遗传性混合型高脂血症小鼠的自发性动脉粥样硬化

目的为探讨高甘油三酯血症对动脉粥样硬化的影响,建立了脂蛋白脂肪酶和载脂蛋白E双基因缺陷的混合型高甘油三酯和高胆固醇血症动物模型。方法比较了双基因以及载脂蛋白E基因缺陷小鼠的血浆甘油三酯,总胆固醇和高密度脂蛋白胆固醇的水平,并对整条主动脉和主动脉流出道进行了动脉粥样硬化病变定量检测。结果发现双基因缺陷小鼠血浆甘油三酯是载脂蛋白E基因缺陷小鼠的3.8倍(5.904±0.505比1.536±0.860g/L),血浆总胆固醇也略有增加,但高密度脂蛋白胆固醇则无明显差异。两种小鼠的主动脉全长及流出道均有明显的粥样硬化,斑块面积占全部动脉的37.2%±10.7%比44.6%±18.1%,但之间无显著差异。结论载脂蛋白E基因缺陷合并脂蛋白脂肪酶缺陷虽然可以出现血浆甘油三酯增高,但动脉粥样硬化病变并没有加重。这可能与血管壁局部脂蛋白脂肪酶的活性相应降低而对动脉粥样硬化抑制作用有关。     

脂蛋白Lp(a)、血浆脂质及其它脂蛋白水平与冠状动脉病变的关系

本文对冠状动脉造影显示出的冠状动脉病变程度进行评分,同时测定血浆脂蛋白Lp(a)(一种胆固醇含量丰富的脂蛋白)、总胆固醇、甘油三酯、低密度脂蛋白胆固醇(LDL胆固醇)、及高密度脂蛋白胆固醇(HDL胆固醇).证实血浆脂蛋白Lp(a)水平可     

非高密度脂蛋白胆固醇对冠状动脉病变的影响

目的 通过回顾性研究探讨不同血脂指标的控制对冠状动脉粥样硬化病变加重的影响.方法 入选在我院成功行支架植入术并于3个月后至1年内回院复查冠状动脉造影的患者,复查时间平均为7.4 ±2.2个月.未行介入治疗的其它冠状动脉若发生狭窄加重大于原来的25%以上定为粥样硬化病变加重.发生冠状动脉粥样硬化病变加重者95例,无变化者307例.患者于入院即介入手术前及复查冠状动脉造影前均测定了血清总胆固醇、甘油三酯、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇,非高密度脂蛋白胆固醇应用公式(总胆固醇-高密度脂蛋白胆固醇)计算.结果 复查时病变加重组和无变化组总胆固醇(4.62±1.14 mmol/L比4.26±1.01 mmol/L)、低密度脂蛋白胆固醇(2.51±0.93 mmol/L比2.25±0.75 mmol/L)及非高密度脂蛋白胆固醇水平(3.52±1.12mmoL/L比3.20±0.98 mmol/L),三者差异均有显著性(P<0.05),应用Logistic多因素分析显示均与病变加重发生 相关.结论 总胆固醇、低密度脂蛋白胆目醇及非高密度脂蛋白胆固醇水平是未行介入治疗的其它冠状动脉粥样硬化病变加重的重要危险因素,应重视冠心病患者非高密度脂蛋白胆固醇水平的有效控制.     

血脂及内皮素水平与冠状动脉疾病严重性的临床研究

目的　为探讨血浆脂质、内皮素水平、冠状动脉疾病 (CAD)严重性之间的关系和相关性。方法　对 2 2 0例冠状动脉造影阳性病人及 10 4例正常对照者的血浆胆固醇 (TC) ,甘油三酯 (TG) ,高密度脂蛋白胆固醇 (HDL c) ,低密度脂蛋白胆固醇 (LDL c) ,载脂蛋白B (apoB) ,脂蛋白a[Lp(a) ]及血浆内皮素 (ET)水平进行了测定。结果　CAD组血浆TC、TG、LDL c、apoB、Lp(a)、ET浓度均显著高于对照组 ,HDL c浓度显著低于对照组 ;CAD三支病变者 ,apoB、Lp(a)水平显著高于CAD单支病变者 (P <0 0 5 ) ;重度病变组ET水平明显高于轻度病变组 (P <0 0 5 )。等级相关分析显示 :冠状动脉病变支数越多 ,狭窄评分越高 ,apoB、Lp(a)、ET的浓度越高。结论　血浆TC、TG、HDL c、LDL c、apoB、Lp(a)、ET与冠状动脉疾病发病有关 ;Lp(a)和ET是动脉粥样硬化的独立危险因素 ;apoB和Lp(a)及ET水平增高与冠状动脉粥样硬化的严重程度密切相关 ;对冠状动脉病疾发病预测和严重性判定具有重要的参考价值和临床意义     

