Experimental Models for the Investigation of High-Density Lipoprotein–Mediated Cholesterol Efflux

Reduction of low-density lipoprotein cholesterol by statin therapy has only modestly decreased coronary heart disease (CHD)-associated mortality in developed countries, which has prompted the search for alternative therapeutic strategies for CHD. Epidemiologic and interventional studies have clearly established an inverse association between plasma levels of high-density lipoprotein (HDL) cholesterol and incidence of atherosclerosis. The atheroprotective benefits of HDL are not only dependent on HDL concentrations (quantity), but also on HDL function (quality). Therefore, several techniques have been recently developed to assess the different properties of HDL. Because reverse cholesterol transport (RCT) is considered a key player in the beneficial action of HDL, this review focuses on the different methods used to evaluate cholesterol efflux. Measuring the in vivo function of HDL could be of significant importance for both the clinical evaluation of an individual patient and to evaluate the effectiveness of different RCT-enhancing therapeutic approaches.     

Clinical and Biological Relevance of Statin-Mediated Changes in HDL Metabolism

Although prospective studies consistently show that individuals with low levels of high-density lipoprotein (HDL) cholesterol are at increased cardiovascular risk, it is still not clear whether or not this relationship still holds in patients treated with statins who have achieved optimal low-density lipoprotein cholesterol levels. Additionally, the hypothesis that statin-mediated increases in HDL cholesterol levels have a impact on cardiovascular risk has not been clearly demonstrated. Statin therapy has little impact on the cholesterol content carried by HDL in the bloodstream (i.e., HDL cholesterol levels), but statins can induce a significant redistribution of HDL particle size, particle concentration, and physicochemical and functional properties. Our objective is to summarize the evidence arising from epidemiological, clinical, and experimental studies that suggests a potential role for statin therapy in the modulation of parameters of HDL metabolism and reverse cholesterol transport.     

Lipoprotein abnormalities in South Asians and its association with cardiovascular disease: Current state and future directions

South Asians have a high prevalence of coronary heart disease (CHD) and suffer from early-onset CHD compared to other ethnic groups. Conventional risk factors may not fully explain this increased CHD risk in this population. Indeed, South Asians have a unique lipid profile which may predispose them to premature CHD. Dyslipidemia in this patient population seems to be an important contributor to the high incidence of coronary atherosclerosis. The dyslipidemia in South Asians is characterized by elevated levels of triglycerides, low levels of high-density lipoprotein (HDL) cholesterol, elevated lipoprotein(a) levels, and a higher atherogenic particle burden despite comparable low-density lipoprotein cholesterol levels compared with other ethnic subgroups. HDL particles also appear to be smaller, dysfunctional, and proatherogenic in South Asians. Despite the rapid expansion of the current literature with better understanding of the specific lipid abnormalities in this patient population, studies with adequate sample sizes are needed to assess the significance and contribution of a given lipid parameter on overall cardiovascular risk in this population. Specific management goals and treatment thresholds do not exist for South Asians because of paucity of data. Current treatment recommendations are mostly extrapolated from Western guidelines. Lastly, large, prospective studies with outcomes data are needed to assess cardiovascular benefit associated with various lipid-lowering therapies (including combination therapy) in this patient population.     

Focusing on high-density lipoprotein for coronary heart disease risk reduction

A low level of high-density lipoprotein (HDL) is an acknowledged risk factor for coronary heart disease (CHD). HDL cholesterol (HDL-C) exerts its primary cardioprotective effect through a reverse cholesterol transport process, and suppression of this process has been the focus of the development of novel therapeutic agents for increasing HDL-C levels. Several strategies can be used to increase HDL-C levels to target cardiovascular risk reduction. This article presents a review of the biologic actions of HDL that can serve as a potential basis for antiatherosclerotic activity and discusses strategies for targeting HDL for CHD risk reduction.     

