Inhibition of cholesteryl ester transfer protein activity: A new therapeutic approach to raising high-density lipoprotein

High-density lipoprotein (HDL) cholesterol levels are inversely associated with risk of atherosclerotic cardiovascular disease (ASCVD), leading to the concept that pharmacologic therapy to raise HDL cholesterol levels may reduce ASCVD risk. There is substantial interest in the concept of inhibition of the cholesteryl ester transfer protein (CETP) as a novel strategy for raising HDL cholesterol levels, as well as reducing levels of atherogenic lipoproteins. This article reviews the physiology of CETP in lipoprotein metabolism and the data in animals and humans that are relevant to the question of whether CETP inhibition may some day be part of the clinical armamentarium for treating dyslipidemia and atherosclerotic vascular disease.     

New insights into the regulation of HDL metabolism and reverse cholesterol transport

The metabolism of high-density lipoproteins (HDL), which are inversely related to risk of atherosclerotic cardiovascular disease, involves a complex interplay of factors regulating HDL synthesis, intravascular remodeling, and catabolism. The individual lipid and apolipoprotein components of HDL are mostly assembled after secretion, are frequently exchanged with or transferred to other lipoproteins, are actively remodeled within the plasma compartment, and are often cleared separately from one another. HDL is believed to play a key role in the process of reverse cholesterol transport (RCT), in which it promotes the efflux of excess cholesterol from peripheral tissues and returns it to the liver for biliary excretion. This review will emphasize 3 major evolving themes regarding HDL metabolism and RCT. The first theme is that HDL is a universal plasma acceptor lipoprotein for cholesterol efflux from not only peripheral tissues but also hepatocytes, which are a major source of cholesterol efflux to HDL. Furthermore, although efflux of cholesterol from macrophages represents only a tiny fraction of overall cellular cholesterol efflux, it is the most important with regard to atherosclerosis, suggesting that it be specifically termed macrophage RCT. The second theme is the critical role that intravascular remodeling of HDL by lipid transfer factors, lipases, cell surface receptors, and non-HDL lipoproteins play in determining the ultimate metabolic fate of HDL and plasma HDL-c concentrations. The third theme is the growing appreciation that insulin resistance underlies the majority of cases of low HDL-c in humans and the mechanisms by which insulin resistance influences HDL metabolism. Progress in our understanding of HDL metabolism and macrophage reverse cholesterol transport will increase the likelihood of developing novel therapies to raise plasma HDL concentrations and promote macrophage RCT and in proving that these new therapeutic interventions prevent or cause regression of atherosclerosis in humans.     

HDL cholesterol efflux capacity and incident cardiovascular events

Background It is unclear whether high-density lipoprotein(HDL) cholesterol concentration plays a causal role in atherosclerosis. A more important factor may be HDL cholesterol efflux capacity, the ability of HDL to accept cholesterol from macrophages, which is a key step in reverse cholesterol transport. We investigated the epidemiology of cholesterol efflux capacity and its association with incident atherosclerotic cardiovascular disease outcomes in a large, multiethnic population cohort.Methods We measured HDL cholesterol level, HDL particle concentration, and cholesterol efflux capacity at baseline in 2924 adults free from cardiovascular disease who were participants in the Dallas Heart Study, a probabilitybased population sample. The primary end point was atherosclerotic cardiovascular disease, defined as a first nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization or death from cardiovascular causes. The median follow-up period was 9.4 years.Results In contrast to HDL cholesterol level, which was associated with multiple traditional risk factors and metabolic variables, cholesterol efflux capacity had minimal association with these factors. Baseline HDL cholesterol level was not associated with cardiovascular events in an adjusted analysis(hazard ratio, 1.08;95% confidence interval [CI], 0.59 to 1.99). In a fully adjusted model that included traditional risk factors,HDL cholesterol level, and HDL particle concentration, there was a 67% reduction in cardiovascular risk in the highest quartile of cholesterol efflux capacity versus the lowest quartile(hazard ratio, 0.33; 95% CI, 0.19 to 0.55). Adding cholesterol efflux capacity to traditional risk factors was associated with improvement in discrimination and reclassification indexes.Conclusions Cholesterol efflux capacity, a new biomarker that characterizes a key step in reverse cholesterol transport,was inversely associated with the incidence of cardiovascular events in a population-based cohort.(From: N Engl J Med 2014; 371:2383-2393 December 18, 2014DOI: 10.1056 / NEJMoa1409065)     

