Apolipoprotein B and apolipoprotein A-I: risk indicators of coronary heart disease and targets for lipid-modifying therapy

Although LDL cholesterol (LDL-C) is associated with an increased risk of coronary heart disease, other lipoproteins and their constituents, apolipoproteins, may play an important role in atherosclerosis. Elevated levels of apolipoprotein (apo) B, a constituent of atherogenic lipoproteins, and reduced levels of apo A-I, a component of anti-atherogenic HDL, are associated with increased cardiac events. Apo B, apo A-I and the apo B/apo A-I ratio have been reported as better predictors of cardiovascular events than LDL-C and they even retain their predictive power in patients receiving lipid-modifying therapy. Measurement of these apolipoproteins could improve cardiovascular risk prediction.     

Genetics of apolipoprotein B and apolipoprotein AI and premature coronary artery disease

Increased low-density lipoprotein (LDL) and decreased high-density lipoprotein cholesterol (HDL-C) predict premature coronary artery disease, as do elevated levels of apolipoprotein B or reduced levels of apolipoprotein AI. Probands were studied of families with common genetic forms of dyslipidaemia to determine if apo B or apo AI define genetic groups and if apo B or apo AI levels relate to premature coronary artery disease risk. Elevated apo B was characteristic of familial hypercholesterolaemia, familial combined hyperlipidaemia (FCHL), and was seen in individuals with elevated Lp(a). Normal apo B levels were seen in familial hypertriglyceridaemia and in 'coronary artery disease with low-HDL cholesterol'. Apo AI levels tended to be low in FCHL and were decreased in 'coronary disease with low-HDL cholesterol'. In familial hypertriglyceraemia, even though HDL-C levels were low, normal apo AI and apo B levels were seen in the absence of premature coronary artery disease. Therefore, in genetic dyslipidaemias elevated apo B levels and reduced apo AI levels (or increased apo B/AI ratio) differ and predict premature coronary artery disease.     

The role of dietary cholesterol in the regulation of postprandial apolipoprotein B48 levels in diabetes

The atherogenicity of intestinally derived postprandial lipoproteins has been confirmed in a number of recent studies. We have shown abnormalities in postprandial lipoprotein metabolism in diabetic patients, a group with an increased susceptibility to atherosclerosis. This study examined the relationship between dietary cholesterol and the postprandial, intestinally derived, apolipoprotein B48 and apolipoprotein B100 from the liver. We compared 10 non-insulin-dependent (Type 2, NIDDM) diabetic patients and 10 age-matched non-diabetic control subjects. Fasting blood was taken and subjects were fed a cholesterol-free, high fat meal. Blood samples were repeated at 2 h, 4 h, 6 h, and 8 h postprandial. The following week fasting blood was collected and subjects were given the same meal with 1g of added cholesterol. Blood was collected at the same time points. Chylomicrons and very low density lipoprotein were isolated by sequential ultracentrifugation and their lipoprotein composition determined. Apolipoproteins B48 and B100 were separated by gradient gel electrophoresis and quantified by densitometric scanning using a low density lipoprotein apolipoprotein B100 standard. Post prandial chylomicron cholesterol and triglyceride increased after the high cholesterol meal in both groups (p < 0.001). The postprandial chylomicron apolipoprotein B48 response of both diabetic and control subjects to the cholesterol meal was less than to the cholesterol-free meal (p < 0.001). Fasting very low density lipoprotein apolipoprotein B48 was higher in diabetic patients compared to control subjects and their postprandial increase following the cholesterol-free meal was significantly greater (p < 0.001). There was a 10-fold increase in the incremental postprandial VLDL apolipoprotein B48 area under the curve after the cholesterol-rich meal in the diabetic patients compared to a 3-fold increase in control subjects. The postprandial very low density lipoprotein apolipoprotein B100 was similar in the two groups with both meals. The study demonstrates a very significant increase in the amount of intestinally derived small apolipoprotein B48-associated particles in the very low density lipoprotein fraction following a cholesterol-rich meal in diabetic patients. Synthesis rather than clearance may be the major cause of the increase in these atherogenic postprandial particles. © 1997 John Wiley & Sons, Ltd.     

