Targeting high-density lipoprotein cholesterol in the management of cardiovascular disease

The association between low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol and the development of coronary heart disease (CHD) is well established. The management of CHD has traditionally focused on the reduction of LDL cholesterol or on the total lipid profile. Yet, treatment strategies for reducing risk in CHD also requires a focus on increasing low HDL cholesterol, as LDL cholesterol reduction alone is insufficient in preventing CHD events. This article reviews the strategies for targeting HDL cholesterol to optimize outcomes in CHD.     

The evolving role of high-density lipoprotein in reducing cardiovascular risk

In many patients with coronary artery disease, a low level of high-density lipoprotein cholesterol (HDL-C), rather than substantially elevated lowdensity lipoprotein cholesterol (LDL-C), is often the predominant lipid abnormality. Although the National Cholesterol Education Program treatment guidelines include HDL-C concentration as a major risk factor for primary prevention, the guidelines' emphasis on LDL-C as the primary target of therapy may cause uncertainty as to whether risk reduction strategies should focus on lowering LDL-C or raising HDL-C in high-risk patients with low HDL-C. Recent clinical trial evidence and epidemiologic data suggest that HDL-C should play a more important role in risk assessment, and that the definition of low HDL-C may need adjustment from the current National Cholesterol Education Program definition of <35 mg/dL to perhaps <40 mg/dL in men and <45 mg/dL in women. Patients with low HDL-C should receive aggressive risk factor modification, and more emphasis on increasing HDL-C may be warranted in addition to lowering LDL-C.     

Use of the plasma triglyceride/high-density lipoprotein cholesterol ratio to identify cardiovascular disease in hypertensive subjects

This analysis evaluated the hypothesis that the plasma triglyceride (TG)/high–density lipoprotein cholesterol (HDL-C) concentration ratio can help identify patients with essential hypertension who are insulin–resistant, with the cardiovascular disease (CVD) risk profile associated with that defect. Data from a community–based study developed between 2003 and 2012 were used to compare CVD risk factors and outcome. Plasma TG/HDL-C cut–points of 2.5 (women) and 3.5 (men) subdivided normotensive (n = 574) and hypertensive (n = 373) subjects into “high” and “low” risk groups. Metabolic syndrome criteria (MetS) were also used to identify “high” and “low” risk groups. The baseline cardio–metabolic profile was significantly more adverse in 2003 in “high” risk subgroups, irrespective of BP classification or definition of risk (TG/HDL-C ratio vs. MetS criteria). Crude incidence of combined CVD events increased across risk groups, ranging from 1.9 in normotensive–low TG/HDL-C subjects to 19.9 in hypertensive–high TG/HDL-C ratio individuals (P for trends <.001). Adjusted hazard ratios for CVD events also increased with both hypertension and TG/HDL-C. Comparable findings were seen when CVD outcome was predicted by MetS criteria. The TG/HDL-C concentration ratio and the MetS criteria identify to a comparable degree hypertensive subjects who are at greatest cardio–metabolic risk and develop significantly more CVD.     

The cholesterol mobilizing transporter ABCA1 as a new therapeutic target for cardiovascular disease

Atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality in Western societies. A hallmark of the developing atherosclerotic lesion is the appearance of cholesterol-laden macrophages in the artery wall. A cell membrane transporter called ABCA1 mediates the removal of excess cholesterol from macrophages into the lipoprotein pathway. This makes ABCA1 a promising new therapeutic target for reducing cholesterol deposits in tissues, eliminating excess cholesterol from the body, and preventing cardiovascular disease.     

高密度脂蛋白与心血管保护的研究进展

多项大规模临床研究显示,血清高密度脂蛋白(HDL)的水平与冠心病存在着密切的联系。HDL胆固醇对心血管的保护作用,体现在可介导胆固醇逆向转运、抗氧化作用、调节内皮功能、抗炎及影响凝血系统等。本文对HDL的结构和代谢进行了回顾,并对其心血管保护作用的新进展进行了综述。     

Serum high-density lipoprotein-cholesterol levels modify the association between plasma levels of oxidatively modified low-density lipoprotein and coronary artery disease in men

