High-density lipoprotein therapeutics and cardiovascular prevention

The field of cardiovascular prevention has long anticipated the evolution of high-density lipoprotein (HDL) therapy from unproven metabolic tweaking to pillar of risk reduction on par with low-density lipoprotein control. However, the convincing epidemiologic data linking HDL cholesterol (HDL-C) and cardiovascular disease risk in an inverse correlation has not yet translated into clinical trial evidence supporting linearity between HDL-C increases and risk reduction, or identifying obvious goals of therapy. Although HDL-C-increasing lifestyle maneuvers and established HDL drugs such as niacin and fibrates are likely to protect the vasculature, the negative results obtained in trials of a cholesteryl ester transfer protein inhibitor remind us that HDL-C increases are not always beneficial. It is becoming clear that a functional HDL is a more desirable target than simply increasing HDL-C levels. The larger objective of improving HDL functionality (with or without HDL-C level changes) is bound to become the guiding principle for pharmaceutical research in this area. Several new compounds currently being tested bridge the classical aim of increasing HDL-C levels with the novel target of improving HDL function.     

WWOX gene is associated with HDL cholesterol and triglyceride levels

Background  

Altered lipid profile, and in particular low HDL and high triglyceride (TG) plasma levels, are within the major determinants of cardiovascular diseases. The identification of quantitative trait loci (QTL) affecting these lipid levels is a relevant issue for predictive purposes. The WWOX gene has been recently associated with HDL levels. This gene is located at chromosome 16q23, a region previously linked to familial combined hyperlipidemia (FCHL) and HDL. Our objective is to perform a genetic association analysis at the WWOX gene region with HDL, TG and TG/HDL ratio.     

Hyperlipidemia in chronic kidney disease

The risk of cardiovascular events and mortality increases as renal function declines. The standard Framingham risk factors contributing to the relative risk of mortality (RRM) are altered or replaced. While obesity predicts loss of renal function, among dialysis patients obesity predicts survival rather than mortality. Among dialysis patients, Low Density Lipoprotein cholesterol (LDL) does not predict mortality; however other risk factors, such as low High Density Lipoprotein cholesterol (HDL) and increased intermediate density lipoproteins (IDL), remain cardiovascular risk factors. While HDL levels are decreased as a result of an increased fractional catabolic rate (FCR) both among obese patients with normal renal function and among dialysis patients, the mechanisms responsible for increased HDL FCR may differ. In patients with advanced kidney disease, HDL fails to mature normally as a result of decreased lecithin cholesterol ester transfer protein (LCAT), leaving cholesterol ester-poor, triglyceride (TG)-rich HDL3 and pre-beta-HDL. Chronic kidney disease (CKD) is associated with insulin resistance, providing another potential mechanistic link to low HDL levels. Increased TG levels are found in an expanded Intermediate Density Lipoprotein (IDL) pool and are associated with mortality risk. Lipoprotein (a) (LP(a)) levels are increased. In patients without renal disease, the concentration of Lp(a) is inversely associated with the size of the apo (a) isoform inherited; Lp (a) levels are increased in patients with kidney disease as consequence of increased concentrations, primarily of the high molecular weight isoform resulting from decreased clearance. Lp (a) levels are also associated with cardiovascular outcome among dialysis patients.     

JCL roundtable: High-density lipoprotein function and reverse cholesterol transport

High-density lipoproteins (HDL) have been known since the 1960s to be associated with protection from atherosclerotic cardiovascular disease. However, the mechanisms of this protection are unclear. The extent to which HDL per se vs other correlated metabolic factors may mitigate atherosclerosis has been seriously questioned. In fact, new epidemiologic studies have found that in some clinical settings, very high HDL cholesterol levels correlate with increased atherosclerotic risk. Most importantly, over the past 2 decades, randomized clinical trials targeting HDL have failed to reproduce the usual epidemiologic inverse relation of HDL cholesterol to atherosclerotic events. In this roundtable discussion, we bring together 3 expert investigators working in the HDL field to elucidate questions of HDL function. One area of agreement is that reverse cholesterol transport remains a primary hypothesis for an anti-atherogenic role of HDL. Bioassays that measure cholesterol efflux capacity of HDL (or of apolipoprotein [apo] B-depleted plasma) have emerged as potentially accurate surrogates for reverse cholesterol transport. ApoA-I is the major functional apoprotein of HDL, but apoE- and apoC-III-containing subpopulations of HDL may have significant roles. Anti- and pro-inflammatory functions of various HDL particles, as well as the role of oxidative and other modifications, are gaining attention.     