脂蛋白(a)与其他脂蛋白和载脂蛋白相关性研究

目的探讨冠心病患者血浆脂蛋白(a)与HDL-C、LDL-C、载脂蛋白(apo)A-Ⅰ、apoB的相关性,评价血脂异常与冠心病的相关性。方法选择因胸痛入院的患者1011例,经冠状动脉造影确诊为冠心病患者613例作为冠心病组,非冠心病患者398例作为对照组。测定脂蛋白(a)、apoA-Ⅰ、apoB、HDL-C和LDL-C,进行相关性分析,并计算apoB/apoA-Ⅰ比值。结果冠心病组的脂蛋白(a)、LDL-C及apoB水平较对照组明显升高(P=0.000);冠心病组脂蛋白(a)水平与LDL-C、apoB呈显著正相关(r=0.135、r=0.168,P0.01),与HDL-C、apoA-Ⅰ无相关性。对照组脂蛋白(a)与LDL-C、apoB呈显著正相关(r=0.201、r=0.236,P0.01),与HDL-C、apoA-Ⅰ无相关性。apoB/apoA-Ⅰ是诊断冠心病最显著的独立危险因素(OR=31.577,95% CI:8.324～11 9.788,P=0.000),其次为脂蛋白(a)(OR=19.446,95% CI:3.831～98.716,P=0.000)。结论脂蛋白(a)与LDL-C、apoB呈正相关,提示三者均为动脉粥样硬化的危险因素;apoB/apoA-Ⅰ和脂蛋白(a)为冠心病的独立危险因素。     

Distribution of glycosaminoglycans in the intima of human aortas: changes in atherosclerosis and diabetes mellitus

Summary Arterial glycosaminoglycans are considered to be important in atherogenesis due to their ability to trap lipid inside the vessel wall and to influence cellular migration and proliferation. Atherosclerotic lesions have displayed an altered glycosaminoglycan content and distribution. Diabetes is a recognized risk factor for atherosclerosis, but no information is available on the arterial glycosaminoglycans in human diabetes. We examined glycosaminoglycans in normal and atherosclerotic intima of non-diabetic and Type 2 (non-insulin-dependent) diabetic patients. Intima was stripped from autopsy samples of thoracic aortas; normal and plaque areas were separated. Glycosaminoglycans were isolated by delipidation, proteolytic digestion, and precipitation and characterized by quantitation of total glycosaminoglycan and evaluation of glycosaminoglycan distribution by electrophoresis and densitometry. Results indicate a significant decrease in total glycosaminoglycan and significant changes in their distribution in atherosclerotic plaques: a relative decrease in heparan sulphate, a relative increase in dermatan sulphate and thus a decrease in the ratio of heparan sulphate to dermatan sulphate. A similar but less marked change in the ratio was found in normal intima of diabetic subjects, while in their plaques this change was more pronounced. This suggests that changes in arterial glycosaminoglycans (especially the ratio of heparan sulphate to dermatan sulphate) precede the development of lesions in diabetes and may be important in atherogenesis.     

High vitamin E plasma levels and low low-density lipoprotein oxidation are associated with the absence of atherosclerosis in octogenarians

