Reduction of lp(a) by different methods of plasma exchange

Summary Lipoprotein(a) has been shown to be an independent risk factor for atherosclerosis. The effect of different forms of plasmapheresis therapy on the removal ofLp (a) is examined. Plasmapheresis is successfully administered in a small number of hypercholesteremic patients who fail to respond to conventional therapy. Comparison of four different methods of plasma exchange (albumin substitution, anti-apoB antibody column, LDL precipitation, filtration) reveals significant differences in effectiveness in the ability to lower plasma Lp(a): plasma exchange with albumin und LDL precipitation seem to be the most effective, plasma filtration the least.Abbreviations Lp(a) lipoprotein(a) - LDL low density lipoprotein - HDL high density lipoprotein - VLDL very low density lipoprotein - DEAE diethylaminoethyl - SD standard deviation - HELP heparin induced extracorporal LDL precipitation - RCA right coronary artery - LAD left anterior descendent coronary artery - AOCB aortocoronary bypass - MI myocardial infarction - apoB apolipoprotein B     

Effect of low-density lipoprotein buoyant density and cholesterol content on the formation of lipoprotein(a) particles

Lipoprotein(a) [Lp(a)] is a unique lipoprotein which resembles low-density lipoprotein (LDL) both in lipid composition and the presence of apolipoprotein B-100 (apo B-100). Lp(a) is, however, distinguishable from LDL by the presence of an additional glycoprotein apolipoprotein(a) [apo(a)], which is covalently attached to apo B-100 by a single disulfide bond. It is now generally accepted that Lp(a) assembly is a two-step process in which the initial non covalent interaction between apo(a) and apo B-100 is mediated by the weak lysine binding sites present in kringle IV types 6, 7 and 8 of apo(a). In the present study, we have investigated the effect of LDL heterogeneity on Lp(a) assembly in a group of 111 individuals. The three parameters of LDL composition assessed in this study were the cholesterol content, the apo B content, and the relative flotation rate (a measure of LDL buoyancy and thus size). We found no correlation between the size of LDL particles and the extent of Lp(a) formation; a weak negative correlation was observed between cholesterol content of LDL and Lp(a) formation (P=0.042). This may suggest a role for free (i. e., surface-associated) cholesterol in the ability of LDL to form Lp(a) particles. Received: 1 June 2001 / Accepted: 2 July 2001     

JCL roundtable—Lipoprotein(a): The emerging risk factor

Lipoprotein(a), or Lp(a), is a major risk factor for atherothrombotic events along with low-density lipoprotein cholesterol and, inversely, high-density lipoprotein cholesterol. Lp(a) also contributes to the progression of calcific aortic stenosis and to the rare occurrence of arterial thrombotic strokes without atherosclerosis in children and younger women. Much has been learned about the inheritance of Lp(a) levels and the relationship between apolipoprotein(a) structure and function. Recent work suggests an intriguing interaction between oxidized phospholipids on Lp(a) and inflammatory interleukin-1 genotypes. New pharmaceutical approaches with antisense and RNA interference technology may achieve up to 90% lowering of Lp(a). This Roundtable includes practical considerations for clinically measuring and responding to Lp(a) levels.     

Apolipoprotein E phenotype and lipoprotein(a) in familial hypercholesterolaemia implication for lipoprotein(a) metabolism