Atherosclerosis and metabolic disease

Cholesterol plays an important role in atherogenesis. Cholesterol-ester that has been carried by circulating low-density lipoprotein particles accumulates in the atherosclerotic plaque. Statins are considered the most potent and effective agents for reducing low-density lipoprotein cholesterol and the incidence of cardiovascular events. Total cholesterol and LDL cholesterol levels, however, are not always a useful marker for distinguishing patients with or without cardiovascular disease. Low levels of high-density lipoprotein cholesterol are the most predictive marker for cardiovascular disease. Low HDL cholesterol levels originate in some genetic and acquired diseases and conditions. Most cases of low HDL cholesterol associated with the development of atherosclerosis are of secondary origin, especially those associated with increasing triglyceride-rich lipoprotein. These conditions are present in insulin-resistant syndrome, namely metabolic syndrome. Type 2 diabetes mellitus and the closely related metabolic syndrome are associated with a significant risk for cardiovascular disease. Recent evidence suggests that both conditions are increasing in epidemic proportions. Dyslipidemia is characterized by increased triglyceride-rich lipoproteins; low high-density lipoprotein cholesterol; small, dense low-density lipoprotein particles; and increased postprandial lipemia. All these lipoprotein disturbances accelerate atherosclerosis. It is likely that many patients will need lipid-modifying therapy to help prevent cardiovascular disease.     

Systemic lupus erythematosus and "lupus dyslipoproteinemia"

A growing body of evidences reinforces the close link between systemic lupus erythematosus (SLE) and atherosclerosis which is due to traditional and nontraditional risk factors for cardiovascular diseases. It is now recognized that SLE has a particular pattern of dyslipoproteinemia characterized by low HDL levels and increased triglycerides, which is aggravated by flares. Multiple mechanisms can induce an altered lipoprotein metabolism in SLE such as cytokines produced during systemic inflammation, autoantibodies and therapy.     

Serum zinc and copper in hypercholesterolemia

For some authors, absolute or relative copper deficiency, with an elevated plasmatic zinc/copper ratio, could be a risk factor in the etiology of cardiovascular diseases by altering lipid metabolism. Animal or human studies carried out with zinc and/or copper supplemented or deficient diets on biochemical lipid parameters, led to inconsistent results. Nevertheless, no study was already done in hypercholesterolemic patients, concerning possible correlation between serum levels of these trace elements and cholesterol, HDL cholesterol and apolipoprotein B blood levels. 67 patients were distributed in three groups according to their hypercholesterolemia. The serum copper concentration was elevated, serum zinc concentration and zinc/copper ratio were decreased in the hypercholesterolemic group (cholesterol greater than 7.7 mmol/l). Serum zinc, copper and zinc/copper ratio were significantly correlated with HDL cholesterol (respectively r = + 0.56 p less than 0.05, r = - 0.68 p less than 0.01, r = + 0.76 p less than 0.001).     

Racial differences in plasma high-density lipoproteins in patients receiving hemodialysis. A possible mechanism for accelerated atherosclerosis in white men

Among 346 nondiabetic patients receiving long-term hemodialysis, cardiovascular mortality was higher in white than in black men (P less than 0.02) but was similar between black and white women, despite the higher incidence of nephrosclerosis in black men and women (59 and 58 per cent vs. 8 and 10 per cent, respectively; P less than 0.0001). There were significant racial differences in plasma lipid and apoprotein levels in a subset of 100 of these patients. The white men had higher levels of plasma triglyceride and lower levels of high-density-lipoprotein (HDL) cholesterol, apoprotein A-I, and apoprotein A-II than black men; concentrations of HDL, apoprotein A-I, and apoprotein A-II were also lower in white than in black women. The distribution of the HDL subfractions HDL2, HDL3, and HDL3D, as determined by zonal ultracentrifugation, was normal in black and abnormal in white men receiving hemodialysis. HDL2 concentrations were higher in black than in white men by both zonal analysis (P less than 0.05) and polyanionic precipitation of the HDL subfractions (P less than 0.01). The distributions and concentrations of HDL2 and HDL3L were similar in black and white women. Thus, there are marked racial differences in HDL in male patients receiving hemodialysis. The abnormalities in HDL and the hypertriglyceridemia in the white men may explain their high rate of cardiovascular mortality.     