Impaired protection against diabetes and coronary heart disease by high-density lipoproteins in Turks

The issue of whether or not incident type 2 diabetes mellitus and coronary heart disease (CHD) can be predicted by high-density lipoprotein (HDL) cholesterol in both sexes needs investigation. A representative sample of 3035 middle-aged Turkish adults free of CHD at baseline was studied with this purpose prospectively over a mean of 7.8 years. High-density lipoprotein cholesterol levels were found to be correlated in women positively with plasma fibrinogen and weakly with waist girth and C-reactive protein, and to be not correlated with fasting insulin. High-density lipoprotein cholesterol protected men against future CHD risk (for a 12-mg/dL increment: relative risk = 0.80 [95% confidence interval, 0.69-0.95]) after multivariable adjustment in logistic regression analyses for age, smoking status, physical activity grade, hypertension, abdominal obesity, diabetes, and lipid-lowering drugs. However, men were not protected against risk of diabetes. In women, HDL cholesterol was not associated with risk for CHD, whereas intermediate (40-60 mg/dL) compared with lower HDL cholesterol levels proved protective against risk of diabetes (relative risk = 0.57 [95% confidence interval, 0.36-0.90]) after adjustments that included apolipoprotein A-I tertiles. Yet higher serum concentrations failed to yield protection against diabetes. It was concluded that HDL particles confer partially lacking protection against cardiometabolic risk among Turks, and this impairment is modulated by sex. This highly important observation may result from a setting of prevailing chronic subclinical inflammation.     

Lipids in type 2 diabetes

Type 2 diabetes increases the risk of cardiovascular disease two- to fourfold compared to the risk in nondiabetic subjects. Although type 2 diabetes is associated with a clustering of risk factors, the cause for an excess risk of cardiovascular disease remains unknown. Lipid and lipoprotein abnormalities in type 2 diabetes include particularly elevated levels of total and very low-density lipoprotein triglycerides and reduced levels of high-density lipoprotein (HDL) cholesterol. Total and low-density lipoprotein (LDL) cholesterol levels are usually normal if glycemic control is adequate but LDL particles are small and dense. According to prospective population-based studies, total cholesterol is a similar risk factor for coronary heart disease (CHD) in patients with type 2 diabetes as it is in nondiabetic subjects. High total triglycerides and low HDL cholesterol may be even stronger risk factors for CHD in patients with type 2 diabetes than in nondiabetic subjects. Recent drug treatment trials have indicated that the lowering of total and LDL cholesterol by statins, and the lowering of total triglycerides and the raising of HDL cholesterol by fibrates, are at least as beneficial in diabetic patients as in nondiabetic subjects in the prevention of cardiovascular disease.     

Controlling lipid levels in diabetes

Coronary heart disease (CHD) is associated with a 2- to 4-times greater risk of morbidity and mortality in patients with type 2 diabetes than in non-diabetic individuals. Dyslipidaemia is an important CHD risk factor in diabetic patients. The key atherogenic features of diabetic dyslipidemia are elevated levels of serum triglycerides, low levels of high density lipoprotein (HDL) cholesterol, and the preponderance of small, dense low density lipoprotein (LDL). As a result, treatment guidelines for diabetic dyslipidaemia recommend elevated LDL cholesterol and triglyceride levels and low HDL cholesterol levels as targets of therapy. Unfortunately, however, these lipid abnormalities often persist dispite best efforts to control hyperglycaemia, improve diet, and increase physical exercise, and therefore demand specific therapeutic intervention. Statins are the first choice for LDL cholesterol lowering as they are effective and well tolerated, and do not have adverse effects on glycaemic control. Furthermore, recent evidence suggests that statins may also be employed to treat moderately elevated levels of triglycerides. An increasing number of primary and secondary prevention trials have shown that lipid-lowering therapy with statins can significantly reduce the risk of CHD events in patients with diabetic dyslipidaemia.     

HDL cholesterol: physiology, pathophysiology, and management

Numerous epidemiological studies have identified high-density lipoprotein cholesterol (HDL) to be an independent risk factor for coronary heart disease (CHD). HDL is an emerging therapeutic target that could rival the impact of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) on LDL and CHD risk reduction. HDL metabolism, HDL kinetics, the concentration of various HDL subclasses, and other genetic factors affecting HDL functionality may all contribute to the anti-atherogenic properties of HDL; thus, standard plasma measurement may not capture the full range of HDL effects. Algorithms have been suggested to treat low HDL levels in subgroups of patients; however, no formal HDL target goals or treatment guidelines have been implemented as there is a lack of strong clinical evidence to support effective pharmacologic therapy for primary risk reduction. Available therapies have a modest impact on serum HDL levels; however, emerging therapies could have a more significant influence.     