The mechanisms regulating plasma levels of lipoprotein(a) [Lp(a)] are largely unknown. A two- to three-fold increase in Lp(a) levels in patients with familial hypercholesterolaemia (FH) has implied that LDL receptor activity may be an important factor in determining plasma Lp(a) levels, as it is in determining low-density lipoprotein (LDL) cholesterol concentration. Common apolipoprotein E (apoE) variants also affect plasma LDL cholesterol levels. We therefore examined the effect of the common apoE variants on plasma Lp(a) levels in 149 patients with heterozygous FH. Patients with the apoE₂ allele (n = 11) had significantly higher plasma levels of LDL cholesterol compared to those with a apoE₃E₃ phenotype, while patients with the apoE₄ isoform had similar levels. However, there was a significant effect of the apoE₂ allele in lowering Lp(a) levels, compared to the apoE₃E₃ group. The median Lp(a) concentration in patients possessing an apoE₂ isoform was 13.1 mg/dl below the median, while in those with an apoE₄ allele the median Lp(a) levels were 4.13 mg/dl higher. There was a marked inverse correlation between plasma Lp(a) and LDL cholesterol concentration in the FH patients carrying the apoE₂ allele. Our data imply that difference in Lp(a) levels observed between FH patients with different apoE isoforms does not result from altered clearance of Lp(a) via the LDL receptor pathway, and suggest that apoE mediated hepatic up-take, or conversion, of remnant particles may be determining Lp(a) production rate.Abbreviations apo apoprotein - CHD coronary heart disease - FH familial hypercholesterolaemia - HDL high-density lipoprotein - LDL low-density lipoprotein - Lp(a) lipoprotein(a)     

Triglyceride and lipoprotein (a) are markers of coronary artery disease severity among postmenopausal women

Objective: After menopause, some women manifest coronary artery disease (CAD) with highly variable angiographic severity. For these women, postmenopausal appearing of some CAD risk factors may have differently influenced the CAD risk and severity. In this study, we attempt to unravel differences in the frequency or intensity of CAD risk factors among postmenopausal women with different angiographic severity. Methods: We studied 182 postmenopausal women (64±6 years) who underwent coronary angiography to investigate thoracic pain. Subjects with no detectable coronary lesions at angiography were recruited to the non-obstructive group and patients with CAD were grouped in one-vessel or multi-vessel groups. We compared clinical variables as the body mass index (BMI), age at menopause, age, hypertension, diabetes and cigarette smoking, and lipid measurements as plasma levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apolipoprotein (apo) A1, apo B and lipoprotein(a) (Lp(a)). Results: Comparing to the non-obstructive group, Lp(a) was twofold higher in the one-vessel group and threefold higher in the multi-vessel group and triglycerides were 34% higher in the one-vessel group and 50% higher in the multi-vessel group. No further difference was found among the three groups. After multivariate logistic regression analysis, triglyceride (odds ratio: 1.01; P=0.0013) and Lp(a) (odds ratio: 1.006; P<0.0001) were independently indicative of the presence of obstructive CAD. Conclusion: We found that both Lp(a) and triglycerides constitute useful markers of CAD severity among postmenopausal women.     

The study of serum apoprotein levels as indicators for the severity of angiographically assessed coronary artery disease

Serum apoprotein A-I (Apo A-I) and B (Apo-B) concentrations were determined in 40 subjects undergoing coronary angiography for past myocardial infarction and angina pectoris, and the authors studied the relationship between the apoprotein concentrations and the severity of coronary artery disease (CAD). During this study, serum total cholesterol, triglyceride, and high-density lipoprotein, low-density lipoprotein, and very low density lipoprotein cholesterol concentrations were determined to control analysis. The results showed that the decrease in serum Apo A-I levels was the best indicator distinguishing CAD from non-coronary artery disease; the Apo B/Apo A-I ratio had the most consistent association with the severity of CAD as assessed by angiography; Apo B/Apo A-I values ranging from 0.98 to 1.00 might be considered critical values for early CAD.     

冠心病患者血浆脂蛋白(a)与载脂蛋白水平检测分析

目的观察脂蛋白(a)与冠心病发展病程之间的关系。方法将冠心病患者498例按病程发展的各期进行分组。以免疫透射比浊法对冠心病患者各组血浆中脂蛋白(a)、载脂蛋白A1、载脂蛋白B水平进行检测。结果冠心病患者血中Lp(a)、ApoB水平明显高于健康对照组(P<0.05)。随着冠状动脉粥样硬化的严重程度逐步增加,血中Lp(a)、ApoB逐步上升,与病程呈正相关关系(r=0.4596,P<0.05)。结论Lp(a)与冠心病病程发展有着密切的联系。检测血中Lp(a)浓度对预防冠状动脉栓塞的发生和发展具有临床指导意义和应用价值。     