硝苯吡啶对高脂血症家兔和患者脂质代谢的影响

本文观察了硝苯吡啶(Nif)对实验性高脂血症、动脉粥样硬化家兔脂质代谢的影响。结果表明,Nif对喂饲胆固醇(Ch)家兔有显著降低血浆总胆固醇、甘油三酯、低密度脂蛋白Ch、载脂蛋白B,升高血浆高密度脂蛋白Ch(HDL-Ch)及其亚类HDL_2-Ch,减少主动脉组织Ch、epoB沉积和粥样病变面积的作用。并观察了37例高血压病伴高脂血症患者,其口服Nif治疗后其血脂变化与动物实验结果一致。Nif影响脂质代谢的机制可能与Nif能加强低密度脂蛋白(LDL)受体途径处理LDL有关。     

血浆脂蛋白(a)与冠状动脉病变的关系

目的　探讨血浆脂蛋白 (a) [LP(a) ]水平与冠状动脉病变程度、范围及稳定性的关系。方法　测定 2 5 6例冠脉造影患者的LP(a)、血浆总胆固醇 (TC)、甘油三酯 (TG)、高密度脂蛋白胆固醇 (HDL CL)、低密度脂蛋白胆固醇 (LDL C)的血浆浓度。结果　 ( 1)患者冠状动脉病变范围越大、程度越重 ,其血浆LP(a)水平越高 (P <0 .0 1) ;( 2 )不稳定性心绞痛患者血浆LP(a)水平高于稳定性心绞痛患者 (P <0 .0 1) ;( 3)血浆LP(a)水平与其它血脂没有相关性。结论　LP(a)与冠脉粥样病变的范围、程度及稳定性相关 ,对冠心病的诊断和预后判断具有一定意义     

男性心肌梗死患者行经皮冠状动脉介入治疗术前非高密度脂蛋白胆固醇与冠状动脉病变的关系研究

目的分析行经皮冠状动脉介入治疗(PCI)的男性心肌梗死患者术前非高密度脂蛋白胆固醇(non-HDL-C)与冠状动脉病变的关系。方法选取2010年11月—2013年10月在我院心内科住院且行冠状动脉造影(CAG)及PCI的男性心肌梗死患者192例,根据Syntax评分将其分为轻度(98例)、中度(55例)及重度(39例)病变组。检测3组患者术前血脂指标,包括:TC、LDL-C、HDL-C、non-HDL-C(non-HDL-C=TC-HDL-C)、TG、载脂蛋白A1(ApoA1)、载脂蛋白B(ApoB)、脂蛋白a〔LP(a)〕水平。结果轻度病变组non-HDL-C为(106.33±20.62)g/L,低于重度病变组的(118.95±15.11)g/L(P0.05)。结论 non-HDL-C可能是男性心肌梗死患者冠状动脉粥样硬化病变程度的较好预测指标。     

