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. Such properties could contribute considerably to the capacity of HDL to inhibit atherosclerosis. Systemic and vascular inflammation has been proposed to convert HDL to a dysfunctional form that has impaired antiatherogenic effects. A loss of anti-inflammatory and antioxidative proteins, perhaps in combination with a gain of proinflammatory proteins, might be another important component in rendering HDL dysfunctional. The proinflammatory enzyme myeloperoxidase induces both oxidative modification and nitrosylation of specific residues on plasma and arterial apolipoprotein A-I to render HDL dysfunctional, which results in impaired ABCA1 macrophage transport, the activation of inflammatory pathways, and an increased risk of coronary artery disease. Understanding the features of dysfunctional HDL or apolipoprotein A-I in clinical practice might lead to new diagnostic and therapeutic approaches to atherosclerosis.

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. I have been joined for this discussion by a cardiovascular epidemiologist, Dr. Rachel Mackey, from the University of Pittsburgh and two clinical lipidologists who have studied and written in depth about this problem. These are Dr. Benjamin Ansell from the University of California in Los Angeles and Dr. Peter Toth from Johns Hopkins University School of Medicine. Our objective in this discussion is to give primary care clinicians our thoughts about the recent research findings and the implications of these data on the best clinical practice.

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. Clinical trials currently in progress will more clearly delineate the cardiovascular effects of adding either ezetimibe or extended-release niacin/laropiprant to statin therapy.

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. SUMMARY: As evidenced by a consistent body of clinical trial data, intensive LDL-C reduction plays a critical role in the mitigation of cardiovascular risk. Yet, the effectiveness of lipid-lowering strategies is offset to a significant degree by both physician and patient factors that limit goal attainment. Despite extensive evidence demonstrating the benefits of lipid-lowering therapy, many patients are still not getting to goal because the transition from physician awareness to clinical practice is lagging. Patient noncompliance to therapy also limits goal attainment, thus resulting in poor health outcomes and increasing managed care costs. CONCLUSION: To overcome the issues surrounding LDL-C goal attainment, interventions designed to increase goal attainment should be based not only on the conclusions of clinical trials but also on successful patientand provider-focused behavioral strategies. Interventions for improving adherence to lipid-lowering medication will provide an opportunity to decrease morbidity, mortality, and hospitalization associated with cardiovascular disease.

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. Finally, the authors discuss the potential role of piHDLs (found in some 45% of patients with systemic lupus erythematosus and 20% of patients with rheumatoid arthritis) in the accelerated atherosclerosis associated with some chronic rheumatic diseases.

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. In the future, characterizing and targeting functional aspects of HDLs may prove to offer therapeutic advantages over current treatment strategies.

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.gov and current guidelines from major cardiovascular societies. STUDY SELECTION AND DATA EXTRACTION: Study selection was prioritized to identify randomized controlled trials over meta-analyses over mechanistic studies; identified studies also included proof-of-concept studies and key phase 1 through 3 trials of novel agents. Study eligibility was assessed by 2 authors; disagreements were resolved by consensus with the third. DATA SYNTHESIS: Of 754 studies identified, 31 randomized controlled trials met the inclusion criteria. Currently available therapeutic and lifestyle strategies, when optimized, increase HDL-C levels by 20% to 30%. While basic and small pilot studies have shown promise, proof that increasing HDL-C levels confers a reduction in major cardiovascular outcomes independent of changes in levels of low-density lipoprotein cholesterol or triglycerides has been more elusive. Some novel therapeutic agents in human studies appear to effectively increase HDL-C levels, whereas other novel strategies that target HDL metabolism or function may have minimal effect on HDL-C levels. CONCLUSIONS: At present there is modest evidence to support aggressively increasing HDL-C levels in addition to what is achieved by lifestyle modification alone. Ongoing clinical trials that target specific pathways in HDL metabolism may help expand cardiovascular treatment options.

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. Some therapeutic approaches that reduce coronary risk, such as statins and therapeutic lifestyle changes, can favorably moderate the characteristics of proinflammatory HDL. In addition, apolipoprotein A-I mimetic peptides and other compounds that target functional aspects of HDL may offer novel approaches to reduction in cardiovascular risk. SUMMARY: Current data suggest that under some conditions HDL can become dysfunctional and even proinflammatory, but this characterization can change with resolution of systemic inflammation or use of certain treatments.

