高密度脂蛋白胆固醇与葡萄糖代谢临床研究新进展

高密度脂蛋白胆固醇(HDL)水平联系着动脉粥样硬化性心血管疾病的保护作用,过去十年研究表明:它可能还具有抗糖尿病保护作用。HDL将胆固醇从周围组织细胞转运到肝脏代谢清除,常被看作是HDL抗动脉粥样硬化最重要的生理作用,然而,HDL还表现出其他保护作用,包括抑制炎症、氧     

急性脑梗死患者血清高密度脂蛋白和载脂蛋白B含量的联合测定

高密度脂蛋白（HDL）具有抗动脉粥样硬化的作用,被认为是动脉粥样硬化的保护因素,ApoB被认为是动脉粥样硬化的危险因素。研究表明,动脉狭窄程度严重者血清中HDL水平明显降低,而ApoB的含量增高。近年国外文献报道HDL水平降低是75岁以上老年人心肌梗死最重要的危险因素。测定其含量可对动脉粥样硬化、心血管疾病的判断和预测提供有价值的指标,具有重要的诊断和预防意义。     

抗动脉粥样硬化的新靶位─高密度脂蛋白受体SR-BI

B族I型清道夫受体 (SR BI)是惟一确认的高密度脂蛋白 (HDL)受体 ,介导胆固醇逆转运的起始和终止步骤 ,即外周组织中胆固醇的流出和肝脏及类固醇激素生成组织中胆固醇的选择性摄取 ,在胆固醇逆转运中起着关键作用。不同组织中SR BI的表达调控研究表明其对心血管疾病具有明显保护作用 ,可以作为筛选新型抗动脉粥样硬化药物的新型分子靶位或用于动脉粥样硬化的基因治疗。     

高密度脂蛋白胆固醇降低的药物治疗

高密度脂蛋白(HDL)胆固醇降低是冠状动脉粥样硬化性心脏病的重要危险因素。HDL具有潜在的抗动脉粥样硬化活性，介导了由外周细胞到肝脏的逆向胆固醇转运，抑制了低密度脂蛋白(LDL)的氧化、单核细胞向内皮的粘附、血管内皮细胞和平滑肌细胞的凋亡及血小板的活化，刺激了血管活性物质的分泌和平滑肌细胞的增殖。HDL代谢的修饰和逆向胆固醇转运的改善是开发新型抗动脉粥样硬化药物有吸引力的靶点。本文叙述了贝特类、他汀类、烟酸和性激素等药物的临床效应，以及在调节HDL代谢中颇有前景的新型治疗策略。     

两种冠心舒对高密度脂蛋白的影响

<正> 酸性粘多糖类药物-冠心舒具有抗凝血、降血脂、抗炎、保护心肌和预防动脉粥样硬化的药理作用。临床观察证明有缓解冠心病心绞痛和改善心电图的疗效,对缺血性脑血管病也有效应。近年来发现血清高密度脂蛋白(HDL)与动脉粥样硬化症的发生为负相关,它能延缓动脉粥样硬化病变的发生,所以有的学者称HDL为“抗动脉粥样硬化保护因子”。本实验主要探讨冠心舒在Triton WR1339所造成急性高脂血症模型的情况下对HDL的影响。     

高密度脂蛋白升高药物的研发现状

高密度脂蛋白(HDL)在胆固醇逆向转运中所发挥的重要作用,使其在近年来开发动脉粥样硬化性心血管疾病药物中占据着主导性地位.按作用机制分类,开发中的HDL升高药物可分为以下7类:胆固醇酯转移蛋白(CETP)抑制剂、过氧化物酶体增殖因子激活受体(PPARs)激动剂、HDL模拟药物、肝X受体(LXR)激动剂、基因治疗、HDL去脂策略及其他.文中就处于开发阶段的HDL升高药物进行了综述.     

辛伐他汀对实验性高脂血症小鼠高密度脂蛋白的影响

目的:探讨辛伐他汀对动脉粥样硬化(As)形成过程中高密度脂蛋白(HDL)性质及其相关酶活性的影响。方法:喂食高脂饲料建立C57BL/6小鼠高脂血症模型,利用辛伐他汀(20mg.kg-1)给予小鼠灌胃8周,血浆经快速蛋白液相色谱(FPLC)分离后酶法检测各脂蛋白的胆固醇水平,酶法测定HDL相关抗氧化酶对氧磷酯酶1(PON1)和血小板活化因子-乙酰水解酶(PAF-AH)活性。结果:辛伐他汀使C57BL/6高脂模型鼠血清总胆固醇水平降低了34.4%,甘油三酯水平下降60.2%,HDL-C水平仅增高7.8%,但HDL相关的PON1和PAF-AH酶活性明显升高。结论:辛伐他汀不仅能显著改善血脂水平,同时能有效增强HDL的抗氧化能力,表现出较强的抗As作用。     