Future Lipid-Altering Therapeutic Options Targeting Residual Cardiovascular Risk

Low-density lipoproteins (LDL) play a causal role in the development of atherosclerosis, and reduction of LDL cholesterol with a statin is a cornerstone in prevention of cardiovascular disease. However, it remains an unmet need to reduce the residual risk on maximally tolerated statin alone or in combination with other drugs such as ezetimibe. Among the new LDL-lowering therapies, PCSK9 inhibitors appear the most promising class. Genetic studies suggest that triglyceride-rich lipoproteins are associated with cardiovascular risk and several promising triglyceride-lowering therapies are at various stages of development. At the opposite end, high-density lipoprotein (HDL) cholesterol seems to not be causally associated with cardiovascular risk, and thus far, trials designed to reduce cardiovascular risk by mainly raising HDL cholesterol levels have been disappointing. Nevertheless, new drugs targeting HDL are still in development. This review describes the new drugs reducing LDL, apolipoprotein(a), and triglyceride-rich lipoproteins, and the strategies to modulate HDL metabolism.     

Lipases and HDL metabolism.

Plasma levels of high-density lipoprotein (HDL) cholesterol are strongly inversely associated with atherosclerotic cardiovascular disease, and overexpression of HDL proteins, such as apolipoprotein A-I in animals, reduces progression and even induces regression of atherosclerosis. Therefore, HDL metabolism is recognized as a potential target for therapeutic intervention of atherosclerotic vascular diseases. The antiatherogenic properties of HDL include promotion of cellular cholesterol efflux and reverse cholesterol transport, as well as antioxidant, anti-inflammatory and anticoagulant properties. The molecular regulation of HDL metabolism is not fully understood, but it is influenced by several extracellular lipases. Here, we focus on new developments and insights into the role of secreted lipases on HDL metabolism and their relationship to atherosclerosis.     

Dysfunctional High-Density Lipoprotein and Atherosclerosis

High-density lipoprotein (HDL) is well established as a negative risk factor for the development of atherosclerosis. Epidemiologic, pathologic, and experimental studies have demonstrated a role for HDL in protection from coronary artery disease. HDL has been demonstrated to reduce the risk from atherosclerosis by multiple pathophysiologic mechanisms. Low-density lipoprotein is a metabolic end product that can be recognized and cleared by specific hepatic receptors with excretion into the bile. However, low-density lipoprotein may also be scavenged in the periphery by the monocyte-macrophage system, with subsequent generation of lipid-laden foam cells. HDL may reduce the atherosclerotic burden by multiple potential mechanisms. HDL can interact with the foam cell to remove cholesterol via receptor-mediated binding, passive diffusion, and alteration of intracellular cholesterol trafficking by ATP binding cassettes. The process of reverse cholesterol transport is a major mechanism by which HDL can remove cholesterol from the periphery, allowing it to be cleared by the liver and then excreted into the bile. However, HDL exhibits multiple additional potential beneficial physiologic effects. Endothelial function and repair is potentiated by HDL. Normal HDL has significant anti-inflammatory and antioxidant activity. Prostacyclin production and improvement in fibrinolytic balance is also attributed to normally functioning HDL. HDL is also intimately related to the metabolism of other circulating lipoproteins. However, multiple clinical studies have identified individuals with a significant atherosclerotic burden despite normal or elevated levels of HDL cholesterol. Clinical conditions associated with inflammation and oxidative stress have adversely altered the normal functions of HDL. Clinical assays have been developed to assess the functionality of HDL. Dysfunctional HDL may be returned to normal by diet, exercise, degree of fat intake, and pharmacologic approaches. Orally active mimetic proteins are in development and have shown clinical promise.     