Severe coronary disease in an adult considered at low cardiovascular disease risk with a healthy lifestyle

Lipoprotein(a) [Lp(a)] is a lipoprotein subclass well-known among the lipid community to accelerate atherosclerosis and promote thrombosis through incompletely understood mechanism. We report a case of a young man with a healthy lifestyle and no major coronary or vascular risk factors who presented to the emergency department with an acute coronary syndrome and was ultimately found to have severe coronary artery disease. A diagnostic workup revealed elevated Lp(a). He was treated with consequent reduction in Lp(a) concentration. This case highlights the need to better understand atypical lipoproteins, how they relate to cardiovascular disease, the implications for screening family members, and the need to standardize patient management guidelines for the purpose of mortality risk reduction.     

Studies on the structure and function of the apolipoprotein(a) gene

Lp(a) is an LDL-like lipoprotein that is a major inherited risk factor for atherosclerosis. It is distinguished from Lp(a) by the addition of apolipoprotein(a). The gene structure of apolipoprotein(a) is homologous to plasminogen, and competition with plasminogen activity may account for some of the pathophysiology associated with Lp(a). Six highly related genes have now been identified, and at least four are found in close proximity in overlapping genomic clones. Studies have begun on the regulation of apolipoprotein (a) gene expression, and the human apolipoprotein(a) gene has been inserted into transgenic mice, where it leads to the development of arterial lesions.     

Elevated lipoprotein(a) levels in patients with acute myeloblastic leukaemia decrease after successful chemotherapeutic treatment

Summary Twenty-two patients with acute myeloblastic leukaemia (AML) were studied to investigate disease-associated changes in lipid metabolism. Lipoprotein (a) [Lp(a)] levels were found to be elevated at the time of diagnosis (median 23 mg/dl; 41% of patient group had levels greater than 25 mg/dl) and diminished after successful chemotherapeutic treatment in 9 of 10 cases, with a maximum decrease from 56 to 10 mg/dl. In contrast, reduced levels of total cholesterol, low density lipoprotein (LDL) and high density lipoprotein (HDL) (medians 137, 87 and 20 mg/dl, respectively) were observed at the time of diagnosis. Cholesterol and HDL levels increased in all 10 and LDL in 9 cases in which complete remission was achieved. These data suggest that the catabolism of LDL-cholesterol might be even more enhanced than assumed to date. Furthermore, it indicates that the Lp(a) level in acute myeloblastic leukaemia is influenced either directly or indirectly by the leukaemic blasts.Abbreviations AML acute myeloblastic leukaemia - Lp(a) lipoprotein (a) - LDL low density lipoprotein - HDL high density lipoprotein - FAB French-American-British - CALGB cancer and leukaemia group B - CR complete remission - TG triglycerides - VLDL very low density lipoprotein - RIA radioimmunoassay - apo(a) apoprotein (a) - HMG-CoA reductase 3-hydroxy-3-methylglutaryl coenzyme A reductase Supported by the Volkswagen Stiftung with a grant to A.N.     

Apolipoprotein(a) phenotypes and lipoprotein(a) concentrations in patients with hyperthyroidism