老年冠心病患者血浆非高密度脂蛋白胆固醇水平的差异

目的探讨在老年冠心病患者的血清非高密度脂蛋白胆固醇的差异。方法选择120例行冠状动脉造影检查的老年患者,冠状动脉造影前空腹采静脉血,分析冠状动脉造影阳性组和对照组之间非高密度脂蛋白胆固醇与其它血脂数据(总胆固醇、甘油三酯、高密度脂蛋白、低密度脂蛋白)差异的显著性及非高密度脂蛋白胆固醇对冠状动脉病变程度的相关性。结果冠状动脉造影阳性组非高密度脂蛋白胆固醇水平显著高于阴性组2.99±1.08mmol/L,一支病变组为3.41±0.59mmol/L,两支病变组为3.70±1.30mmol/L,三支病变组为3.77±1.10mmol/L,(P<0.001)并且非高密度脂蛋白的水平随冠状动脉病变支数逐渐增高,与冠状动脉狭窄分数相关(r=0.36,P<0.001);而两组间甘油三酯,高密度脂蛋白水平无统计学差异(P>0.05)。结论血清非高密度脂蛋白胆固醇对于老年人是一项简便实用的冠心病风险评估指标。     

女性血浆脂蛋白(a)与冠状动脉病变的关系

目的:探讨女性血浆脂蛋白(a)[Lp(a)]水平与冠状动脉病变程度及范围的关系。方法:72例女性根据冠状动脉造影结果,分为冠心病组和非冠心病组,测定Lp(a)、TC、TG、HDL-C、LDL-C、载脂蛋白A(apoA)、载脂蛋白B(apoB)的血浆浓度。结果:冠心病组患者中血浆Lp(a)水平明显高于非冠心病组患者(P<0.05);血浆Lp(a)水平在冠状动脉闭塞及多支病变患者中显著升高。结论:女性血浆Lp(a)水平与冠状动脉粥样病变的程度及范围有关,是病变严重程度的一个预测因素。     

脂质代谢水平与冠状动脉粥样硬化病变的关系

目的 探讨脂质代谢水平与冠状动脉粥样硬化病变的关系.方法 回顾性分析182 例疑似冠状动脉粥样硬化病变患者的资料,均实施冠状动脉数字减影血管造影(DSA)检查,将有冠状动脉粥样硬化病变者列为研究组,否则列为对照组.检测受试者血浆甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDLC)、低密度脂蛋白胆固醇(LD...     

Lp(a) enhances coronary atherosclerosis in transgenic Watanabe heritable hyperlipidemic rabbits

Elevated plasma levels of LDL and lipoprotein (a) [Lp(a)] are associated with an increased risk of atherosclerosis and coronary heart disease. However, it is not known whether Lp(a) would enhance the atherogenic effect of LDL on coronary atherosclerosis and myocardial infarction. To address this issue, we cross-bred human Lp(a) transgenic (Tg) rabbits with Watanabe heritable hyperlipidemic (WHHL) rabbits and evaluated the long-term (at the age of 2 years) effects of Lp(a) on the development of coronary atherosclerosis. Compared to non-Tg WHHL rabbits, Tg WHHL rabbits did not show significant changes in plasma total cholesterol, triglycerides, or HDL-C. However, Tg WHHL rabbits showed significantly larger lesions in the right coronary arteries (p<0.05). Immunohistochemical staining revealed that the lesions of Tg WHHL rabbits were enriched in the extracellular matrix contents whereas the cellular components were not different from those in non-Tg WHHL rabbits. Increased atherosclerosis in the coronary arteries in Tg WHHL rabbit hearts was also associated with a higher incidence of chronic ischemia and myocardial infarction. These results suggest that increased plasma levels of Lp(a) enhance coronary atherosclerosis and myocardial infarction in the setting of hypercholesterolemia.     

Enhanced aortic atherosclerosis in transgenic Watanabe heritable hyperlipidemic rabbits expressing lipoprotein lipase