Role of circulating high-density lipoprotein and triglycerides in coronary artery disease: risk and prevention

A substantial body of evidence suggests that circulating levels of high-density lipoprotein (HDL) and certain triglyceride-carrying lipoproteins may, like low-density lipoprotein (LDL), be important risk factors in the development of atherosclerotic coronary artery disease (CAD). Furthermore, both low HDL cholesterol and high triglyceride levels are frequently associated with other CAD risk factors, whose correction, often by hygienic means, may reduce CAD risk without fear of adverse side effects. However, the available evidence is not yet sufficiently coherent and compelling to justify guidelines (analogous to those for LDL cholesterol) for specific pharmacologic treatment of low plasma HDL cholesterol or moderately elevated plasma triglyceride levels to prevent CAD.     

Apolipoprotein A-I versus HDL cholesterol in the prediction of risk for myocardial infarction and stroke

PURPOSE OF REVIEW: To compare the potential of high-density lipoprotein (HDL) cholesterol and apolipoprotein (apo) A-I, the major protein in HDL particles, in predicting cardiovascular risk. Pros and cons for using these risk markers are discussed. RECENT FINDINGS: Both HDL cholesterol and apoA-I are in most clinical conditions antiatherogenic - the higher the values, the lower the cardiovascular risk. Methodological and physiological factors speak in favour of using apoA-I rather than HDL cholesterol as a marker of risk. In prospective risk studies and in lipid-lowering trials it has been shown that the apoB/A-I ratio, which reflects the cholesterol balance between all potentially atherogenic (apoB) and antiatherogenic lipoproteins (apoA-I), is a better risk marker than low-density lipoprotein cholesterol, HDL cholesterol and lipid ratios in predicting cardiovascular risk and response to lipid lowering induced by statins. Practical advantages speak in favour of using apoB and apoA-I - fasting is not needed to analyze and interpret the values of apoB and apoA-I. SUMMARY: New guidelines should be developed in which target values for apoB and apoA-I are defined to enable the use of these new strong risk markers/factors in clinical practice.     

Detection and evaluation of dyslipoproteinemia

Screening for dyslipoproteinemias should be undertaken in all individuals older than 20 years of age at least once every 5 years. The initial screening, as recommended by the Adult Treatment Guidelines Panel of the National Cholesterol Education Program, is to determine the concentration of total blood cholesterol. This initial determination can be made on blood obtained in the nonfasting state. Further evaluation of the patient's lipoprotein concentrations is dependent upon the presence of other cardiovascular risk factors. in the absence of definite coronary heart disease, hypertension, diabetes mellitus, a family history of coronary artery disease, cigarette smoking, or severe obesity, the patient with a total blood cholesterol concentration less than 200 mg/dL requires no specific instruction and should have a repeated screening performed within 5 years. Patients with blood cholesterol concentrations greater than 200 mg/dL should have their lipoprotein profiles determined if they have atherosclerotic cardiovascular disease or two other cardiovascular disease risk factors. The lipoprotein profile includes the determination of fasting cholesterol and triglyceride and HDL cholesterol concentrations. From these values, the LDL cholesterol concentration can be calculated. This LDL cholesterol concentration is central in selecting the appropriate therapy. HDL cholesterol concentrations may be useful in evaluating patients with ischemic heart disease. Concentrations of HDL cholesterol less than 35 mg/dL are associated with increased risk for coronary artery disease. Although there is currently no convincing evidence that support the specific treatment of depressed HDL cholesterol concentrations, therapy directed to modulating lipoprotein metabolism in patients with heart disease and low HDL concentrations may be of benefit. Patients with recurrent abdominal pain, pancreatitis, and eruptive xanthomatosis frequently have fasting hypertriglyceridemia concentrations exceeding 1000 mg/dL. These patients should be identified in order to effectively reduce their triglyceride concentrations, which can prevent these complications.     