S1P1 and S1P3 are potential markers of cardiac microangiopathy in diabetes

The prevalence of diabetes is rising rapidly throughout the world, accompanying with the increased occurrence of cardiovascular diseases in clinic. For now, the diagnosis of diabetic cardiovascular diseases has mainly based on the measurement of glucose levels in blood and cardiac function via electrocardiogram and ultrasound cardiogram. However, growing evidence strongly suggests that the assessment of Sphingosine-1-phosphate receptor 1/3 (S1P1/3) own advantages over present measurements in predicting the risk of developing diabetic cardiovascular diseases. This hypothesis may provide concept foundation for improving early diagnosis of cardiac microangiopathy in diabetes.     

高密度脂蛋白-内皮型一氧化氮合酶信号通路在心血管系统中的作用及其影响因素的研究进展

<正>大量的流行病学研究表明,高密度脂蛋白(highdensity lipoprotein,HDL)水平与心血管疾病的患病风险呈负相关,但是HDL在机体内行使保护功能的详细机制尚不清楚~([1])。除了HDL介导的胆固醇逆向转运外,HDL还具有其它多重功能,如抗炎、促进一氧化氮(nitric oxide,NO)合成和促进内皮修复的作用,近来越来越多的研究聚焦于HDL介导的细胞信     

High-density lipoproteins: A consensus statement from the National Lipid Association

For >4 decades it has been recognized that elevated serum levels of high-density lipoprotein cholesterol (HDL-C) are associated with reduced risk of cardiovascular disease (CVD) and its sequelae. Many prospective observational studies performed around the world have confirmed an inverse relationship between HDL-C and cardiovascular risk in people irrespective of sex, race, or ethnicity. Consequently, it was assumed that, by extension, raising HDL-C through lifestyle modification and pharmacologic intervention would reduce risk of CVD. Animal studies are consistent with this assumption. Lipid treatment guidelines around the world promoted the recognition of HDL-C as a therapeutic target, especially in high-risk patients. Some post hoc analyses from randomized controlled trials also suggest that raising HDL-C beneficially affects the risk of CVD. However, a number of recent randomized studies putatively designed to test the “HDL hypothesis” have failed to show benefit. The results of these trials have caused many clinicians to question whether HDL-C is a legitimate therapeutic target. In response to the many questions and uncertainties raised by the results of these trials, the National Lipid Association convened an expert panel to evaluate the current status of HDL-C as a therapeutic target; to review the current state of knowledge of HDL particle structure, composition, and function; and to identify the salient questions yet to be answered about the role of HDL in either preventing or contributing to atherosclerotic disease. The expert panel's conclusions and clinical recommendations are summarized herein. The panel concludes that, although low HDL-C identifies patients at elevated risk, and much investigation suggests that HDL may play a variety of antiatherogenic roles, HDL-C is not a therapeutic target at the present time. Risk stratified atherogenic lipoprotein burden (low-density lipoprotein cholesterol and non–HDL-C) should remain the primary and secondary targets of therapy in patients at risk, as described by established guidelines. The National Lipid Association emphasizes that rigorous research into the biology and clinical significance of low HDL-C should continue. The development of novel drugs designed to modulate the serum levels and functionality of HDL particles should also continue. On the basis of an enormous amount of basic scientific and clinical investigation, a considerable number of reasons support the need to continue to investigate the therapeutic effect of modulating HDL structure and function.     

lncRNA在心血管疾病中作用的研究进展

正长链非编码RNA(long noncoding RNA,lnc RNA)是一类转录本长度超过200个核苷酸的RNA分子,是RNA聚合酶II转录的副产物,起初它被认为是基因组转录的"噪音",不具有生物学功能。近些年来的研究表明,lnc RNA参与了X染色体沉默,基因组印记以及染色质修饰,转录激活,转录干扰,核内运输等多种重要的调控过程,lnc RNA的这些调控作用     

A Longitudinal Analysis of Alteration in Lecithin-Cholesterol Acyltransferase and Paraoxonase Activities Following Laparoscopic Cholecystectomy Relative to Other Parameters of HDL Function and the Acute Phase Response