Acute changes in serum lipids and lipoprotein subclasses in triathletes as assessed by proton nuclear magnetic resonance spectroscopy.

Exercise is associated with changes in lipids that may protect against coronary heart disease (CHD). In this study of 28 triathletes, we analyzed acute changes in serum lipid and lipoprotein concentrations after completion of the 1995 World Championship Hawaii Ironman Triathlon. With standard laboratory assays, we demonstrate significant decreases in total cholesterol, VLDL cholesterol, ApoB100, and Lp(a). Total HDL cholesterol increased significantly immediately after the race. With a novel proton NMR spectroscopy assay, we demonstrate that smaller diameter LDL particles, corresponding to small, dense LDL, declined by 62%. Moreover, larger HDL subclasses, whose levels are inversely associated with CHD, increased significantly by 11%. Smaller HDL subclasses, which have been directly associated with CHD in some studies, acutely decreased by 16%. Therefore, exercise not only acutely induces changes in lipoprotein concentrations among the standard species in a manner that favorably affects CHD risk, but also induces favorable changes in specific lipoprotein subclass size distribution that also may alter CHD risk independently of the total lipoprotein serum concentration.     

Sex and time differences in the associations of non-high-density lipoprotein cholesterol versus other lipid and lipoprotein factors in the prediction of cardiovascular death (The Rancho Bernardo Study)

Non-high-density lipoprotein (HDL) cholesterol (total cholesterol [TC] minus HDL cholesterol) has been suggested as the preferred lipid fraction to predict cardiovascular disease. We compared the ability of lipids, lipoproteins, the ratio of total to HDL cholesterol (TC/HDL), and non-HDL cholesterol to predict fatal coronary heart disease (CHD) and cardiovascular disease in 1,386 women and 1,094 men (mean age 69 years). After 10 years, there were more deaths in men (n = 310) than women (n = 268), but the proportions of deaths attributed to CHD (23% and 25%, respectively) and cardiovascular disease (48% and 47%) were similar. In men, age-adjusted values for non-HDL cholesterol, TC/HDL ratio, and triglycerides each predicted a significantly increased risk of CHD and cardiovascular disease; none of these associations was independent of pack-years of smoking, systolic blood pressure, fasting plasma glucose, body mass index, and physical activity. In women, age-adjusted non-HDL cholesterol levels did not predict CHD or cardiovascular disease events before or after adjusting for these covariates and for estrogen replacement therapy. In women, only the ratio of TC to HDL cholesterol predicted CHD and cardiovascular disease deaths independent of estrogen use and other risk factors. Observed associations were sensitive to time, being evident in women at 3 and 5 years, and lost thereafter, but not apparent before 10 years in men. Thus, non-HDL cholesterol is not superior to individual lipids, lipoproteins, or their ratios in the prediction of cardiovascular death in older adults.     

Apolipoprotein A-I mimetic peptides: potential role in atherosclerosis management

Atherothrombotic vascular disease continues to be a leading cause of morbidity and mortality in much of the world. Although a healthy lifestyle and low-density lipoprotein cholesterol lowering significantly reduce cardiovascular morbidity and mortality, substantial number of adverse vasoocclusive events continue to occur. These realities have brought attention to additional therapies that could further reduce cardiovascular events. High-density lipoprotein (HDL)/apolipoprotein A-I (apo A-I)-based therapies are a potential therapeutic strategy against atherothrombotic vascular disease because of the known inverse relationship between HDL cholesterol and coronary heart disease, favorable and pleotrophic biologic effects of HDL/apo A-I, results of preclinical experimental studies, and emerging proof of concept in clinical studies. A variety of HDL/apo A-I-based therapies are currently under investigation, including synthetic peptides that mimic the function of HDL. Such apo A-I mimetic peptides are the focus of this review.     