L-folic acid supplementation in healthy postmenopausal women: effect on homocysteine and glycolipid metabolism

CONTEXT: Hyperhomocysteinemia as well as alterations of glycemic and lipidic metabolism are recognized as risk factors for cardiovascular diseases. OBJECTIVE: The aim of this study was to examine the effect of L-folic acid supplementation on homocysteine (Hcy) and related thiols, such as cysteine (Cys) and Cys-glycine (Cys-Glyc) pathways and their relationship to glucose, insulin, and lipidic metabolism in normoinsulinemic postmenopausal women. DESIGN: This study was a randomized placebo, not double-blind, trial. SETTING: The study was performed in an academic research center. PATIENTS OR OTHER PARTICIPANTS: Twenty healthy postmenopausal women were selected. No patient was taking drugs known to affect lipid or glucose metabolism. INTERVENTION(S): Patients underwent two hospitalizations before and after 8 wk of L-acid folic (7.5 mg/d) or placebo administration. The glycemic metabolism was studied by an oral glucose tolerance test and a hyperinsulinemic euglycemic clamp. Hcy metabolism was studied by a standardized oral methionine-loading test. MAIN OUTCOME MEASURE(S): Hcy, Cys, and Cys-Glyc, basally and after a methionine loading test, were measured. Basal insulin, glucose, and peptide C levels as well as area under the curve for insulin, area under the curve for peptide, hepatic insulin extraction, and metabolic index were assayed. The total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol levels and the cholesterol/HDL and LDL/HDL ratios were also measured. RESULTS: The total basal Hcy concentration and the plasma postmethionine loading Hcy values were significantly decreased (P < 0.01) in L-folic acid-treated patients, whereas postmethionine loading Cys-Glyc levels were markedly increased (P < 0.02). Furthermore, L-folic acid intake induced a significant improvement in carbohydrate metabolism through an increase in fractional hepatic insulin extraction (P < 0.05) and peripheral insulin sensitivity (P < 0.02) in normoinsulinemic women. HDL levels considerably increased, inducing an improvement in other atherosclerotic indexes, such as cholesterol/HDL and LDL/HDL ratios (P < 0.03). CONCLUSIONS: These results show that folic acid supplementation lowers plasma Hcy levels and improves insulin and lipid metabolism, reducing the risk of cardiovascular disease.     

卵磷脂胆固醇酰基转移酶与动脉粥样硬化性心血管病

卵磷脂胆固醇酰基转移酶(LCAT)是血浆脂蛋白中催化游离胆固醇酯化的关键酶,在高密度脂蛋白代谢和胆固醇逆转运中起着重要作用。尽管LCAT研究已经进行了半个世纪,其与动脉粥样硬化性心血管病的关系仍存在较大争议。本文就LCAT生物化学特性、在脂代谢中的作用机制、与心血管病的关系及准确测定存在的问题等作一综述。     

Importance of lipoprotein metabolism parameters in the clinical and angiographic severity of coronary artery disease.

Coronary artery disease that is clinically and angiographically significant is associated to important biochemical parameters with direct interference in lipoprotein and apoprotein metabolism. The purpose of our study was to evaluate the importance of several lipoprotein metabolic parameters in the clinical and angiographic severity of chronic coronary artery disease. In a population with the diagnosis of ischemic coronary artery disease, we assessed the degree of angiographic (single- versus multivessel disease) and clinical (C.C.S. I-IV classification) severities. In each patient, we determined the value of total cholesterol, triglycerides, HDL and LDL cholesterol, HDL 2 and 3, apoprotein AI and B, lipoprotein (a), anti-phospholipid antibodies and C reactive protein. Our results showed that some parameters were significant in the comparison between a normal group and the global coronary artery disease population, such as the value of total cholesterol, HDL cholesterol, HDL 2, apoprotein AI and B lipoprotein (a) and anti-phospholipid antibodies. In the distinction of coronary artery disease subgroups, in relation to C.C.S. < or = 2 and > or = 3 classes, some factors could be discriminated, such as HDL cholesterol, HDL 2, total cholesterol/HDL, lipoprotein (a), anti-phospholipid antibodies and C reactive protein. In the distinction between classes C.C.S. < or = 2 and AMI, the levels of triglycerides, HDL cholesterol, HDL 2, total cholesterol/HDL, lipoprotein (a) and anti-phospholipid antibodies were significant. In the division between single vessel versus multivessel coronary artery disease we found significant values of HDL cholesterol, HDL 2, total cholesterol/HDL, apoprotein AI, lipoprotein (a), anti-phospholipid antibodies and C reactive protein. In conclusion, our present study endorses the clinical role of lipids and plasma lipoproteins in the determination of several cardiovascular risk factors, but introduction of new parameters such as lipoprotein (a) and the anti-phospholipid antibodies can be very useful for a better and global understanding of the pathophysiological processes and distinction of higher risk subgroups for extension and degree of severity of ischemic coronary artery disease.     

