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)     

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     

Increased levels of lipoprotein(a) in non-smoking aortic dissection patients

OBJECTIVES: To investigate lipoprotein(a) (Lp(a)) serum levels in patients with aortic dissection and the influence of smoking on the level of Lp(a) in aortic dissection patients. METHODS: An age-and sex-matched case-control study was conducted. Lp(a) levels in patients with aortic dissection (n = 52) and healthy subjects (n = 104) were studied. The strength of associations between Lp(a) serum levels and aortic dissection was assessed by means of multivariate logistic regression analysis. RESULTS: Patients with aortic dissection had significantly higher Lp(a) serum levels (median, 17.6 mg/dl; range, 6.4-88.7 mg/dl) compared to healthy individuals (median, 12.4 mg/dl; range, 4.9-26.4 mg/dl) (p = 0.005). The Lp(a) concentration in non-smoking patients with aortic dissection (median, 19.1 mg/dl, range, 10.5-88.7 mg/dl) significantly surpassed that of the smoking patients with aortic dissection of comparable age (median, 10.7 mg/dl; range, 6.4-22.1 mg/dl) (p < 0.0001). Multivariate analysis confirmed an independent association between Lp(a) and aortic dissection in the non-smoking population (p = 0.001). CONCLUSIONS: Serum Lp(a) level is significantly elevated in non-smoking patients with aortic dissection independently of other cardiovascular risk factors. Therefore, determination of Lp(a) levels may be important in identifying subjects at risk of aortic dissection among nonsmokers.     

类风湿性关节炎患者的血清脂蛋白a水平与炎症指标相关性分析

目的 通过对类风湿性关节炎(RA)患者组与对照组(正常健康者)脂蛋白a(Lp-a)与脂代谢水平的比较,分析RA患者血清中的Lp-a水平与系统性炎症进展的风险相关性.方法 选取30例RA患者(血清类风湿因子阳性)与30例正常健康者,年龄为25～80岁,性别分布相同,采集血样并检测其脂代谢水平(Lp-a、甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)和极低密度脂蛋白胆固醇(VLDL-C))与炎症反应指标(肿瘤坏死因子α(TN F-α)、白细胞介素6(IL-6)和C反应蛋白(CRP)),对数据进行统计学分析.结果 与对照组比较,RA患者组的血清Lp-a水平显著增高(P＜0.001),HDL-C水平显著降低(P＜0.05),而TC、TG、LDL-C与VLDL-C水平则无明显变化,差异均无统计学意义(P＞0.05).同时,RA患者组的TNF-α、IL-6及CRP水平较对照组均显著增高(P＜0.05),且TNF-α与Lp-a水平的升高有相关性(r=0.753,P＜0.001).结论 RA患者常伴有高水平的Lp-a,且Lp-a水平的升高与RA患者的全身性炎症反应增强具有相关性,Lp-a水平可作为RA患者的风险评价指标.     

Morphological detection and quantification of lipoprotein(a) deposition in atheromatous lesions of human aorta and coronary arteries

Summary Lipoprotein(a), as an atherogenic particle, represents an independent risk factor for coronary heart disease. In the present study the morphological distribution of apoprotein (a) and apoprotein B within the arterial wall is described. Apoprotein B, a constituent of very low-density lipoprotein, low-density lipoprotein and lipoprotein(a) has previously been demonstrated in atheromatous lesions. Lipoprotein(a) possesses an additional protein, designated apoprotein (a). Autopsy material (n=74) from the left coronary artery and from the thoracic aorta has been examined by means of immunohistochemistry and both apoprotein (a) and apoprotein B were detected, primarily associated with the extracellular matrix and accumulating in lesions in the arterial wall. The staining pattern for both antigens was almost always found to be congruent, suggesting that the detection of (a)-antigen has to be attributed at least in part to the presence of lipoprotein(a). It is concluded that both low-density lipoprotein and lipoprotein(a) have an important role in the pathogenesis of atherosclerosis.     

Relationship between lipoprotein(a) levels, oxidative stress, and blood pressure levels in patients with essential hypertension