Lipoprotein(a) [Lp(a)] is a low-density lipoprotein (LDL) particle in which apolipoprotein B-100 (apoB) is attached to a glycoprotein called apolipoprotein(a) [apo(a)]. Apo(a) has several genetically determined phenotypes differing in molecular weight, to which Lp(a) concentrations in plasma are inversely correlated. High plasma levels of Lp(a) are associated with atherosclerotic diseases. It is therefore of interest to study whether factors other than the apo(a) gene locus are involved in the regulation of Lp(a) concentrations. We measured plasma concentrations of Lp(a) and other lipoproteins and determined apo(a) phenotypes in 31 patients with hyperthyroidism, before and after the patients had become euthyroid by treatment. The mean concentration of LDL cholesterol rose from 2.67 to 3.88 mmol/l (P<0.01), apoB rose from 0.79 to 1.03 g/l (P<0.01), and the median Lp(a) concentration increased from 9.74 to 18.97 mg/dl (P<0.01) on treatment. Lp(a) concentrations were inversely associated to the size of the apo(a) molecule both before (P< 0.01) and after treatment (P<0.01). The increase in Lp(a) was significant patients with high molecular weight apo(a) phenotypes (n = 9; P<0.01) and in patients with low molecular weight apo(a) phenotypes (n=16; P< 0.01), but not in those with apo(a) null types (n = 6; P = 0.5). The low levels LDL cholesterol and apoB in untreated hyperthyroidism may result from increased LDL receptor activity. The increase in Lp(a) levels were not correlated with the increase in LDL cholesterol or apoB. Most other clinical evidence indicates that the LDL receptor is not important in Lp(a) catabolism, and we suggest that the low Lp(a) levels seen in thyroid hormone excess are caused by an inhibition of Lp(a) synthesis.Abbreviations Lp(a) lipoprotein(a) - apo(a) apolipoprotein(a) - apoB apolipoprotein B-100 - LDL low-density lipoprotein - HDL high-density lipoprotein - TG triglycerides - T ₄ thyroxine - T ₃ triiodothyronine - TSH thyrotropin     

Lp(a)与LDL氧化修饰的比较

脂蛋白（a）［Lp（a）］是一种特殊的血浆脂蛋白,其结构、理化性质和脂质组成与低密度脂蛋白（LDL）极为相似。氧化低密度脂蛋白（Ox－LDL）在动脉粥样硬化（AS）的发生、发展中起重要作用,Lp（a）的氧化亦发生于体内动脉壁。在体外,Lp（a）能经铜离子（Cu2＋）介导发生氧化修饰,但与LDL相比,Lp（a）氧化的延迟时间是LDL的1．62倍,氧化速率和氧化程度均只有LDL的63％,故Lp（a）对氧化的敏感性和氧化程度均较LDL为低,其高度致AS作用,难以完全用较高的氧化敏感性来加以解释。     

Effects on lipids and lipoproteins in women treated with oestradiol and progesterone

Thirty women with climacteric symptoms were treated for 4 months with 2 mg 17β-oestradiol and different doses of progesterone (50, 100 or 200 mg). The concentrations of total and free cholesterol, phospholipids, triglycerides (TG), apoprotein A1 and apoprotein B were determined in high-density lipoprotein (HDL), low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) fractions and in serum. HDL levels increased and LDL levels decreased, while TG levels in VLDL remained unchanged, which indicates that the lipoprotein pattern is oestrogen-induced and that progesterone exerts little or no influence.     

Coronary atheroma in the cynomolgus monkey: Predictive value of serum and cutaneous lipoprotein measurement

Summary Hyperlipaemia was induced by a high fat diet in 11 cynomolgus monkeys. Morphological study of coronary arteries was carried out in 5 coronary samples from these 11 monkeys. The degree of arterial involvement was compared with the serum and cutaneous lipoprotein levels. These experimental data confirm that cutaneous apoprotein B measurement is the best marker for evaluation of coronary atheroma.     

The relation of risk factors to the development of atherosclerosis in saphenous-vein bypass grafts and the progression of disease in the native circulation. A study 10 years after aortocoronary bypass surgery

We examined 82 patients 10 years after saphenous-vein aortocoronary bypass surgery to determine their angiographic status and to relate those findings to the risk factors for coronary-artery disease. Of 132 grafts shown to be patent 1 year after surgery, only 50 were unaffected at 10 years. The remainder were narrowed (43) or occluded (39). Disease progression in coronary arteries without grafts was also frequent, both in vessels that were normal (15 of 32) and in those with minor stenosis (25 of 53). New lesions did not develop in 15 patients, whereas they did in 67--in the grafts, the native vessels, or both. There was no significant difference between the two groups in the incidence of hypertension, diabetes, or smoking, whereas plasma levels of very-low-density lipoproteins (VLDLs) and low-density lipoproteins (LDLs) were higher, and high-density lipoprotein (HDL) levels were lower in those with new disease than in those without. Univariate analysis showed that plasma cholesterol and triglyceride levels were significantly higher at the time of surgery and at the 10-year examination in those with new lesions. Multivariate analysis indicated that among the lipoprotein indexes, levels of HDL cholesterol and plasma LDL apoprotein B best distinguished the two groups. The findings indicate that atherosclerosis in these patients was a progressive disease, frequently affecting both the grafts and the native vessels, and that the course of such disease may be related to the plasma lipoprotein levels.     

