides improves HDL's anti-inflammatory functions, and these as well as other medications may represent a novel pathway through which to target atherosclerosis.

Reduced treatment success in lipid management among women with coronary heart disease or risk equivalents: results of a national survey.

Background: This survey assessed and compared National Cholesterol Education Program (NCEP) Third Adult Treatment Panel lipid treatment goal achievement for men versus women undergoing treatment of dyslipidemia.

Methods: Patients receiving treatment for dyslipidemia from physicians (N = 376) in the United States who were high prescribers of lipid medications were enrolled in the NCEP Evaluation Project Utilizing Novel E-Technology (NEPTUNE) II. Data from a single office visit were collected and entered into the NEPTUNE software on a personal digital assistant and uploaded to a central database via the Internet.

Mechanisms of disease: proatherogenic HDL--an evolving field.

It is well known that, in large populations, HDL-cholesterol levels are inversely related to the risk of atherosclerotic clinical events; however, in an individual, the predictive value of an HDL-cholesterol level is far from perfect. As a result, other HDL-associated factors have been investigated, including the quality and function of HDL in contradistinction to the level of HDL-cholesterol. Regarding their quality, HDL particles are highly heterogeneous and contain varying levels of antioxidants or pro-oxidants, which results in variation in HDL function.

High-density lipoprotein: is it always atheroprotective?

High-density lipoproteins (HDLs) are appropriately recognized for their many atheroprotective functions, including reverse cholesterol transport, as well as antioxidant, anti-inflammatory, and antithrombotic effects. Furthermore, the inverse relationship between HDL cholesterol and atherosclerosis is well documented in many populations. However, there is an increasing body of evidence that there are circumstances in which HDL may not be protective, and may in fact paradoxically promote vascular inflammation and oxidation of low-density lipoproteins.

High-density lipoprotein function recent advances.

Although high-density lipoproteins (HDL) possess many features that contribute to the association between elevated HDL cholesterol and protection from atherosclerosis, these lipoproteins may be modified in certain individuals and/or circumstances to become proinflammatory. The ability of HDL to inhibit or paradoxically to enhance vascular inflammation, lipid oxidation, plaque growth, and thrombosis reflects changes in specific enzyme and protein components. The anti-inflammatory and proinflammatory functional properties of HDL can now be assessed using cell-based and cell-free assays.

Evidence for a combined approach to the management of hypertension and dyslipidemia.

The recognition that hypertension and dyslipidemia coexist more often than would be expected by chance and that their combination increases the risk of coronary heart disease (CHD) has important implications for patient management. Patients with cardiovascular disease (CVD) and healthy individuals with multiple CVD risk factors--including concomitant dyslipidemia and hypertension-are the primary focus of updated treatment guidelines for CVD prevention. There is a need for a treatment paradigm shift from the diagnosis and treatment of individual CVD risk factors to the assessment and management of total CVD risk.

Results of the National Cholesterol Education (NCEP) Program Evaluation ProjecT Utilizing Novel E-Technology (NEPTUNE) II survey and implications for treatment under the recent NCEP Writing Group recommendations.

The most recent national survey of compliance with the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) guidelines was completed before ATP III and showed significant underachievement of low-density lipoprotein (LDL) cholesterol goals. The NCEP Evaluation ProjecT Utilizing Novel E-Technology (NEPTUNE) II was a national survey conducted in 2003. Of the 4,885 patients, 67% achieved their LDL cholesterol treatment goal, including 89%, 76%, and 57%, respectively, in the 0 or 1 risk factor, > or = 2 risk factors or coronary heart disease (CHD), and CHD risk equivalent categories.

The double jeopardy of HDL.

The ability of high-density lipoprotein (HDL) to promote cholesterol efflux is thought to be important in its protection against cardiovascular disease. Anti-inflammatory properties of HDL have emerged as additional properties that may also be important. HDL appears to have evolved as part of the innate immune system functioning to inhibit inflammation in the absence of an acute phase response (APR) but functioning to increase inflammation in the presence of an APR.

Apolipoprotein A-I mimetic peptides.

Despite identical amino acid composition, differences in class A amphipathic helical peptides caused by differences in the order of amino acids on the hydrophobic face results in substantial differences in antiinflammatory properties. One of these peptides is an apolipoprotein A-I (apoA-I) mimetic, D-4F. When given orally to mice and monkeys, D-4F caused the formation of pre-beta high-density lipoprotein (HDL), improved HDL-mediated cholesterol efflux, reduced lipoprotein lipid hydroperoxides, increased paraoxonase activity, and converted HDL from pro-inflammatory to antiinflammatory.