High plasma levels of lipoprotein(a) [Lp(a)] are considered a risk factor for the development of coronary artery disease. In vitro experiments have shown that oxidized Lp(a) is able to impair the arterial endothelium-dependent dilation, thus suggesting a possible role of Lp(a) in the genesis of essential hypertension. The aim of our work was to investigate the correlation of blood pressure levels with plasma Lp(a) concentration, apo(a) isoform size, and peroxidative stress in patients with essential hypertension. The study was performed in 54 untreated hypertensive patients whose blood pressure was monitored for 24 h by ambulatory blood pressure monitoring. Lp(a) concentration was measured by a double monoclonal antibody-based enzyme immunoassay demonstrated to be insensitive to apo(a) size heterogeneity. Apo(a) isoforms were determined by a high-resolution SDS-agarose gel electrophoresis followed by immunoblotting. A significant correlation was found between Lp(a) levels and the night-time systolic and diastolic pressures (r=0.32, P<0.05, and r=0.30, P<0.05, respectively), as well as with the mean night-time fall in systolic and diastolic blood pressures (r=0.28, P<0.05 and r=0.29, P<0.05, respectively). These relationships were further potentiated when peroxidative stress data were taken into consideration (r=0.37 and r=0.40, P<0.01 for the night-time systolic and diastolic pressures, respectively and r=0.34 and r=0.38, P<0.01 for the night-time fall in systolic and distolic blood pressures, respectively). Apo(a) isoform size did not affect these relationships. Our data suggest that Lp(a) and peroxidative stress may be involved as cofactors in essential hypertension, with a mechanism that remains to be elucidated. Received: 16 July 2001 / Accepted: 15 September 2001     

Ischemic stroke in a young adult with extremely elevated lipoprotein(a): A case report and review of literature

Lipoprotein(a) [Lp(a)] is an apolipoprotein(a) molecule bound to 1 apolipoprotein B-100. Elevated levels of Lp(a) are thought to be an independent risk factor for atherosclerosis and to promote thrombosis through incompletely understood mechanisms. We report a 34-year-old man with an ischemic stroke in the setting of an extremely high Lp(a) level—212 mg/dL. He developed severe carotid artery stenosis over a 6-year period and had thrombus formation post-carotid endarterectomy. To our knowledge, this case is unique because the Lp(a) is the highest reported level in a patient without renal disease. Moreover, this is the first reported case of the youngest individual with a stroke presumably related to development of carotid plaque over a 6-year period. The thrombotic complication after endarterectomy may have been related to the prothrombotic properties of Lp(a). Of note, the Lp(a) level did not respond to atorvastatin but did decrease 15% after aspirin 325 mg was added although his Lp(a) levels were variable, and it is not clear that this was cause and effect. This case highlights the need to better understand the relation between Lp(a) and vascular disease and the need to screen family members for elevated Lp(a). We also review treatment options to lower Lp(a) and ongoing clinical trials of newer lipid-lowering drugs that can also lower Lp(a).     

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.     

脂蛋白(a)基因单核苷酸多态性与钙化性主动脉瓣疾病及冠心病的关系

目的 探讨脂蛋白(a)[Lp(a)]基因单核苷酸多态性(SNP)与钙化性主动脉瓣膜疾病(CAVD)、冠心病(CHD)的相关性。方法 前瞻性研究。纳入2018年1-12月天津市胸科医院心内科CAVD或CHD住院患者248例,根据心脏超声多普勒、冠状动脉造影或冠状动脉CT检查结果分为两组:CAVD组101例、CHD组147例;同时选取2018年3-12月天津市胸科医院体检中心排除CAVD或CHD的171位健康体检者为对照组。检测各组Lp(a)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)、载脂蛋白A(ApoA)、载脂蛋白B(ApoB)等生化指标,采用SNaPshot SNP分型技术对Lp(a)基因rs7770628、rs6415084、rs10455872三个位点进行基因分型;采用二元logistic回归分析不同基因型及Lp(a)水平对钙化性主动脉瓣疾病及冠心病发病的影响,采用线性回归分析不同基因型及ApoB水平对Lp(a)水平的影响。结果 三组间比较,患者BMI和饮酒史差异均无统计学意义(P值均＞0.05),性别、年龄、吸烟史、糖尿病史、高血压病史差异均有统计学意义(P值均＜0.05)。Lp(a) 检测值在对照组、CAVD组、CHD组分别为23.6(9.4,48.6)、37.2(16.5,79.6)、46.7(21.5,104.6)nmol/L,三组间比较差异有统计学意义(H=13.337,P<0.01);LDL值各组分别为(2.74±0.80)、(3.07±0.81)、(3.14±1.18)mmol/L,三组间差异有统计学意义(F=3.662,P<0.05);HDL值各组分别为(1.24±0.93)、(1.18±0.30)、(1.09±0.33 )mmol/L,三组间比较差异有统计学意义(F=4.281,P<0.05);ApoA值各组分别为(1.42±0.25)、(1.30±0.26)、(1.26±0.26) g/L,三组间比较差异有统计学意义(F=7.339,P<0.01);ApoB检测值各组分别为0.97(0.82, 1.10)、1.04(0.87, 1.26)、1.12(0.88, 1.31)g/L,三组间比较差异有统计学意义(H=3.948,P<0.05)。Lp(a)基因rs7770628位点对照组、CAVD组、CHD组TT基因型分别为130(76.0%)、75(74.3%)、103(70.1%),CT基因型分别为36(21.1%)、23(22.8%)、40(27.2%),CC基因型分别为5(2.9%)、3(2.9%)、4(2.7%),三组间比较差异无统计学意义(F=1.718,P＞0.05);Lp(a)基因rs6415084位点对照组、CAVD组、CHD组TT基因型分别为5(2.9%)、2(2.0%)、4(2.7%),CT基因型分别为33(19.3%)、20(19.8%)、32(21.8%),CC基因型分别为133(77.8%)、79(78.2%)、111(75.5%),三组间比较差异无统计学意义(F=0.551,P＞0.05);Lp(a)基因rs10455872位点对照组、CAVD组、CHD组AA基因型分别为171(100%)、99(98.0%)、147(100%),AG基因型分别为0(0.0%)、2(2.0%)、0(0.0%),三组间比较差异无统计学意义(P=0.058)。经logistic回归分析,与对照组相比, CAVD组及CHD组的Lp(a)水平更高,其差异有统计学意义,但未发现Lp(a)基因rs7770628及rs6415084两个位点的基因分布频率的差异有统计学意义(P>0.05)。线性回归结果表明,rs7770628以及rs6415084两个基因位点的基因分布均与Lp(a)水平升高有关。rs10455872位点只有2例SNP基因型为AG,且皆出现于CAVD组。结论 Lp(a)基因rs7770628、rs6415084位点的基因分布均与Lp(a)的升高有关,Lp(a)高表达与CAVD以及CHD患病具有相关性。     