OBJECTIVES: To identify the biological characteristics of older subjects with vascular successful aging (VASA), defined as the absence of instrumental signs and clinical symptoms of atherosclerosis in the extracoronary and coronary vessels. DESIGN: A cross-sectional study. SETTING: A university-affiliated outpatient clinic. PARTICIPANTS: Sixty older subjects (30 with VASA and 30 controls with moderate carotid atherosclerosis (AG group)) from a sample of 705 subjects age 75 and older consecutively screened. MEASUREMENTS: Clinical examination; ultrasonographic examination of carotid, vertebral, abdominal aortic, iliac, and femoral arteries; electrocardiogram; and laboratory evaluation (lipid profile, lipophilic antioxidants, and markers of low-density lipoprotein (LDL) oxidation). RESULTS: Compared with controls, there were more females in the VASA group (82% vs 50%, P <.01), and fewer previous smokers (20.5% vs 52.5%, P <.01). Vitamin E/total cholesterol levels both in plasma (4.81 vs 3.51 micromol/mmol, P <.001) and in isolated LDLs (2.71 vs 1.86 microg/mg LDL cholesterol (LDL-C), P <.01), were higher in the VASA group, as was the resistance of LDLs to in vitro oxidation (as indicated by a longer duration of the lag phase: 80.2 vs 65.6 minutes, P <.001). The level of fluorescent products of lipid peroxidation (FPLPs) in native LDLs was lower in the VASA group (13.5 vs 18.8 URF/mg LDL-C, P <.001). Multivariate logistic regression analysis showed that only plasma vitamin E level (odds ratio (OR) = 6.04, 95% confidence interval (CI) = 1.48-24.63) and FPLPs in LDLs (OR = 0.53, 95% CI = 0.31-0.91) were independently associated with VASA. CONCLUSIONS: These results suggest that an appropriate level of vitamin E and a low level of LDL oxidation might be important for reaching advanced age without developing atherosclerosis.     

Associations between apolipoprotein B, apolipoprotein AI, the apolipoprotein B/AI ratio and coronary heart disease: a literature-based meta-analysis of prospective studies

OBJECTIVES: To assess associations of circulating levels of apolipoprotein (apo) AI, apoB and the apoB/AI ratio (apoB/A) with risk of incident coronary heart disease (CHD). DESIGN: Literature-based meta-analysis of prospective studies. DATA SOURCES: Prospective studies in essentially general populations that reported on associations between apoAI, apoB or apoB/A and first incident CHD outcomes. Studies were identified by computer-based searches and by manual searches of the relevant literature. RESULTS: Data from 23 relevant studies were identified. For apoAI, with 6333 CHD cases in 21 studies, comparison of individuals in the bottom third with those in the top third of baseline values yielded a combined relative risk of 1.62 (95% confidence interval: 1.43-1.83), i.e. an inverse association. For apoB, a combined analysis of 6320 CHD cases from 19 studies gave a relative risk of 1.99 (1.65-2.39) for a comparison of individuals in the top third versus those in the bottom third of baseline values. For apoB/A, with 3730 CHD cases from seven studies, a comparison of individuals in the top third versus the bottom third of baseline values gave a combined relative risk of 1.86 (1.55-2.22). These associations were somewhat stronger following correction for within-person variations in apolipoprotein levels. There was evidence of heterogeneity amongst the published studies, but it was only partly explained by available study-level characteristics. CONCLUSIONS: The present quantitative review suggests the existence of moderately strong associations between baseline levels of each of apoAI, apoB, and apoB/A and risk of CHD. More detailed analysis, perhaps based on individual participant data from prospective studies, could help to overcome several limitations in the present review and to clarify any relevance of these apolipoproteins to disease prediction and aetiology.     