石家庄地区352例健康人血清高密度脂蛋白—胆固醇正常值分析

高密度脂蛋白-胆固醇(HDL-C)与动脉粥样硬化的关系已引起人们的关注。目前,有人认为 HDL-C 不仅不引起动脉粥样硬化,而且具有抗动脉粥样硬化的作用。国内南京、上海、宁波已有血清 HDL-C 正常值报告,而北方地区则报告甚少。本文就石家庄地区健康人群HDL-C 的水平做了调查,报告于下。     

理性看待高密度脂蛋白

由于新药toreetrapib的临床研究未获预期结果 ,以及残存心血管危险性这一概念的提出,近年人们再次对高密度脂蛋白(HDL)及高密度脂蛋白-胆固醇(HDL-C)给予高度关注.研究提示,在关注HDL-C水平的同时,不能忽视HDL的功能状态.目前最有效和安全的升高HDL-C水平的方法 还是生活方式调节,主要包括锻炼、减轻体重和戒烟等.     

高密度脂蛋白胆固醇低下与心血管疾病及其药物干预

高密度脂蛋白胆固醇(HDL-C)低下是心血管疾病的独立危险因素,HDL-C≤40mg／dL者冠心病发病率增加。HDL—C≥60mg／dL具有心血管保护效益,对HDL-C低下合并多重危险因素及冠心病等危症患者。改变生活方式和使用调血脂药物干预,可以降低心血管相关事件的发生率与患者死亡率。     

Clinical Practices in the Treatment of Arterial Hypertension in Portugal

The inverse correlation between high-density lipoprotein (HDL) levels and cardiovascular disease has driven several investigators to target the increase in this lipoprotein to prevent atherosclerosis and its complications. However, many reports have demonstrated that the use of HDL cholesterol (HDL-C) levels as a means to prevent and treat atherosclerosis has mainly resulted in negative outcomes. These findings may help to increase our knowledge of HDL metabolism and its protective effect. There is evidence that the mechanism by which HDL-C levels are raised has a great impact on cardiovascular outcomes. When the increase in HDL-C levels is secondary to greater synthesis, a strong beneficial effect in the prevention of cardiovascular diseases is observed. Even small increases in HDL-C levels induce a marked reduction in cardiovascular events; this has been observed during treatment with fibrates. In contrast, when the increase in HDL-C levels is secondary to a reduction in HDL catabolism, unexpectedly, the opposite effects are usually noted. Even dramatic increases in HDL-C levels are not associated with better cardiovascular outcomes. In fact, these increases have been related to a greater number of cardiovascular-related deaths. This became clear from the results of trials that tested inhibitors of cholesteryl ester transfer protein (CETP). We suggest that increases in reverse cholesterol transport are more important than HDL-C levels. Strong evidence is provided by individuals that express apolipoprotein (apo)A-I Milano. These individuals have extremely low HDL-C levels due to greater catabolism of the lipoprotein. However, reverse cholesterol transport is increased in these individuals and, as a consequence, they have a low incidence of cardiovascular diseases. We reinforce that, in clinical practice, the currently recommended levels of HDL-C should still be a major target to be aimed for. However, in the research field, we emphasize the need to look for other methods to improve reverse cholesterol transport, irrespective of HDL-C levels.     

The potential for CETP inhibition to reduce cardiovascular disease risk

ABSTRACT

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.

Objectives: This paper reviews the evidence for an atheroprotective role of higher levels of HDL‐C, the function of CETP in cholesterol metabolism, and the concept of CETP inhibition as a potential new strategy for decreasing cardiovascular risk. An analysis of clinical studies of CETP inhibition was also performed.

Methods: MEDLINE (1966 to June 2006), EMBASE (1974 to June 2006), and cardiology conference proceedings were searched for clinical trials of CETP inhibition.

Results: Thirteen reports involving vaccine-based and pharmacological inhibition of CETP were found. Modest and inconsistent elevation of HDL‐C was observed with vaccine-based therapy, whereas HDL-C elevation with pharmacological inhibitors was greater and more consistent.

Conclusions: Elevation of HDL‐C via CETP inhibition appears to be a potentially promising approach to reduce cardiovascular disease. Preliminary studies suggest benefits of CETP inhibition on serum lipid levels, and ongoing studies should establish the effects on atherosclerosis and cardiovascular events.     

Emerging options in the treatment of dyslipidemias: a bright future?