We investigated the association among plasma levels of oxidatively modified low-density lipoprotein (Ox-LDL), high-density lipoprotein-cholesterol (HDL-C), and the prevalence of coronary artery disease (CAD) in a case-control study. Cases (n = 183, male [M]/female [F]:138/45, age: 64.9 +/- 10.6 years) were defined as patients with angiographically proven coronary atherosclerosis (>/=50% stenosis) and controls were subjects with normal coronary arteries (n = 74, M/F:36/38, age: 57.6 +/- 14.4 years). Plasma Ox-LDL levels were measured by a sensitive detection method using the monoclonal antibody DLH3. In women, both Ox-LDL and lipid variables were similar between cases and controls. In men, cases had significantly lower (P <.05) levels of HDL-C (39.1 +/- 10.3 v 42.8 +/- 10.9 mg/dL) and apolipoprotein (apo) A-I than controls, while the difference in Ox-LDL between cases and controls was not significant (1.05 +/- 0.79 and 0.83 +/- 0.65 ng/10 microg LDL protein, respectively). However, HDL-C levels interacted with the association between Ox-LDL levels and CAD in males: increased Ox-LDL levels were significantly associated with CAD after controlling for age when HDL-C levels were high, but were not associated with CAD when HDL-C levels were low, as assessed by a multiple logistic regression analysis. In addition, the combination of HDL-C and Ox-LDL levels was a better indicator for CAD in males than HDL-C levels alone (-2 log likelihood, 24.1 v 19.4) after controlling for age and conventional risk factors of CAD, while Ox-LDL levels were not significantly associated with CAD. HDL-C levels interact with the association between plasma Ox-LDL levels and CAD in men, and increased Ox-LDL levels are an indicator of CAD in male subjects with high HDL-C levels.     

Associations between serum high-density lipoprotein cholesterol or apolipoprotein AI levels and common genetic variants of the ABCA1 gene in Japanese school-aged children

ATP-binding cassette transporter A1 (ABCA1) plays an important role in apolipoprotein AI (apoAI)-mediated cholesterol efflux from peripheral cells. The mild changes in ABCA1 activity due to genomic variation might be associated with interindividual variations in serum high-density lipoprotein cholesterol (HDL-C) and apoAI levels, or primary hypoalphalipoproteinemia in the general population. In the present study, we analyzed the relationships between 5 single nucleotide polymorphisms (SNPs) and 2 insertion/deletion polymorphisms in the 5' flanking region and 5 missense polymorphisms of the ABCA1 gene and serum lipid levels in healthy school-aged children. We detected significant associations between the K219R and V771M polymorphisms, and HDL-C or apoAI levels. The present data support the proposition that the K219 allele is an anti-atherogenic allele with increased cholesterol efflux activity. Similarly, the M771 allele appears to be anti-atherogenic, although the frequency of the M771 allele is low.     

Influence of high-density lipoprotein cholesterol and rheological factors on the sex difference in cardiovascular disease

BACKGROUND: It is well established that the incidence of cardiovascular disease among men is higher than that among women. OBJECTIVE: To determine whether differences between men and women in terms of a range of conventional and rheological risk factors could explain this sex difference. DESIGN: This was a population-based cohort study (the Edinburgh Artery Study). METHODS: Men and women aged 55-74 years (n = 1592) were selected at random from the general population of Edinburgh and followed up for 5 years. Baseline cardiovascular risk factors were measured and related to incidence of disease among men and women. RESULTS: Men had higher levels of cigarette smoking, haematocrit and blood viscosity and lower levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and plasma fibrinogen than did women. The incidences of cardiovascular events among men and women were 48.3 and 26.1 per 1000 person-years, respectively. Adjustment for level of HDL cholesterol reduced the male:female ratio for sex-specific incidence rates of cardiovascular events from 1.80 [95% confidence interval (CI) 1.43-2.27] to 1.34 (95% CI 1.04-1.73). This reduction was partially reversed after further adjustment for the other cardiovascular risk factors. The impact of blood viscosity, plasma viscosity and plasma level of fibrinogen on the risk of cardiovascular disease was higher for men than it was for women (multivariate relative risk for blood viscosity were 1.24, 95% CI 1.08-1.43, for men and 0.81, 95% CI 0.61-1.06, for women). CONCLUSIONS: Levels of HDL cholesterol levels in women being higher than those in men may explain some, but not all, of the sex difference in incidence of cardiovascular disease. Greater susceptibility of men to rheological factors might also be important.     

Regulation of plasma low density lipoprotein levels in postmenopausal women

To study the regulation of plasma low density lipoprotein (LDL) cholesterol in postmenopausal women (n = 79), fasting plasma lipids and lipoproteins, the fractional catabolic rate (FCR) and production rate for LDL apolipoprotein B (apo B), cholesterol absorption, apolipoprotein E phenotype and polymorphisms of the apo B and 7alpha-hydroxylase genes were determined. The level of LDL cholesterol was related to FCR (r= -0.757, P < 0.001) and the production (r= 0.531, P < 0.001) of LDL apo B and body mass index (r = 0.265, P <0.05). In contrast, cholesterol absorption efficiency, apolipoprotein E phenotype, EcoRI and XbaI polymorphisms of the apo B gene and the polymorphism of 7alpha-hydroxylase gene were found to have no significance for the regulation of LDL cholesterol concentration in these postmenopausal women.     