稳定型冠心病患者血清低密度脂蛋白胆固醇和载脂蛋白B浓度与SYNTAX评分的关系

目的探讨稳定型冠状动脉粥样硬化性心脏病(stable coronary artery disease,SCAD)患者血清低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL-C)和载脂蛋白B浓度与SYNTAX评分的关系。方法回顾性选择2016年1月至2017年12月在宝鸡市中心医院接受冠状动脉造影检查确诊的SCAD患者150例作为研究对象,根据SYNTAX评分结果将患者分为0~22分组(低分组,n=80)、23~32分组(中分组,n=40)和33分以上组(高分组,n=30)。SYNTAX评分与不同临床特征间的相关性采用Spearman相关性分析和多元线性回归分析。结果3组患者血小板分布宽度(platelet distribution width,PDW)、红细胞分布宽度(red cell distribution width,RDW)、纤维蛋白原、总胆固醇、高密度脂蛋白胆固醇(high density lipoprotein-cholesterol,HDL-C)、LDL-C、脂蛋白a、载脂蛋白A1、载脂蛋白B、SYNTAX评分比较,差异有统计学意义(P<0.05)。Spearman相关性分析结果显示,SYNTAX评分与HDL-C、载脂蛋白A1呈负相关(P<0.05),与纤维蛋白原、总胆固醇、LDL-C、PDW、RDW、脂蛋白a、载脂蛋白B呈正相关(P<0.05)。多元线性回归分析结果显示,HDL-C、LDL-C、纤维蛋白原、载脂蛋白B均是影响冠状动脉病变的危险因素(P<0.05)。结论随着血清LDL-C、载脂蛋白B浓度的升高,SCAD患者SYNTAX评分升高,冠状动脉病变严重程度加重。血清LDL-C、载脂蛋白B浓度可作为判断SCAD患者冠状动脉病变严重程度的参考指标。     

Treatment of familial hypercholesterolaemia: a controlled trial of the effects of pravastatin or cholestyramine therapy on lipoprotein and apolipoprotein levels

Abstract. The efficacy and safety of a new, selective inhibitor of cholesterol synthesis, pravastatin, and the bile acid-binding resin, cholestyramine, were compared in a randomized, double-blind study of 120 patients with familial hypercholesterolaemia. After a run-in period of 8-10 weeks with assessment of dietary habits, the patients were treated with pravastatin + placebo, placebo + cholestyramine, or placebo alone. Active pravastatin therapy was initiated with 10 mg b.i.d. for 6 weeks, and was increased to 20 mg b.i.d. for the following 6 weeks. Cholestyramine was given at 24 gd^?1, or the highest tolerable dose. After 6 weeks of therapy, serum total and LDL cholesterol levels were reduced by 17% and 21%, respectively, on pravastatin treatment, whereas the corresponding reductions with cholestyramine treatment were 24% and 30%, respectively. With an increased dose of pravastatin, serum and LDL cholesterol concentrations were reduced by 23% and 28%, respectively, after 12 weeks; the effect of cholestyramine was unchanged. HDL cholesterol levels increased in response to pravastatin, by 7% and 9% after 6 and 12 weeks, respectively. Concomitant changes in the concentrations of apolipoproteins B and AI were observed. Three patients discontinued the study because of side-effects: two subjects were treated with pravastatin and one was given placebo. The prevalence of side-effects (including laboratory abnormalities) was 35% for pravastatin, 30% for placebo, and 53% (significantly higher) for cholestyramine. We conclude that pravastatin, in a 40 mg daily dose, is as effective as cholestyramine in lowering LDL cholesterol in familial hypercholesterolaemia. Since the frequency of side-effects is higher with cholestyramine, pravastatin offers a promising alternative for the therapy of this genetic disease.     

Immunoassay of human plasma apolipoprotein B

A specific and precise double antibody immunoassay for human plasma apolipoprotein B (apoB) was developed and applied in normolipidemic and hyperlipidemic subjects. The intra-assay coefficient of variation was ca. 9%. The distributions of total apoB and low density lipoprotein (LDL) apoB in a randomly selected, healthy, fasting population (n = 349) was slightly skewed with a mean total apoB of 81 mg/100 ml and LDL apoB of 72 mg/100 ml. The 90th percentile cutoffs for total apoB and LDL apoB were 106 and 97 mg/100 ml, respectively. Regarding total apoB, women showed a statistically significant increase (r = 0.463, p less than 0.001) with age (30-65) and an average annual increment of plasma apoB of 1.1 mg/100 ml. In contrast, men showed only a slight increase of apoB from the 4th to 5th decade, with an average annual increment of 0.7 mg/100 ml (r = 0.201, 0.02 less than p less than 0.05). Similarly, regarding LDL apoB, women showed an increase of 1.0 mg/100 ml/year from the 4th to 7th decade (r = 0.501, p less than 0.001), whereas men's LDL apoB did not increase significantly with age (r = 0.114, 0.2 less than p less than 0.3, for ages 30-49). Six of ten normal young subjects showed essentially no physiological variation in fasting apoB levels over a 10-wk period, whereas four had a variation of ca. 5% or less. LDL apoB represented ca. 90% of the total apoB in normolipidemic and type II plasma samples (86% in type IV samples) but only 68% in type III plasmas (n = 7). The ratios of LDL cholesterol-LDL apoB were similar for the random and hyperlipoproteinemic groups, ranging from a high of 1.8 for type IIa to a low of 1.5 for type IV. The ratio of cholesterol to apoB was significantly elevated (p less than 0.002) in the d less than 1.006 fraction of the type III plasma samples compared to the random and type II groups.     