Correlation of P-selectin and lipoprotein(a), and other lipid parameters in preeclampsia

Preeclampsia is a pregnancy specific disorder and is thought to be associated with generalized endothelial dysfunction. P-selectin, an adhesion molecule, mediates the interaction of monocytes, platelets, and endothelial cells. Increased P-selectin levels and altered lipid and lipoprotein metabolism were reported in preeclampsia and during pregnancy. In order to investigate the relationship between serum P-selectin and lipoprotein(a), and other lipid parameters, 28 preeclampsia [13 severe (group I) and 15 mild preeclampsia (group II), 15 healthy pregnant (group III) and 20 non-pregnant (group IV)] women were investigated. Serum P-selectin, lipoprotein(a), total cholesterol, triglyceride, and high density lipoprotein cholesterol were measured and low-density lipoprotein cholesterol was derived. Serum P-selectin concentrations were consistently and significantly higher in the severe preeclampsia group than in the mild preeclampsia, healthy pregnancy, and non-pregnant control groups (P<0.0001, for all). The mild preeclampsia group also had increased serum P-selectin concentrations compared with the healthy pregnancy group and non-pregnant controls (P<0.05 and P<0.0001, respectively). Serum P-selectin and lipoprotein(a) levels revealed a significant and linear increase with the severity of preeclampsia. There were also significant (in groups I and II) and borderline (in groups III and IV) correlations between P-selectin and total cholesterol. The present study suggests that P-selectin may be an additional risk marker for preeclampsia, and may be useful in distinguishing women with mild and severe preeclampsia and normal pregnancy. Received: 9 November 2001 / Accepted: 6 February 2002     

Lipoprotein lipase activity in patients with combined hyperlipidaemia

The aetiology of familial combined hyperlipidaemia remains obscure, with both genetic and environmental factors contributing to the phenotype, which is frequently associated with premature coronary heart disease. We have studied lipoprotein lipase (LPL) activity and hepatic lipase (HL) activity in patients with coronary heart disease to determine whether variation in lipase activities contributes to this phenotype. Forty-one patients (mean age 50 years; 30 male) were selected on the basis of cholesterol levels above 6.5 mmol/l and triglyceride levels above 2.2 mmol/1, with apoprotein B values over the 90th percentile. There was a family history of premature coronary heart disease in 78% and a personal history in 64%, at mean age 44, the patient group therefore predominantly corresponded to the common definition of familial combined hyperlipidaemia, appropriate in the absence of molecular markers. None of the patients was diabetic; hypertension and smoking were not over represented. Blood samples were taken following intravenous administration of heparin (100IU/kg body wt), and LPL and HL activities were measured. Mean post-heparin LPL was significantly lower in patients than controls 10 min after heparin administration (2.98 ± 1.04 and 3.86 ± 0.93 mol ml^-1 h^-1, respectively, P = 0.001), and 37% patients had values below the 10th percentile of controls. Both male and female patients had significantly higher HL activities than their respective controls at 5, 10, 20 and 30 minutes postheparin. As expected, both female patients and controls had lower HL activities than males, although this sex difference did not reach statistical significance in the patient group. Mean lipid and lipoprotein results were: cholesterol 8.2 mmol/1; triglycerides 4.2 mmol/l; high-density lipoprotein cholesterol 0.90 mmol/1; apoprotein Al 122 mg/dl; apoprotein B 171 mg/dl; lipoprotein (a) 23 mg/dl (median 10 mg/dl). High-density lipoprotein cholesterol and triglycerides were negatively correlated (r = -0.26, P = 0.05). HL was significantly related to body mass index at all time points whereas the negative correlation between post-heparin LPL and body mass index was significant only 30 min after heparin administration. Post-heparin LPL was only weakly correlated with triglycerides 10 and 20 min after heparin administration. These lipid and lipoprotein results are clearly potentially atherogenic as indicated by the extent of premature coronary heart disease in the group described. A decrease in LPL activity may contribute to this pattern.Abbreviations FCHL familial combined hyperlipidaemia - CHD coronary heart disease - LPL lipoprotein lipase - HL hepatic lipase - HDL high-density lipoprotein - VLDL very low density lipoprotein; - apo apoprotein - TG triglyceride - BMI body mass index Correspondence to: M. Seed     