INTRODUCTION: Hypercholesterolemia is a major risk factor for cardiovascular disease (CVD). Low-density lipoprotein cholesterol (LDL-C) reduction has been demonstrated to decrease CVD-related morbidity and mortality. However, several patients do not reach LDL-C target levels with the currently available lipid lowering agents, particularly statins. Lipid and non-lipid parameters other than LDL-C may account for the residual CVD risk after adequate LDL-C lowering with statins. AREAS COVERED: This review focuses on the efficacy and safety of emerging drugs aiming at high-density lipoprotein cholesterol (HDL-C) elevation (i.e., recombinant or plasma-derived wild-type apolipoprotein (apo) A-I, apo A-I mimetic peptides, reconstituted mutant HDL, partially delipidated HDL and cholesterol ester transfer protein inhibitors), microsomal triglyceride transfer protein inhibitors and antisense oligonucleotides. EXPERT OPINION: Several lipid modifying agents in development may potently reduce the residual CVD risk. Ongoing and future studies with clinical outcomes will clarify their efficacy in clinical practice.     

HDL as a target in the treatment of atherosclerotic cardiovascular disease

Lipid abnormalities are among the key risk factors for cardiovascular disease. Indeed, lipid-modifying drugs - in particular, the statins, which primarily lower plasma levels of low-density lipoprotein (LDL) cholesterol - considerably reduce the risk of cardiovascular events, leading to their widespread use. Nevertheless, it seems that there might be limits to the degree of benefit that can be achieved by lowering LDL-cholesterol levels alone, which has led to increased interest in targeting other lipid-related risk factors for cardiovascular disease, such as low levels of high-density lipoprotein (HDL) cholesterol. In this article, we first consider the mechanisms that underlie the protective effect of HDL cholesterol, and then discuss several strategies that have recently emerged to increase levels of HDL cholesterol to treat cardiovascular disease, including nuclear receptor modulation, inhibition of cholesteryl ester transfer protein and infusion of apolipoprotein/phospholipid complexes.     

HDL-cholesterol: is it really good? Differences between apoA-I and HDL

Since the very first report showing the regression of established atherosclerotic lesions by means of high-density lipoprotein cholesterol (HDL-C) plasma fraction, much information has been generated about the protective role of HDL-C in atherosclerosis. Nonetheless, this positive point of view about HDL has been nearly surpassed since modern informations concerning torcetrapib have appeared. Disappointment was palpable when its pivotal morbidity-and-mortality clinical trial, ILLUMINATE, was abruptly stopped due to excess mortality amongst the group randomized to receive torcetrapib. In this work we will try to put things in perspective. Lowering low-density lipoprotein cholesterol (LDL-C) levels with statins is a proven strategy for reducing the cardiovascular disease (CVD) risk. Despite the impressive benefits of statins, there remain a significant proportion of treated patients in which cardiovascular events are not prevented. Low HDL-C levels are an important independent risk factor for CVD. There is a need to develop suitable therapies to reduce this residual risk through HDL-C related mechanisms. Therefore, we will first review HDL-C pathways and we will subsequently state the new pharmacological approaches to HDL-C metabolism.     

Is raising HDL a futile strategy for atheroprotection?

The dramatic failure of clinical trials evaluating the cholesterol ester transfer protein inhibitor torcetrapib has led to considerable doubt about the value of raising high-density lipoprotein cholesterol (HDL-C) as a treatment for cardiovascular disease. These results have underscored the intricacy of HDL metabolism, with functional quality perhaps being a more important consideration than the circulating quantity of HDL. As a result, HDL-based therapeutics that maintain or enhance HDL functionality warrant closer investigation. In this article, we review the complexity of HDL metabolism, discuss clinical-trial data for HDL-raising agents, including possible reasons for the failure of torcetrapib, and consider the potential for future HDL-based therapies.     

Modulation of high-density lipoprotein cholesterol metabolism and reverse cholesterol transport