The effect of serum lipid regulation on the development of femoral atherosclerosis in hyperlipidaemia: a non-randomized controlled study

The development of femoral atheroma after 1 year of treatment with diet and nicotinic acid plus fenofibrate was studied in 45 asymptomatic, hyperlipidaemic, middle-aged male subjects in a non-randomized controlled study. The median serum very low density lipoprotein (VLDL) cholesterol concentration and the low density lipoprotein (LDL) cholesterol concentration were lowered by 67% and 36%, respectively, in the treatment group. The median serum high density lipoprotein (HDL) cholesterol concentration was increased by 23%. Femoral atheroma was estimated by overall atherosclerosis score (OAS). Changes in femoral atherosclerosis were estimated by intrapair comparison of angiograms. Progression was found in 24% and 40% in the treatment and control groups, respectively. Regression occurred in 29% and 0%, respectively. The OAS decrease correlated with reductions in VLDL cholesterol and systolic blood pressure.     

载脂蛋白B基因XbaⅠ位点多态性与中青年人颈动脉粥样硬化的关系

目的:探讨载脂蛋白B(apoB)基因变异与颈动脉粥样硬化的关系。方法:对56例颈动脉粥样硬化患者及50名非颈动脉粥样硬化者的apoB基因的XbaⅠ位点的多态性进行了研究。检测两组颈动脉内膜-中膜厚度(IMT)及斑块指数(PI)。结果:观察组X^ 等位基因频率明显高于对照组。观察组含X^ 等位基因型者总胆固醇、低密度脂蛋白-胆固醇、apoB水平显著高于X^-X^-基因型者；观察组含X^ 基因型者IMT比X^-X^-基因型明显增厚且含X^ 等位基因型者颈动脉PI比X^-X^-基因型亚组明显增大。结论:apoB基因XbaⅠ的X^ 等位基因与颈动脉粥样硬化有一定关联。     

Apolipoprotein B gene polymorphisms, lipoproteins and coronary atherosclerosis: a study of young myocardial infarction survivors and healthy population-based individuals.

Association studies were carried out in a sample of 87 patients from Sweden who had survived a myocardial infarction (MI) before the age of 45, and 91 age-matched healthy individuals, to compare the impact of polymorphisms at the apolipoprotein (apo) E and B gene loci on among-individual differences in plasma lipid traits and progression of atherosclerosis. In the group of healthy individuals, polymorphisms creating the common apo E isoforms were, as expected, associated with significant differences in total and low density lipoprotein (LDL) cholesterol (11.7% and 11.6% of sample variance). For apo B, the polymorphism with the largest effect on apo B levels (16% of sample variance) was the C to T transition 265 bp 5' of the cap site, in the promoter (detectable by MspI). Both this polymorphism and the threonine2488 neutral substitution (detectable by XbaI) were associated with significant effects on LDL-cholesterol (8.3% and 9.3% of sample variance, respectively). The asparagine/serine4311 polymorphism was associated with a significant effect on high density lipoprotein (HDL) cholesterol alone, and there was no significant association with the glutamate/lysine4154 polymorphism (detectable by EcoRI) or the leucine-alanine-leucine (LAL) insertion/deletion polymorphism in the signal peptide. In the patients, polymorphisms creating the three common apo E isoforms were associated with large effects on cholesterol, apo B and triglyceride levels (19.9%, 20.3% and 23.9% of sample variance) of similar magnitude as in the healthy individuals. Apo B polymorphisms were found to be associated with much smaller effects on lipid traits than in the healthy individuals. The only significant association was between the asparagine/serine4311 polymorphism and HDL-triglyceride levels. However, global severity of coronary atherosclerosis at the first angiography was found to be significantly associated with the LAL insertion/deletion polymorphism (P = 0.008). Thus variation at the apo B gene locus is associated with the development of atherosclerosis, but the data suggests that this may act through mechanisms not directly related to effects on measured lipid traits.     