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.     

ATP-binding cassette A1 protein and HDL homeostasis

For three decades, low-density lipoprotein (LDL) dominated research into cholesterol metabolism and atherosclerosis, whereas scant attention was paid to high-density lipoprotein (HDL), an equally important risk factor for cardiovascular disease. This low interest reflected the lack of knowledge about physiological HDL receptors. As a result, our understanding of HDL-cell interactions failed to develop alongside that of LDL, and mechanisms through which atheroprotective HDL promoted clearance of cholesterol from peripheral cells remained poorly-defined. Interest was kindled with the recognition that scavenger receptor class B, type I is the cell-surface protein in hepatocytes and steroidogenic tissues which selectively extracts cholesteryl esters from HDL. Greater impetus still was given by the discovery that mutations in the gene encoding the ATP-binding cassette transporter, class A1 (ABCA1) are the cause of Tangier disease, a rare recessive disorder with near-absent plasma HDL. The ABCA1 transmembrane protein is crucial for efficient efflux of cellular cholesterol and HDL maturation and has emerged as a promising therapeutic target for cardiovascular disease. The hope is that new drugs, regulating ABCA1 activity and HDL homeostasis, will accelerate cholesterol efflux from lipid-laden foam cells and thus promote regression of atherosclerotic lesions.     

Triglycerides, high-density lipoprotein cholesterol, and risk of ischemic heart disease: a view from the Copenhagen Male Study

The role of lipids and lipoproteins as important risk factors of ischemic heart disease (IHD) is well established. With the demonstration in large-scale randomized clinical trials that aggressive lowering of low-density lipoprotein (LDL) cholesterol levels with statins reduced the risk of IHD, the central role of LDL cholesterol in the pathogenesis of IHD was proven. However, many IHD cases occur in people with normal LDL cholesterol levels, and it is well known that the ability to predict who will develop IHD based on LDL cholesterol levels alone is limited. Plasma triglycerides and high-density lipoprotein (HDL) cholesterol are two other lipid variables that over the years have attracted attention in cardiovascular epidemiology. Recently, much more attention has been paid to the relationship between triglycerides, HDL cholesterol, and risk of IHD because the combined lipid profile of a high fasting triglyceride level and a low HDL cholesterol level is the characteristic dyslipidemia in the metabolic syndrome X. The objective of the present review article is to use data from the Copenhagen Male Study to demonstrate that, in men, fasting hypertriglyceridemia is a strong risk factor of IHD independent of other major risk factors of IHD, and that the combined lipid profile of a high fasting triglyceride level and a low HDL cholesterol level, the characteristic dyslipidemia in the metabolic syndrome X, is a very strong and important risk factor of IHD, at least as strong and important as a high LDL cholesterol level.     

Combined Impact of Alcohol and Tobacco: Implications for Cardiovascular Disease

Alcohol and tobacco are important modifiable risk factors for prevention of atherosclerosis and cardiovascular disease. There is a strong association between habitual alcohol drinking and smoking. Alcohol shows diverse effects on progression of atherosclerosis mainly through its blood pressure–elevating and high-density lipoprotein (HDL) cholesterol–raising actions. In addition to atherogenic actions, smoking modifies associations between alcohol consumption and cardiovascular risk factors. A positive association of alcohol consumption with blood pressure and inverse associations of alcohol consumption with low-density lipoprotein (LDL) cholesterol and non-HDL cholesterol were more prominent in smokers than in nonsmokers. Both in smokers and nonsmokers, HDL cholesterol tended to be higher with an increase in alcohol consumption. Therefore, blood pressure elevation and LDL cholesterol reduction by drinking are suggested to be greater in smokers than in nonsmokers. Further prospective studies on whether and how smoking influences associations of alcohol consumption with atherosclerotic risk factors and cardiovascular events are needed.     