Lipoprotein (a), low-density,intermediate-density lipoprotein,and blood pressure in a young male population

Summary Both hypercholesterolemia and hypertension are risk factors for atherosclerotic vascular disease, and elevated cholesterol levels occur more frequently than expected in patients with hypertension. Elevated levels of intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL) were shown to be atherogenic, and LDL, comprising the major cholesterol-carrying fraction in human plasma, are structurally related to lipoprotein (a) [Lp(a)], a further risk factor for atherosclerosis. In the present study we investigated 200 male employees (mean age 26±7 years) to determine whether the relationship of IDL and Lp(a) to systemic blood pressure is similar to the reported correlations between total and LDL cholesterol and systemic blood pressure. To this end blood pressure was measured several times in each individual, and lipids, lipoprotein-cholesterol, apolipoprotein B (apo B), and Lp(a) were determined in fasting serum. IDL cholesterol and apo B, the main protein component of IDL and LDL correlated with blood pressure. However, levels of Lp(a) correlated neither with systolic or diastolic blood pressure nor with lipoprotein cholesterol, body weight, or age. Although IDL and Lp(a) are considered lipoprotein risk factors for atherosclerosis, levels of Lp(a), unlike IDL, are not related to blood pressure, body weight, or age. Our data suggest different metabolic and pathophysiological mechanisms of the risk factors, IDL, LDL, and Lp(a).Abbreviations VLDL very low density lipoprotein - IDL intermediate-density lipoprotein - LDL low-density lipoprotein - ApoB Apolipoprotein B - Lp(a) lipoprotein (a) - BMI body mass index Dedicated to Prof. Dr. N. Zöllner on the occasion of his 70th birthday     

Lipoprotein(a). A potential bridge between the fields of atherosclerosis and thrombosis

Lipoprotein(a) (Lp[a]) represents a class of plasma lipoprotein particles that have overall characteristics similar to low-density lipoproteins but distinct from them by having apolipoprotein B100 linked to apolipoprotein(a) by disulfide bridge(s). This protein has recently been shown to have a striking amino acid sequence homology with plasminogen, a serine protease zymogen that on activation to plasmin promotes the conversion of fibrinogen to fibrin. The high incidence of Lp(a) in the plasma of patients with cardiovascular disease has been noted by many investigators. The new knowledge being rapidly acquired on the structure of Lp(a) should facilitate the understanding of the mechanism of its atherogenicity and perhaps shed light on its possible physiologic role.     

脑卒中患者血清脂蛋白(a)的变化及临床意义

目的 :探讨脑卒中患者血清脂蛋白 (a) [LP(a) ]含量的变化 ,以阐明LP(a)与脑卒中的关系及作用机制。方法 :采用酶联免疫吸附试验 (ELISA)双抗体夹心法检测 10 0例患者和 6 0例正常对照LP(a)的含量。结果 :脑卒中组LP(a)水平高于对照组 (P <0 0 1)。脑卒中合并糖尿病患者LP(a)水平明显高于不合并糖尿病患者 (P <0 0 1)。结论 :LP(a)是脑卒中患者相对独立的危险因素 ,它的水平可作为判断脑卒中患者的预后指标之一。