Evidence for a role of regulatory T cells in mediating the atheroprotective effect of apolipoprotein B peptide vaccine

Abstract. Wigren M, Kolbus D, Dunér P, Ljungcrantz I, Söderberg I, Björkbacka H, Fredrikson GN, Nilsson J. (Malmö University Hospital, Lund University; Malmö University, Malmo; Sweden) Evidence for a role of regulatory T cells in mediating the atheroprotective effect of apolipoprotein B peptide vaccine. J Intern Med 2011; 269 : 546–556. Objectives. Autoimmune responses against oxidized low‐density lipoprotein are considered to play an important pro‐inflammatory role in atherosclerosis and to promote disease progression. T‐regulatory cells (Tregs) are immunosuppressive cells that have an important part in maintaining self‐tolerance and protection against autoimmunity. We investigated whether aBp210, a prototype atherosclerosis vaccine based on a peptide sequence derived from apolipoprotein B, inhibits atherosclerosis through the activation of Tregs. Design. Six‐week‐old Apoe^?/? mice were immunized with aBp210 and received booster immunizations 3 and 5 weeks later, as well as 1 week before being killed at 25 weeks of age. Results. At 12 weeks, immunized mice had increased expression of the Treg marker CD25 on circulating CD4 cells, and concanavalin A (Con A)‐induced interferon‐γ, interleukin (IL)‐4, and IL‐10 release from splenocytes was markedly depressed. At 25 weeks, there was a fivefold expansion of splenic CD4+ CD25+ Foxp3 Tregs, a 65% decrease in Con A‐induced splenic T‐cell proliferation and a 37% reduction in the development of atherosclerosis in immunized mice. Administration of blocking antibodies against CD25 neutralized aBp210‐induced Treg activation as well as the reduction of atherosclerosis. Conclusions. The present findings demonstrate that immunization of Apoe^?/? mice with the apolipoprotein B peptide vaccine aBp210 is associated with activation of Tregs. Administration of antibodies against CD25 results in depletion of Tregs and blocking of the atheroprotective effect of the vaccine. Modulation in atherosclerosis‐related autoimmunity by antigen‐specific activation of Tregs represents a novel approach for treatment of atherosclerosis.     

Lipid lowering in severe familial hypercholesterolaemia: efficacy and safety of a new regenerating system for selective apheresis of apolipoprotein B-containing lipoproteins

Preliminary experience of the efficacy and safety of a new regenerating system for selective extracorporeal removal of apolipoprotein B-containing lipoproteins is described. Four patients with familial hyperlipoproteinaemia were studied on 10 occasions. A system of two, parallel, dextran sulphate cellulose columns was used, and plasma was processed continuously by passage through one of the columns while the other was being regenerated. With this procedure, reductions of very low density and low density lipoprotein cholesterol levels by 73 and 43%, respectively, could be achieved after treatment for 2.5-3 h (1000-3200 ml of plasma volume). No clinically relevant changes in the concentrations of other plasma proteins, including high density lipoproteins, were observed, and the treatment was well tolerated. We conclude that continuous selective apolipoprotein B apheresis is a safe and efficient lipid-lowering procedure which may be used both for metabolic investigations and for studies on possible regression of atherosclerosis.