Targeting cholesteryl ester transfer protein for the prevention and management of cardiovascular disease

Epidemiologic studies have shown that the concentration of high-density lipoprotein cholesterol (HDL-C) is a strong, independent, inverse predictor of coronary heart disease risk. This identifies HDL-C as a potential therapeutic target. Compared with low-density lipoprotein cholesterol (LDL-C)-lowering agents, however, currently available HDL-raising drugs are relatively ineffective. Consequently, recent years have seen considerable efforts expended on identifying new drugs that can raise HDL-C. Cholesteryl ester transfer protein (CETP) plays an important role in cholesterol metabolism, being responsible for the transfer of cholesteryl esters from HDL to very low-density lipoproteins and LDLs. The observation that Japanese populations with CETP deficiency exhibited high levels of HDL-C has led to the concept that drugs targeting CETP activity may elevate HDL-C levels and potentially decrease cardiovascular risk. Support of this proposition has been obtained in rabbits where inhibition of CETP activity is markedly antiatherogenic. Two CETP inhibitors-torcetrapib and JTT-705-are currently in the preliminary stages of clinical development. Initial studies with these drugs in humans show that they substantially increase HDL-C levels and modestly decrease LDL-C levels. Larger, long-term, randomized, clinical end point trials are required to determine whether the beneficial effects of CETP inhibitors on lipoprotein metabolism can translate into reductions in cardiovascular events.     

Targeting cholesteryl ester transfer protein for the prevention and management of cardiovascular disease.

Epidemiologic studies have shown that the concentration of high-density lipoprotein cholesterol (HDL-C) is a strong, independent, inverse predictor of coronary heart disease risk. This identifies HDL-C as a potential therapeutic target. Compared with low-density lipoprotein cholesterol (LDL-C)-lowering agents, however, currently available HDL-raising drugs are relatively ineffective. Consequently, recent years have seen considerable efforts expended on identifying new drugs that can raise HDL-C. Cholesteryl ester transfer protein (CETP) plays an important role in cholesterol metabolism, being responsible for the transfer of cholesteryl esters from HDL to very low-density lipoproteins and LDLs. The observation that Japanese populations with CETP deficiency exhibited high levels of HDL-C has led to the concept that drugs targeting CETP activity may elevate HDL-C levels and potentially decrease cardiovascular risk. Support of this proposition has been obtained in rabbits where inhibition of CETP activity is markedly antiatherogenic. Two CETP inhibitors-torcetrapib and JTT-705-are currently in the preliminary stages of clinical development. Initial studies with these drugs in humans show that they substantially increase HDL-C levels and modestly decrease LDL-C levels. Larger, long-term, randomized, clinical end point trials are required to determine whether the beneficial effects of CETP inhibitors on lipoprotein metabolism can translate into reductions in cardiovascular events.     

Apolipoproteins AI and B as therapeutic targets

Currently the apolipoprotein B:AI ratio integrates information about the potential for cardiovascular disease (CVD) risk reduction better than any other lipid or lipoprotein index. Certainly it could, with benefit, replace serum cholesterol and HDL cholesterol in the estimation of CVD risk. Defining the therapeutic target of statin therapy in terms of serum apolipoprotein B (apo B) rather than LDL cholesterol could also help to optimize statin treatment. Deciding whether a therapeutic response is adequate also requires knowledge of whether there is persisting hypertriglyceridaemia, because this gives an indication of whether small dense LDL is likely to have been satisfactorily reduced. Raising low levels of HDL, probably best measured as apo AI, may also prove to be an important aim of treatment. This is, however, a more complex issue and also depends on the mechanism by which a particular therapy alters HDL levels and on whether the capacity of HDL to perform its anti-inflammatory and antioxidative functions is restored. A meta-analysis of randomized clinical trials of statins in which apo B and apo AI have been reported could provide valuable information.     