OBJECTIVE: This study was designed to address the effects of increased lipoprotein lipase (LPL) activity on atherosclerosis in the setting of LDL receptor deficiency. METHODS: We generated transgenic (Tg) Watanabe heritable hyperlipidemic (WHHL) rabbits overexpressing human LPL and compared their plasma lipids and aortic atherosclerosis with non-Tg WHHL rabbits. RESULTS: Increased expression of LPL significantly ameliorated hypertriglyceridemia and hypercholesterolemia in Tg WHHL rabbits [64% reduction in total cholesterol (TC) and 91% reduction in triglycerides (TG) vs. non-Tg]. In spite of this beneficial effect of LPL, Tg WHHL rabbits had two-fold greater aortic atherosclerosis than non-Tg WHHL rabbits. Analysis of plasma lipoprotein profiles revealed that increased LPL activity in Tg WHHL rabbits resulted in the dramatic reduction of large TG-rich lipoproteins (VLDL, d<1.006 g/ml and IDL, d=1.006-1.02) but concomitant increases in LDL fractions, especially those of small and dense LDL particles (d=1.04-1.06, 2.6-fold over non-Tg). Using apoB-containing lipoproteins, we found that small-sized LDL from Tg WHHL rabbits contained more oxidizable substrate and exhibited higher affinity to biglycan than large TG-rich LDL of non-Tg WHHL rabbits. CONCLUSIONS: We conclude that in the absence of LDL receptor function, increased LPL activity accelerates the catabolism of large TG-rich VLDL (possibly via the LRP pathway) and subsequently improves hyperlipidemia. However, LPL may also enhance the generation and accumulation of small dense LDLs, which are more atherogenic.     

Transgenic rabbits expressing human apolipoprotein(a) develop more extensive atherosclerotic lesions in response to a cholesterol-rich diet

High lipoprotein(a) [Lp(a)] levels constitute an independent risk factor for the development of atherosclerosis. However, the relationship between Lp(a) and atherosclerosis is not fully understood. To examine the effect of Lp(a) on the development of atherosclerosis, we studied transgenic rabbits expressing human apolipoprotein(a) [apo(a)], which was assembled into Lp(a) in the plasma. Human apo(a) transgenic rabbits fed a 0.3% cholesterol diet for 16 weeks had more extensive atherosclerotic lesions than did nontransgenic rabbits, although the cholesterol levels in the plasma of both groups were similarly elevated. Compared with the lesions in control rabbits, the areas of the atherosclerotic lesions in human apo(a) transgenic rabbits were significantly increased in the aorta, the iliac artery, and the carotid artery. Furthermore, human apo(a) transgenic rabbits on a cholesterol-rich diet had a greater degree of coronary atherosclerosis than did control rabbits. Immunohistochemical analysis revealed that human apo(a) was frequently deposited in the atherosclerotic lesions of transgenic rabbits. We conclude that Lp(a) may have proatherogenic effects in the setting of a cholesterol-rich diet in transgenic rabbits.     

Endothelial Lipase Exerts its Anti-Atherogenic Effect through Increased Catabolism of β-VLDLs

Aim: Endothelial lipase (EL) plays an important role in lipoprotein metabolism. Our recent study showed that increased hepatic expression of EL attenuates diet-induced hypercholesterolemia, thus subsequently reducing atherosclerosis in transgenic (Tg) rabbits. However, it is yet to be determined whether increased EL activity itself per se is anti-atherogenic or whether the anti-atherogenic effect of EL is exclusively dependent on its lipid-lowering effect.Methods: To determine the mechanisms underlying EL-mediated anti-atherogenic effect, we fed Tg and non-Tg rabbits diets containing different amounts of cholesterol to make their plasma cholesterol levels similarly high. Sixteen weeks later, we examined their lipoprotein profiles and compared their susceptibility to atherosclerosis.Results: With Tg and non-Tg rabbits having hypercholesterolemia, the plasma lipids and lipoprotein profiles were observed to be similar, while pathological examinations revealed that lesion areas of both aortic and coronary atherosclerosis of Tg rabbits were not significantly different from non-Tg rabbits. Moreover, Tg rabbits exhibited faster clearance of DiI-labeled β-VLDLs than non-Tg rabbits.Conclusion: The results of our study suggest that the enhancement of β-VLDL catabolism is the major mechanism for atheroprotective effects of EL in Tg rabbits.     