Effects of tibolone on lipoprotein(a) and HDL subfractions

Objective: To determine the effects of tibolone, a synthetic steroid used to alleviate climacteric symptoms and prevent osteoporosis, on lipoprotein metabolism, with particular reference to lipoprotein(a) levels and HDL subfraction profiles.Design: Thirty nine postmenopausal women were treated with tibolone (Livial) 2.5 mg/day for 6 months and fasting serum lipoprotein levels were estimated at 0, 2, 4 and 6 months. Results: Lipoprotein(a) levels were reduced significantly over the 6 months from a median level of 245 (range <60–780) mg/I to 152 (range <60–530) mg/l, a reduction of 39% in the median level. A decrease was observed in approximately two thirds of the women. Reductions were noted in all 6 subjects whose pretreatment levels were high, although concentrations remained at a level associated with increased risk in all but one. There were significant decreases in triglycerides and VLDL cholesterol and no significant change in LDL cholesterol. There was a significant reduction of 18% in HDL cholesterol and a 26% reduction in the HDL₂:HDL₃ ratio. Conclusion: The reduction in lipoprotein(a) levels may have a beneficial effect on cardiovascular risk, which could go some way towards balancing the potentially adverse effect on the cardiovascular system caused by the reduction in HDL cholesterol.     

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     

Long-term effect of lovastatin alone and in combination with cholestyramine on lipoprotein (a) level in familial hypercholesterolemic subjects

Summary We have determined the effect of lovastatin alone or in combination with cholestyramine on lipoprotein (a) [Lp(a)] levels in 59 heterozygotes for familial hypercholesterolemia (FH) treated for 33.8 (±6.1) months. The median pretrial Lp(a) value was 10.2 mg/100 ml, which is twice the median value in healthy people examined at the Institute of Medical Genetics, University of Oslo. The median Lp(a) level was insignificantly reduced by 10.3% during the first 20 weeks when the subjects were on a standardized medication of increasing doses of lovastatin and cholestyramine. The first 20 weeks were followed by usual care treatment period, and a further decrease in Lp(a) level to 16.2% (P=0.0012) was observed at the end of the study. Comparison between the 20 subjects on lovastatin monotherapy and the 31 subjects on the combined therapy of lovastatin and cholestyramine, revealed that the subjects on monotherapy had a median reduction of 20.1%, and the subjects on the combined therapy had a reduction of 15.4%. Thus, it appears that the reduction in Lp(a) level could be ascribed to lovastatin alone.Abbreviations ALAT alanine aminotransferase - ALP alkaline phosphatase - ASAT aspartate aminotransferase - CK creatine phosphokinase - FH familial hypercholesterolemia - GT glutamyl transpeptidase - HDL high density lipoprotein - HMG CoA 3-hydroxy-3-methylglutaryl coenzyme A - LDL low density lipoprotein - Lp(a) lipoprotein (a) - apo(a) apoprotein (a)     

脂蛋白(a)[Lp(a)]的增高与妊高征

目的探讨脂蛋白(a)Lp(a)与妊高征之间的关系.方法应用ELISA法测定29例非妊高征孕妇(非妊高征组)及19例妊高征患者(妊高征组)的血清Lp(a)水平.结果(1)妊高征组血清Lp(a)水平为(394.5895±210.717)mg/L,高于非妊高征组(180.1896±123.221)mg/L,两组间比较,差异有显著性(P＜0.01).(2)Lp(a)最高值发生于子痫患者.结论Lp(a)与妊高征关系密切,Lp(a)的增高与妊高征之间很可能存在因果关系.