The composition of high-density lipoprotein (HDL) changes during inflammation; however, potential changes of HDL function during inflammation and the effects of acute phase proteins that are either on the HDL particles or in the serum have not been clarified. The concentrations of C-reactive protein (CRP), serum amyloid A protein (apoSAA) isoforms, lipids and apolipoproteins, and the activities of lecithin-cholesterol acyltransferase (LCAT) and paraoxonase (PON) were measured before and after laparoscopic cholecystectomy, in 12 patients with cholecystolithiasis to clarify the function of acute-phase HDL and the relationship between acute-phase proteins and HDL functions. Both acute-phase apoSAA (A-apoSAA) and CRP increased, reached their maximum levels 3–6 days after the operation, and then returned to preoperative levels after 2 weeks. In contrast, apolipoproteins and LCAT decreased reciprocally, reached their minimum levels 3–6 days after the operation, and returned to preoperative levels after 2 weeks. However, PON decreased 3–6 days after the operation, and remained low even after 2 weeks. At the nadir the mean activities of LCAT and PON were 56 and 76% of the preoperative levels, respectively. HDL-cholesterol or constitutive apoSAA did not change significantly. LCAT has been reported to be involved in reverse-cholesterol transport and PON to be preventive for lipid peroxidation of low-density lipoprotein in vitro . Thus, during the acute phase of inflammation, HDL may be altered to an atherogenic state due to a decrease in LCAT and PON activities. Therefore, this longitudinal analysis was carried out to determine whether HDL function is modified in a single episode of inflammation and thus may contribute to the occurrence of atherosclerotic disease in patients with chronic or recurrent acute inflammation.     

Distribution of electrophoretically separated serum high density lipoprotein subfraction levels among healthy students and its alteration in patients with liver diseases

In an attempt to evaluate high density lipoprotein (HDL) subfraction levels in liver diseases, HDL was separated by a precipitation method with dextran sulfate-Mg2+ from sera of 289 healthy adults and 50 patients with liver diseases. The HDL was subdivided into HDL2e and HDL3e by Utermann's polyacrylamide gel electrophoresis with lauric acid. Ultracentrifugally separated HDL2 and HDL3 roughly corresponded to HDL2e and HDL3e, respectively. Male and female groups had different distributions of HDL2e/HDL3e ratios. Among healthy males, 121 cases had ratios less than 1.0 (mean +/- SD = 0.72 +/- 0.39, n = 150), while among healthy females, the ratios were generally larger than those of males and varied widely from 0.2 to 6.6 (mean +/- SD = 1.77 +/- 1.05, n = 139). Low levels of HDL-cholesterol were found in patients with liver diseases, except those with mild alcoholic liver injury and intrahepatic cholestasis. Apparent decreases in HDL3e, but not in HDL2e, were found in all cases with liver diseases investigated, even in those who did not show decreases in the total HDL level, when male and female patients were analyzed separately. The analysis of HDL subfractions by the present method is simple and useful for the study on altered lipid metabolism in liver diseases.     

Cholesterol Concentrations and Cardiovascular Reactivity to Stress in African American College Volunteers

Cholesterol levels and cardiovascular responses to emotionally arousing stimuli were examined in 60 healthy African American males and females. Cardiac output, stroke volume, contractile force, heart rate, and blood pressure were measured as the participants viewed two racially noxious scenes on videotape. Total serum cholesterol, high-density lipoproteins (HDL), low-density lipoproteins (LDL), and triglycerides were measured within 2 weeks of viewing the scenes. Multiple regression analysis showed that LDL and HDL were significant predictors of blood pressure responses. A correlation analysis revealed that total serum cholesterol and LDL were positively correlated with stroke volume, contractile force, and blood pressure reactivity. A possible relationship among stress, -adrenergic activity, and nonmetabolized free fatty acids is discussed. These findings suggest that cardiovascular reactivity to stress may be a new risk factor for heart and vascular diseases.     

Differences in body composition and cardiovascular and Type 2 diabetes risk factors between migrant and British‐born British Pakistani women

There is a high prevalence of cardiovascular disease and Type 2 diabetes in people of South Asian origin living in affluent western countries. We do not know whether or how risk factors for these diseases change in subsequent generations born in the west. Findings that birth‐weight is inversely associated with abdominal obesity and risk of cardiovascular disease and Type 2 diabetes in later life suggest that those born in the west may have lower levels of risk than migrants. We assessed 30 migrants from Pakistan to the UK, 30 British‐born British Pakistani women, and 25 British‐born women of European origin. British‐born British Pakistani women were taller (P = 0.05), had a lower waist to hip ratio (P = 0.04), lower mean fasting glucose levels (P = 0.03), lower mean triglyceride levels (P = 0.03), and higher mean HDL levels (P < 0.001) than migrant British Pakistani women. Levels of fasting insulin, HOMA‐IR, and blood pressure were not significantly different in the two British Pakistani groups. Thus, we found healthier levels of several cardiovascular and Type 2 diabetes risk factors in British‐born British Pakistani women than in migrant British Pakistani women. These findings might be related to the effects of early environment or to other factors, such as differences in health behaviors. British‐born British Pakistani women also differed from British‐born European women, having a more adverse body composition, but healthier levels of HDL cholesterol and blood pressure. Am. J. Hum. Biol., 2008. © 2008 Wiley‐Liss, Inc.