Macrophage-derived lipoprotein lipase increases aortic atherosclerosis in cholesterol-fed Tg rabbits

Lipoprotein lipase (LPL) produced by macrophages is upregulated in the atherosclerotic lesions; however, it is not fully understood whether increased macrophage-derived LPL is pro-atherogenic. To examine the hypothesis that macrophage-derived LPL in the arterial wall enhances atherosclerotic lesion formation, we generated transgenic (Tg) rabbits that express the human LPL transgene under the control of the human scavenger receptor enhancer/promoter, which drives macrophage-specific expression of the human LPL gene. We fed Tg and non-Tg littermate rabbits a diet containing 0.3% cholesterol for 16 weeks and compared their lipoproteins and aortic atherosclerosis. We found that there was no difference in plasma lipid or lipoprotein profiles between Tg and non-Tg rabbits; however, atherosclerotic lesions were significantly increased in Tg compared to non-Tg rabbits. There was a 1.4-fold increase in total aortic en face lesions and a 2-fold increase in intimal lesions evaluated by image analysis system. Furthermore, immunohistochemical staining revealed that the increased atherosclerotic lesions present in Tg rabbits were characterized by marked accumulation of macrophage-derived foam cells and frequently associated with the deposition of oxidized LDL. These results support the notion that macrophage-derived LPL in the arterial wall is pro-atherogenic, possibly via the enhancement of foam cell formation during atherogenesis.     

Association of elevated lipoprotein(a) levels and coronary heart disease in NIDDM patients. Relationship with apolipoprotein(a) phenotypes

Summary Non-insulin-dependent diabetes mellitus (NIDDM) is a strong and independent risk factor for coronary heart disease. We assessed the potential relationship between plasma Lp(a) levels, apo(a) phenotypes and coronary heart disease in a population of NIDDM patients. Seventy-one patients with coronary heart disease, who previously have had transmural myocardial infarction, or significant stenosis on coronary angiography, or positive myocardial thallium scintigraphy, or in combination, were compared with 67 patients without coronary heart disease, who tested negatively upon either coronary angiography, myocardial thallium scintigraphy or a maximal exercise test. The prevalence of plasma Lp(a) levels elevated above the threshold for increased cardiovascular risk (>0.30 g/l) was significantly higher (p=0.005) in patients with coronary heart disease (33.8%) compared to the control group (13.4%). The relative risk (odds ratio) of coronary heart disease among patients with high Lp(a) concentrations was 3.1 (95% confidence interval, 1.31–7.34;p=0.01). The overall frequency distribution of apo(a) phenotypes differed significantly between the two groups (p=0.043). However, the frequency of apo(a) isoforms of low apparent molecular mass (700 kDa) was of borderline significance (p=0.067) between patients with or without coronary heart disease (29.6% and 16.4%, respectively). In this Caucasian population of NIDDM patients, elevated Lp(a) levels were associated with coronary heart disease, an association which was partially accounted for by the higher frequency of apo(a) isoforms of small size. In multivariate analyses, elevated levels of Lp(a) were independently associated with coronary heart disease (odds ratio 3.48, p=0.0233).Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - IDDM insulin-dependent diabetes mellitus - CHD coronary heart disease - Lp(a) lipoprotein(a) - apo(a) apolipoprotein(a) - apoB apolipoprotein B - HMGCoA reductase hydroxymethylglutaryl coenzyme A reductase     

Higher level of plasma cholesteryl ester transfer activity from high-density lipoprotein to Apo B-containing lipoproteins in subjects with angiographically detectable coronary artery disease

Background and hypothesis: Plasma high-density lipoprotein cholesterol (HDL-C) levels correlate inversely with the incidence of coronary artery disease. In order to ascertain whether the transfer activity is related to coronary atherosclerosis, we studied plasma cholesteryl ester transfer activity (CETA) from HDL to apo B-containing lipoproteins in a consecutive series of 64 Japanese men aged <60 years who had undergone diagnostic coronary angiography. Methods: The subjects were divided into two groups: those who had ≥50% luminal stenosis in one or more coronary arteries (Group 1) and those who had <50% stenosis (Group 2). Results: CETA was 20.8±6.0%/2h in 38 subjects in Group 1. significantly higher than 17.4±6.9%/2h in 26 subjects in Group 2(p<0.05). Plasma HDL-C levels in Group 1 were significantly lower than those in Group 2(p<0.05). CETA correlated inversely with HDL-C levels (r = ?0.46, p<0.001). Plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and Lp(a) levels did not differ significantly between the two groups. There was no significant correlation between CETA and either LDL-C or TG levels. Conclusion: Results suggest that high CETA is realted to low plasma HDL-C levels and may lead to the development of coronary atherosclerosis. Also, CETA was independent of plasma LDL-C or TG levels.     