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. METHODS: Twenty subjects with active RA (mean Disease Activity Score 5.13 +/- 0.92) without dyslipidemia and no history of coronary artery disease were randomized in a double-blind placebo-controlled trial to receive 80 mg of atorvastatin (A) or placebo (P) daily in addition to stable antirheumatic drug therapy. Disease activity variables were followed over 12 weeks and the anti-/proinflammatory properties of HDL were determined by a cell-free assay (CFA) that measures lipid oxidation products. RESULTS: After 12 weeks, subjects completing the A protocol had a mean reduction in CFA values of 14.8 +/- 21.7%, while subjects completing P protocol had a mean increase in CFA values of 7.1 +/- 13.2% (p = 0.026). There was a trend for a decrease in highly sensitive C-reactive protein (hs-CRP) over 12 weeks in the A group compared to an increase in hs-CRP in the P group (p > 0.05), but changes in measures of clinical disease activity and plasma cytokine/intercellular adhesion molecule-1 levels were not significantly different in the A and P groups. CONCLUSION: In patients with active RA, HDL was rendered more antiinflammatory by high-dose atorvastatin compared to placebo. Functional characterization of HDL may warrant further investigation as a method of cardiovascular risk assessment in RA patients without traditional coronary risk factors. (ClinicalTrials.gov number NCT00356473).

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 anti-inflammatory and pro-inflammatory functional properties of HDL can now be assessed using cell-based and cell-free assays. Acute or chronic systemic inflammation and the metabolic syndrome appear to render HDL pro-inflammatory. In contrast, statins and experimental agents such as apolipoprotein A-1 mimetics render HDL more anti-inflammatory. The 2 main classes of existing drugs for HDL modification are fibric acid derivatives, also known as "fibrates," and niacin- containing compounds. In several controlled and prospective intervention studies, patients with low HDL-C and additional risk factors benefited from treatment with fibrates or niacin. However, an increase in HDL-C did not lead to a decrease in cardiovascular events in all trials.

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. RESULTS: Of the 4885 patients evaluated, 2103 (43%) were women. NCEP Third Adult Treatment Panel low-density lipoprotein cholesterol (LDL-C) goal achievement was similar between women and men with 0 or 1 risk factor (89% and 88%, respectively) and 2 or more risk factors (75% and 76%, respectively). However, fewer women than men achieved goal in the coronary heart disease and risk equivalents (CHD + CHD RE) category (50% vs 60%, respectively; P < .001). Logistic regression analyses examining the association between sex and LDL-C treatment goal achievement, and evaluating potential confounding by other predictors of treatment success, indicated an age-adjusted odds ratio of 0.66 (95% confidence interval, 0.56-0.77; P < .001) and a multivariate odds ratio of 0.76 (95% confidence interval, 0.62-0.93; P = .009) for women compared with men in the CHD + CHD RE category. CONCLUSIONS: Female sex was associated with lower likelihood of LDL-C goal achievement among patients with CHD + CHD RE. This relationship remained significant after adjustment for other significant predictors of treatment success.

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. It has been postulated that HDL functions to promote reverse cholesterol transport. Recent studies support this role for HDL but also indicate that HDL is a modulator of systemic inflammation. In the absence of inflammation, HDL has a complement of antioxidant enzymes that work to maintain an anti-inflammatory state. In the presence of systemic inflammation, these antioxidant enzymes can be inactivated and HDL can accumulate oxidized lipids and proteins that make it proinflammatory. Under these conditions the main protein of HDL, apolipoprotein A-I, can be modified by reactive oxygen species. This modification impairs the ability of HDL to promote cholesterol efflux by the ATP-binding cassette transporter A-1 pathway. Animal studies and small-scale human studies suggest that measures of the quality and novel functions of HDL might provide an improved means of identifying subjects at increased risk for atherosclerotic events, compared with the current practice of only measuring HDL-cholesterol levels. The quality and function of HDL are also attractive targets for emerging therapies.

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. Recent studies have provided insight as to specific chemical modifications and structural changes within HDL associated with this phenotype. The presence of proinflammatory HDL coincides with conditions associated with chronic systemic inflammation, including atherosclerosis.

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. Acute or chronic systemic inflammation and the metabolic syndrome appear to render HDL proinflammatory. In contrast, statins and experimental agents such as apolipoprotein A-1 mimetics render HDL more anti-inflammatory. Functional characterization of HDL is a promising method for enhanced assessment of cardiovascular risk and effectiveness of risk reduction.

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. Goals for each CVD risk factor need to be intensified when multiple sources of risk are present. Patients who have no overt disease but who have multiple CVD risk factors are now understood to be at high risk and should be the target of aggressive primary preventive strategies to avert unnecessary morbidity and mortality. It is also becoming clear that CVD risk factors interact at the level of the endothelium to promote atherosclerosis. Furthermore, recent clinical trials, including those assessing atherosclerotic progression and CVD endpoints, have demonstrated the effectiveness of interventions targeted at multiple risk factors for CVD.