High-density lipoprotein cholesterol levels as a marker of reverse cholesterol transport

Dramatic advances have been made over the last decade in understanding the role of low-density lipoprotein (LDL) in atherosclerotic cardiovascular diseases and how to manage elevated levels of LDL cholesterol. Understanding the role of high-density lipoprotein (HDL) and how to intervene therapeutically in HDL action offers the possibility of even greater benefits. Epidemiologic studies have shown a strong inverse relation between HDL cholesterol and the risk of coronary artery disease (CAD). Whereas several subfractions of HDL can be identified, none convincingly offers better predictive value than total HDL cholesterol. Apolipoprotein A-I, the major apolipoprotein of HDL, also is inversely related to atherosclerotic risk. Unfortunately, measurements of HDL cholesterol or apolipoprotein A-I are considerably less precise and less accurate than measurements of total or LDL cholesterol. The biologic phenomena responsible for these epidemiologic relations are not yet clear. Moreover, several apparently contradictory observations and puzzling exceptions to the simplistic inverse relation of HDL cholesterol to CAD suggested by epidemiologic studies have created considerable confusion. The current confusion is not likely to be resolved until HDL metabolism and the cellular and molecular events responsible for the apparent protective effects of HDL are better understood. One current hypothesis that could explain the protective effects of HDL is that it mediates reverse cholesterol transport, the process by which cholesterol is removed from sites of deposition and delivered to the liver for excretion. From the standpoint of current therapy, each intervention that changes HDL cholesterol levels must be evaluated individually, on its own merit, in light of its effect on atherosclerosis and coronary events rather than on alterations in HDL cholesterol levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

高密度脂蛋白亚类与心血管疾病的现状分析

高密度脂蛋白是一类异质性脂蛋白,其亚类表现出在抗动脉粥样硬化功能和心血管保护作用方面的差异性,并随年龄、性别等的差异也发生动态变化。影响高密度脂蛋白功能和亚类分布的药物或许是改善心血管风险更有效的方法。文章就高密度脂蛋白亚类的检测、抗动脉粥样硬化功能以及与心血管疾病的相关性等进行综述,为人类心血管疾病的防治提供新视角。     

Lipoprotein levels in morbidly obese patients with massive,surgically-induced weight loss

Abnormalities in lipoprotein metabolism are among the risk factors for atherosclerotic cardiovascular disease frequently present in patients with morbid obesity. We have examined the effects of dietary restriction induced by gastric bypass surgery on plasma lipoprotein levels in 22 morbidly obese patients. Operation induced weight loss in all patients. Postoperatively (12 +/? 7 mo), triglycerides decreased from 146.4 +/? 67 (mean +/? S.D. before operation) to 104 +/? 44 mg/dl (p < 0.01), total cholesterol decreased from 187 +/? 52 to 166 +/? 39 mg/dl (p < 0.025), LDL cholesterol levels decreased from 119 +/? 42 to 104 +/? 36 mg/dl (p < 0.038), and HDL cholesterol levels increased from 40.1 +/? 10.1 to 45.2 +/? 9.5 mg/dl (p < 0.012). HDL cholesterol to LDL cholesterol ratio increased from 0.37 +/? 0.13 to 0.48 +/? 0.21 (p < 0.01). The results of apo A-1, A-2 and B determinations (n = 12) paralleled the changes in lipoprotein levels. $\text{Apo A1}\text{Apo A2}$ ratio increased suggesting an increase in the concentration of HDL2. We conclude that weight loss following gastric bypass surgery is associated with favorable changes in lipoprotein metabolism which may help prevent or delay the development of atherosclerotic cardiovascular disease. The mechanism responsible for the lipoprotein changes remains to be determined.