Transgenic rabbits expressing human apolipoprotein (a).

Elevated plasma levels of lipoprotein (a) [Lp(a)] constitutes an independent risk factor for coronary heart disease, stroke, and restenosis. Over the past years, our understanding of the genetics, metabolism and pathophysiology of Lp(a) have increased considerably. However, the precise mechanism(s) by which this atherogenic lipoprotein mediates the development of atherosclerosis remains unclear. This is partly due to the lack of appropriate animal models since apolipoprotein (a) [apo(a)], a distinct component of Lp(a) is found only in primates and humans. Development of transgenic mice expressing human apo(a) has provided an alternative means to investigate many aspects of Lp(a). However, human apo(a) in transgenic mice can not bind to murine apoB to form Lp(a) particles. In this aspect, we generated transgenic rabbits expressing human apo(a). In the plasma of transgenic rabbits, unlike the plasma of transgenic mice, about 80% of the apo(a) was associated with rabbit apo B and was contained in the fractions with density 1.02-1.10 g/ml, indicating the formation of Lp(a). Our study suggests that transgenic rabbits expressing human apo(a) exhibit efficient assembly of Lp(a) and can be used as an animal model for the study of human Lp(a).     

国人健康男女及冠心病患者血浆脂蛋白(a)水平

为了了解国人人群脂蛋白(a)的分布及水平,探讨脂蛋白(a)与冠心病及其它血脂与载脂蛋白的关系,本文应用单价抗载脂蛋白(a)及抗载脂蛋白B抗体夹心酶联法测定668名健康人血浆脂蛋白(a),测得(?);122.34±141.97mg/L,M为81.07mg/L(0～1 250mg/L),呈典型的正偏态分布,无性别年龄差异,与其它脂类及载脂蛋白不相关。48例冠心病患者血浆脂蛋白(a)水平及>200mg/L的频率分布均明显高于同年龄对照组,提示高脂蛋白(a)水平是致动脉粥样硬化的一个独立危险因素。     

Mechanism of Action of Gemfibrozil on HDL Metabolism and Atherosclerosis in WHHL Rabbits

We investigated the mechanism of action of gemfibrozil on high-density lipoproteins (HDL) and apolipoprotein (apo) A-I metabolism and atherogenesis in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model of familial hypercholesterolemia and HDL deficiency. Two-month-old WHHL rabbits were fed either a normal control diet or a diet containing 0.5% gemfibrozil for 12 months. In vivo apo A-I kinetics, the fractional rate of cholesterol esterification in HDL (FER_HDL), which reflects the reactivity of HDL to lecithin:cholesterol acyltransferase, and a morphometrical analysis of atherosclerotic lesions in the descending thoracic aorta, were examined. At12 months, the mean levels of serum total cholesterol, LDL cholesterol (LDL-C), and HDL cholesterol (HDL-C) in both groups had decreased to approximately 53%, 57%, and 87% of the initial levels (at 0 month), respectively, which is characteristic of homozygous WHHL rabbits of the physiologic influence of aging, and no differences in the levels of serum LDL-C, HDL-C, and triglycerides were found between the two groups. Rabbits treated with gemfibrozil exhibited a decreased FER_HDL (38% of the controls, P = 0.039). Gemfibrozil induced a significant increase in the total mass of apo A-I (1.7-fold, P < 0.05) and in the rate of apo A-I synthesis (1.6-fold, P< 0.05). The atherosclerotic intimal area was positively correlated with serum LDL-C (P = 0.02) in both groups, but gemfibrozil did not affect the atherosclerotic intimal area. These results indicate that 12 months of treatment with gemfibrozil did not protect against atherosclerosis despite a significant increase in apo A-I synthesis and enhanced HDL function through FER_HDL. It is possible that both the qualitative and quantitative improvement in HDL by gemfibrozil cannot overcome the massive and long-term exposure of the vascular wall to LDL in these animals. This revised version was published online in July 2006 with corrections to the Cover Date.