Beneficial effects of high-density lipoprotein (HDL) on stent biocompatibility and the potential value of HDL infusion therapy following percutaneous coronary intervention

Several epidemiological studies have shown a clear inverse relationship between serum levels of high-density lipoprotein cholesterol (HDL-C) and the risk of atherosclerotic cardiovascular disease (ASCVD), even at low-density lipoprotein cholesterol levels below 70 mg/dL. There is much evidence from basic and clinical studies that higher HDL-C levels are beneficial, whereas lower HDL-C levels are detrimental. Thus, HDL is widely recognized as an essential anti-atherogenic factor that plays a protective role against the development of ASCVD. Percutaneous coronary intervention is an increasingly common treatment choice to improve myocardial perfusion in patients with ASCVD. Although drug-eluting stents have substantially overcome the limitations of conventional bare-metal stents, there are still problems with stent biocompatibility, including delayed re-endothelialization and neoatherosclerosis, which cause stent thrombosis and in-stent restenosis. According to numerous studies, HDL not only protects against the development of atherosclerosis, but also has many anti-inflammatory and vasoprotective properties. Therefore, the use of HDL as a therapeutic target has been met with great interest. Although oral medications have not shown promise, the developed HDL infusions have been tested in clinical trials and have demonstrated viability and reproducibility in increasing the cholesterol efflux capacity and decreasing plasma markers of inflammation. The aim of the present study was to review the effect of HDL on stent biocompatibility in ASCVD patients following implantation and discuss a novel therapeutic direction of HDL infusion therapy that may be a promising candidate as an adjunctive therapy to improve stent biocompatibility following percutaneous coronary intervention.     

Genetics of Cholesterol Efflux

Plasma levels of high-density lipoprotein cholesterol (HDL-C) show an inverse association with coronary heart disease (CHD). As a biological trait, HDL-C is strongly genetically determined, with a heritability index ranging from 40 % to 60 %. HDL represents an appealing therapeutic target due to its beneficial pleiotropic effects in preventing CHD. This review focuses on the genetic basis of cellular cholesterol efflux, the rate-limiting step in HDL biogenesis. There are several monogenic disorders (e.g., Tangier disease, caused by mutations within ABCA1) affecting HDL biogenesis. Importantly, many disorders of cellular cholesterol homeostasis cause a reduced HDL-C. We integrate information from family studies and linkage analyses with that derived from genome-wide association studies (GWAS) and review the recent identification of micro-RNAs (miRNA) involved in cellular cholesterol metabolism. The identification of genomic pathways related to HDL may help pave the way for novel therapeutic approaches to promote cellular cholesterol efflux as a therapeutic modality to prevent atherosclerosis.     

Prevalence of low high-density lipoprotein cholesterol in patients with documented coronary heart disease or risk equivalent and controlled low-density lipoprotein cholesterol

Current guidelines identify low-density lipoprotein (LDL) cholesterol as the primary target for cardiovascular prevention but also recognize low high-density lipoprotein (HDL) cholesterol as an important secondary target. This study was conducted to determine the prevalence of low HDL cholesterol in a contemporary ambulatory high-risk population across various LDL cholesterol levels, including patients taking statins. Screening of 44,052 electronic medical records from a primary care practice identified 1,512 high-risk patients with documented coronary heart disease (CHD) or CHD risk equivalents. Low HDL cholesterol (< or =40 mg/dl in men, < or =50 mg/dl in women) was present in 66% of the 1,512 patients. Low HDL cholesterol was prevalent across all LDL cholesterol levels but most prevalent in patients with LDL cholesterol < or =70 mg/dl (79% vs 66% in those with LDL cholesterol 71 to 100 mg/dl and 64% in patients with LDL cholesterol >100 mg/dl, p <0.01). Low HDL cholesterol was equally and highly prevalent in patients taking statins (67%) and those not taking statins (64%) (p = NS). HDL cholesterol and LDL cholesterol levels correlated poorly (R(2) = 0.01), and this was unaffected by gender or statin treatment. In conclusion, in high-risk patients with CHD or CHD risk equivalents, low HDL cholesterol levels remain prevalent despite statin treatment and the achievement of aggressive LDL cholesterol goals.     

The triglyceride issue: a view from Framingham

Triglycerides make up the overwhelming proportion of dietary fat consumed in the United States and other industrialized nations. Triglyceride elevation is directly associated with relative weight and age in both sexes, oral contraceptive use in women, and the development of diabetes mellitus. Triglyceride elevations are a highly significant independent risk factor for coronary heart disease (CHD) in women. They appear to be important in men with low high-density lipoprotein (HDL) cholesterol (less than 40 ml/dl). Dangerously high levels of triglyceride are associated with a high total cholesterol/HDL cholesterol ratio, which is an excellent indicator of CHD risk in both sexes. Individuals with elevated triglycerides should be considered at risk for CHD unless the total cholesterol/HDL cholesterol ratio is under 3.5. In practice, however, only about 10% of individuals with elevated triglycerides prove to have such low total cholesterol/HDL cholesterol ratios.     