Low high-density lipoprotein (HDL)-cholesterol (C) is an important risk factor for coronary heart disease. In vitro, HDL exerts several potentially anti-atherogenic effects including reverse cholesterol transport (RCT) from peripheral cells to the liver. Hence, raising HDL-C has become an interesting target for anti-atherosclerotic drug therapy. Levels of HDL-C and the composition of HDL subclasses in plasma are regulated by apolipoproteins, lipolytic enzymes, lipid transfer proteins, receptors, and cellular transporters. The interplay of these factors leads to RCT and determines the composition and thereby the anti-atherogenic properties of HDL. Recent findings suggest that the mechanism of HDL modification rather than a sole increase in HDL-C determines the efficacy of anti-atherosclerotic drug therapy. In several controlled and prospective intervention studies, patients with low HDL-C and additional risk factors benefited from treatment with fibrates or statins. However, in only some of the fibrate trials was prevention of coronary events in patients with low HDL-C and hypertriglyceridaemia related to an increase in HDL-C. This may be because currently available drugs increase HDL-C levels only moderately and because HDL levels per se do not necessarily correlate with the functionality of HDL. However, several novel targets to modify RCT have emerged from the recent understanding of HDL synthesis, maturation and catabolism. The four major targets for an anti-atherogenic strategy in HDL metabolism include stimulation of apoA-I synthesis and secretion, the stimulation of ABCA1 expression, the inhibition of cholesterol ester transfer protein, and the up-regulation of scavenger receptor BI. These and other modulations of HDL metabolism are thought to result in improved RCT making them attractive targets for the development of new regimens of anti-atherogenic drug therapy.     

Significance of High Density Lipoprotein-Cholesterol in Cardiovascular Risk Prevention

In the approach to lipid-related risk factors for cardiovascular diseases, serum high density lipoprotein-cholesterol (HDL-C) levels bear a particular significance as this lipoprotein is considered to be an antiatherogenic factor mainly, but not only, because of its influence and impact on reverse cholesterol transport. Hence the need and requirement to consider serum HDL-C levels for both primary and secondary prevention of cardiovascular disease. A particularly important aspect is the association of the 'low HDL syndrome' with the metabolic syndrome. These factors force us to consider serum HDL-C level as a therapeutic target by itself, or even in association with low density lipoprotein-cholesterol (LDL-C) levels when the latter are increased. This review stresses the aspects connecting serum HDL-C levels and cardiovascular risk, and looks at the populations that should be considered amenable to therapeutic management because of low serum HDL-C levels. We review therapeutic strategies, both pharmacological and nonpharmacological. The aim of this review is to present therapeutic management recommendations for correcting the proportion of cardiovascular risk that is attributable to changes in HDL-C. Serum HDL-C levels of >40 mg/dL must be a therapeutic target in primary and secondary prevention. This goal is particularly important in patients with low serum HDL-C levels and ischemic heart disease (IHD) or its equivalents, even if the therapeutic target for serum LDL-C levels (<100 mg/dL) has been achieved. The first choice for this clinical condition is fibric acid derivates. The same therapeutic option should be considered in patients without IHD with low serum HDL-C levels and high cardiovascular risk (>20%), hypertriglyceridemia, type 2 diabetes mellitus, or metabolic syndrome.     

Investigational CETP antagonists for hyperlipidemia and atherosclerosis prevention

INTRODUCTION: Reverse cholesterol transport (RCT) is a function of high-density lipoproteins (HDL) in humans and higher species. It is enabled by the cholesteryl ester transfer protein (CETP), a high molecular weight protein exchanging cholesteryl esters in HDL for triglycerides in very low-density lipoproteins (VLDL). Inhibition of CETP may provide a useful strategy to raise HDL, the protective lipoprotein fraction in plasma. AREAS COVERED: Evaluation based on clinical and experimental findings of the three drugs developed or in advanced development for CETP inhibition. EXPERT OPINION: Inhibition of CETP, both inherited and drug induced, at times leads to dramatic elevations of HDL-cholesterol (HDL-C) levels. Epidemiological data presently available do not, however, provide convincing evidence that reduced CETP levels or activity due to genetic factors and associated with HDL-C elevations, reduce cardiovascular risk. Indeed, the opposite may be true in some instances. All the three CETP inhibitors were the object of experimental and clinical evaluation. Large clinical trials with torcetrapib led to very negative findings, that is, raised cardiovascular morbidity and mortality in addition to raised risk of cancer and sepsis. Off-target effects of the drug, such as aldosterone retention and raised blood pressure, were believed to provide an explanation for these negative findings. The two newer agents, dalcetrapib and anacetrapib, do not exert off-target effects. The two drugs differ because anacetrapib has a more dramatic effect on HDL cholesterolemia (+139%) versus more moderate effects of dalcetrapib (+20-30%). Anacetrapib, however, may impair formation of pre-β HDL, that is, the primary particles in the process of cholesterol removal. The initial large trial with anacetrapib (DEFINE study) in coronary patients on statin treatment, appeared to confirm a remarkable HDL raising property, together with some reduction in vascular end points, in particular coronary procedures. The issue of other potentially harmful effects of CETP inhibition (sepsis and others) has yet to be clarified. Large clinical end-point trials, however, will be necessary to provide convincing evidence that, in addition to raising HDL-C, CETP inhibitors provide a valid additional treatment, for example, to statins in patients with coronary heart disease (CHD) or at high risk of CHD.