Reduced plasma high-density lipoprotein cholesterol in hyperthyroid mice coincides with decreased hepatic adenosine 5'-triphosphate-binding cassette transporter 1 expression

The aim of the study was to investigate the influence of severe hyperthyroidism on plasma high-density lipoprotein cholesterol (HDL-C). Recently, it was shown in mice that increasing doses of T(3) up-regulate hepatic expression of scavenger receptor class B, type I, resulting in increased clearance of plasma HDL-C. Here, we show that severe hyperthyroidism in mice did not affect hepatic expression of scavenger receptor class B, type I, but reduced hepatic expression of ATP-binding cassette transporter 1, accompanied by a 40% reduction of HDL-C. The sterol content of bile, liver, and feces was markedly increased, accompanied by up-regulation of hepatic cholesterol 7alpha-hydroxylase, and ATP-binding cassette transporter 5, which is known to promote biliary sterol secretion upon dimerization with ATP-binding cassette transporter 8. Both control and hyperthyroid mice exerted identical plasma clearance of iv injected [(3)H]HDL-C, supporting the view that severe hyperthyroidism does not affect HDL-C clearance but, rather, its formation via hepatic ATP-binding cassette transporter 1.     

Low high-density lipoprotein cholesterol and cardiovascular disease: risk reduction with statin therapy

A low level of high-density lipoprotein cholesterol (HDL-C) is a major risk factor for cardiovascular disease; however, patients with low levels of HDL-C without raised low-density lipoprotein cholesterol (LDL-C) levels are not currently eligible for lipid-lowering therapy. Many individuals with low levels of HDL-C have a combination of cardiovascular risk factors that include high LDL particle concentrations. Lowering LDL particle concentration and its surrogate measure, LDL-C, is an important approach to reducing cardiovascular risk. Statins are the most effective agents for lowering levels of LDL and can significantly increase levels of HDL-C. Extending statin therapy to patients with low levels of HDL-C but with LDL-C levels below target may have benefits for cardiovascular disease reduction in these patients.     

The role of high-density lipoprotein in inflammation

High-density lipoprotein (HDL) appears to have evolved as part of the innate immune system, which in part uses an enhanced oxidative state as a nonspecific means of protecting against many pathogens. In the absence of acute or chronic inflammation, HDL is anti-inflammatory in mice, rabbits, and humans. However, with the onset of a systemic inflammatory state such as what occurs in atherosclerosis, HDL becomes pro-inflammatory, enhancing the inflammatory response. The major apolipoprotein of HDL is apoA-I, which may be altered by oxidative processes in patients with atherosclerosis. As a result, HDL from such patients is less efficient in promoting cellular cholesterol efflux. The ability of HDL to inhibit the inflammatory properties of oxidized phospholipids and low-density lipoproteins is also significantly altered. In mice and monkeys, the administration of an apoA-I-mimetic peptide renders pro-inflammatory HDL anti-inflammatory, improves HDL-mediated cellular cholesterol efflux; in mice, it dramatically inhibits atherosclerosis. Understanding the role of HDL in inflammation may lead to new diagnostic and therapeutic approaches to atherosclerosis and other inflammatory conditions.     

An emerging role for the miR-26 family in cardiovascular disease

In response to acute myocardial infarction (MI), a complex series of cellular and molecular signaling events orchestrate the myocardial remodeling that ensues weeks to months after injury. Clinical, epidemiological, and pathological studies demonstrate that inadequate or impaired angiogenesis after myocardial injury is often associated with decreased left ventricular (LV) function and clinical outcomes. The microRNA family, miR-26, plays diverse roles in regulating key aspects of cellular growth, development, and activation. Recent evidence supports a central role for the miR-26 family in cardiovascular disease by controlling critical signaling pathways, such as BMP/SMAD1 signaling, and targets relevant to endothelial cell growth, angiogenesis, and LV function post-MI. Emerging studies of the miR-26 family in other cell types including vascular smooth muscle cells, cardiac fibroblasts, and cardiomyocytes suggest that miR-26 may bear important implications for a range of cardiovascular repair mechanisms. This review examines the current knowledge of the miR-26 family’s role in key cell types that critically control cardiovascular disease under pathological and physiological stimuli.