HDL – „Game over“?

The failure of recent clinical trials to improve cardiovascular outcome via pharmacological high density lipoprotein (HDL) cholesterol manipulation and findings that genetically increased concentrations of HDL cholesterol in plasma do not lower the risk of myocardial infarction may question the usefulness of HDL cholesterol as a measure in clinical practice. Cholesteryl ester transfer protein (CETP) inhibition was shown to raise HDL cholesterol levels but the CETP inhibitors torcetrapib and dalcetrapib have shown no clinical benefit. The broad spectrum of lipid-modifying activity of niacin, including HDL cholesterol (HDL), low-density lipoprotein (LDL) cholesterol, triglycerides and lipoprotein (a) did not translate into improved clinical outcome in the AIM-HIGH trial and the HPS2-THRIVE trial. New pharmacological data contribute to explanations why evaluating the effects of the combination of extended release (EC) niacin with the prostaglandin D(2) receptor antagonist laropiprant in the HPS2-THRIVE trial showed no improvement in cardiovascular outcome. That HDL cholesterol is a poor metric for targeted intervention and methodological issues of the trials are parts of the current controversy. It has been established that HDL is heterogeneous and contains particles with different lipid compositions and separate anti-atherosclerotic functions. Low HDL due to genetic mutations in apoA-I, the structural protein of HDL, can be causative in syndromes with premature atherosclerosis. It is known that HDL cholesterol has a role as a marker of a high risk for dyslipoproteinemia; however, HDL function may be a preferable measure in the future. Data from ongoing outcome studies with the newer CETP inhibitors anacetrapib and evacetrapib will be crucial for the future of HDL as an important approach to decreasing cardiovascular morbidity and mortality.     

Efficacy of cholesterol levels and ratios in predicting future coronary heart disease in a Chinese population

In this study, we assessed the efficacy of various lipid and lipoprotein measurements at baseline for predicting the risk for coronary heart disease (CHD) and determined the associated risk of CHD in subgroups stratified by different lipid and lipoprotein screening strategies to evaluate the adequacy of current total and low-density lipoprotein (LDL) cholesterol-based approaches in lipid management. We analyzed data from the Chin-Shan Community Cardiovascular Cohort study, a Chinese population-based prospective cohort study that began in 1990. During an 8-year follow-up period, 213 of 3,159 participants (6.7%) without CHD (aged > or =35 years) developed CHD. The total cholesterol/high-density lipoprotein (HDL) cholesterol ratio was the most powerful lipoprotein predictor of future CHD (hazard ratio 1.21 for a 1.0 increment in ratio; p <0.001). Subjects with "high-risk" LDL cholesterol levels (>160 mg/dl) and low total cholesterol/HDL cholesterol ratios (< or =5) had an incidence of CHD similar to those with low levels of both LDL cholesterol (< or =130 mg/dl) and total cholesterol/HDL cholesterol ratios (4.9% vs 4.6%). In contrast, subjects with "low-risk" LDL cholesterol levels (< or =130 mg/dl) and high total cholesterol/HDL cholesterol ratios (>5) had a 2.5-fold higher incidence of CHD than those with similar LDL cholesterol levels but low total cholesterol/HDL cholesterol ratios (p <0.001). Compared with using an LDL cholesterol level of 130 mg/dl as the cut-off point, using a total cholesterol/HDL cholesterol ratio of 5 was associated with superior specificity (73% vs 59%, p <0.001) and accuracy (72% vs 58%, p <0.001), and similar sensitivity (50% vs 53%). Our data indicate that current guidelines for lipid management may misclassify subjects with high levels of HDL and LDL cholesterol as well as those with low levels of HDL and LDL cholesterol. Using the ratio of total to HDL cholesterol as the initial screening tool can obviate this discrepancy.