脂蛋白a在动脉粥样硬化性心血管疾病中的临床研究进展

［摘要］　脂蛋白a［Lp(a)］水平的升高是冠状动脉疾病、脑卒中、外周动脉疾病及钙化性主动脉瓣狭窄等动脉粥样硬化性心血管疾病（ASCVD）的独立危险因素。有研究证实,即使将低密度脂蛋白胆固醇水平控制在理想范围内,高Lp(a)水平仍然会增加ASCVD的风险。该文从Lp(a)及其致病机制、Lp(a)水平与ASCVD的关系、高Lp(a)血症的治疗等作一综述。     

脂蛋白(a)水平与冠状动脉病变程度的关系

日益增多的临床和基础研究支持脂蛋白(a)[Lp(a)]是冠心病的一个独立危险因素.但是,血清Lp(a)水平与冠状动脉病变程度的关系尚存有争议.本研究旨在探讨血清Lp(a)水平与冠状动脉病变程度的关系.     

血清脂蛋白(a)水平与冠状动脉病变程度的关系

目的:探讨血清脂蛋白a[Lp(a)]水平与冠状动脉病变程度的关系。方法:318例住院患者,根据冠状动脉造影分为冠心病组(189例)和非冠心病组(129例),冠心病组又根据冠脉病变情况又分为单支病变组(93例)、双支病变组(60例)及三支病变组(36例),检测各组血清Lp(a)水平,探讨血清Lp(a)水平与冠状动脉病变的关系。结果:与非冠心病组比较,冠心病组血清Lp(a)水平明显升高[(14.89±14.71)mg/dl比(21.15±13.71)mg/dl],P0.01;随着冠状动脉病变支数的增加,血清Lp(a)水平逐渐升高,与单支病变组比较,三支病变组血清Lp(a)水平[(21.99±13.05)mg/d比(26.94±10.32)mg/d]显著升高;与单支病变组和双支病变组比较,三支病变组Lp(a)异常率(16.2%、15.0%比25.0%)明显升高(P均0.05);Logistic回归分析结果表明Lp(a)是冠心病的独立危险因素(OR=1.56,P=0.024)。结论:血清脂蛋白a与冠状动脉病变及其程度密切相关,可作为一项预测冠心病及其严重程度的指标。     

脂蛋白a与冠状动脉支架术后再狭窄的相关性研究

目的:探讨血清脂蛋白(a)[Lp(a)]水平与冠状动脉支架置入术后支架内再狭窄的关系. 方法:检测152例行经皮球囊冠状动脉成形术加支架置入术的患者Lp(a)水平并调查其一般临床资料,术后行冠状动脉造影随访.采用Logistic多因素逐步回归分析.结果:Logistic多因素逐步回归分析显示,Lp(a)升高是支架术后支架内再狭窄发生的独立危险因素,P=0.036,其RR为2.648,95%可信区间为1.066～6.575.其他因素如吸烟、糖尿病、支架类型在再狭窄与正常组间也存在明显区别,差异有统计学意义,与支架内再狭窄发生有关. 结论:Lp(a)水平升高是发生冠状动脉支架术后再狭窄的独立危险预测因素.     

无症状人群中血清脂蛋白a与冠状动脉钙化相关性的研究

目的:探究在无任何症状人群中血清脂蛋白a[LP(a)]与冠状动脉钙化的关系。方法:纳入首都医科大学附属北京安贞医院健康体检中心,就诊的无任何症状个体,患者行冠状动脉CTA检查,收集影响患者钙化的各项生化检查(包括LP(a)),同时收集患者钙化积分情况,依据钙化和LP(a)水平将患者进行分组,并用Logistic回归分析LP(a)和冠状动脉钙化的关系。结果:共纳入412例患者,其中钙化患者150例,无钙化患者262例,钙化患者在年龄、男性比例、Scr、UA、BMI、FGB、吸烟比例、高血压、糖尿病、脂蛋白a方面高于无钙化患者,在HDL-C、eGFR方面低于无钙化组。调整上述危险因素后发现LP(a)水平升高与冠状动脉钙化相关,随着LP(a)升高,OR值和95%CI依次为[2.322(1.144～4.715),P0.05;3.690(1.811～7.519),P0.05;4.191(2.039～8.617),P0.05]。结论:LP(a)水平和冠状动脉钙化风险以及钙化程度相关,LP(a)的升高可能意味着更高的心血管疾病发生风险。     

脂蛋白(a)水平影响因素及其与长寿的关系

<正>脂蛋白(Lp)(a)是一种独特的血浆脂蛋白大分子复合物,由富含胆固醇的低密度脂蛋白(LDL)样微粒通过载脂蛋白(Apo)B100与Apo(a)由一个二硫键交链在一起。它于1963年由挪威学者Berg~([1])首先发现并命名报道后,有多项研究相继证实其为动脉粥样硬化的危险因素,高Lp(a)水平是心血管疾病的独立危险因子,就如同低密度脂蛋白胆固醇(LDL-C)一     

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。     

脂蛋白(a)与心血管疾病的研究进展

脂蛋白(a)[Lp(a)]是一种特殊类型的脂蛋白颗粒,流行病学及临床试验均显示其在动脉粥样硬化进程中起着重要作用,是心血管疾病的重要潜在性危险因素。大量国内外研究提示,Lp(a)与冠心病、脑卒中、主动脉钙化狭窄等疾病密切相关,但Lp(a)作为危险因素的临床界值、Lp(a)与低密度脂蛋白胆固醇(LDL-C)的危险因素关系、Lp(a)的治疗方案等仍存在争议。本文就目前关于Lp(a)的临床研究、争议、治疗方案及新兴疗法的进展作一综述。     

不同性别血浆脂蛋白(a)浓度与冠状动脉病变严重程度的关系

目的:研究中国不同性别血浆脂蛋白(a)[Lp(a)]浓度与冠状动脉粥样硬化程度的关系。方法:将男女患者分别按冠状动脉狭窄程度分组,并计算冠状动脉病变积分,比较各组Lp(a)的差异及与冠状动脉积分的相关性。结果:无论男性还是女性,4组不同病变的Lp(a)浓度分布差异有统计学意义,P<0.01;仅多支病变组与0支病变组比较差异有统计学意义,女性P<0.01,男性P<0.05。绝经后女性Lp(a)水平高于绝经前,P<0.05。结论:在中国,Lp(a)水平与冠状动脉粥样硬化的严重程度成正相关关系,且女性和男性都存在。女性绝经后血浆Lp(a)浓度升高,血浆Lp(a)浓度受性激素的调节。     

血清脂蛋白a水平与冠状动脉钙化的相关性分析

目的探讨因胸痛接受冠状动脉CT检查的患者血清脂蛋白a[Lp(a)]水平与冠状动脉钙化(CAC)之间的相关性。方法共入选1085例因胸痛在阜外医院接受冠状动脉CT检查的患者,根据Agatston评分算法计算冠状动脉钙化评分(CACS)。所有入选患者均检测了血脂谱和Lp(a)水平。结果根据CACS进行分组,CACS>0分组(460例)患者血清Lp(a)水平明显高于CACS=0分组(625例)患者[23.60(14.73,44.56)mg/dl比12.73(5.56,31.10)mg/dl,P<0.001],差异有统计学意义。多元线性回归分析显示,血清Lp(a)浓度与CACS呈正相关(β=0.543,P<0.001)。曲线下面积(AUC)值显示血清Lp(a)水平在预测CACS方面具有正确的区分效力(AUC=0.71,95%CI 0.68~0.74,P<0.001)。Lp(a)的最佳截断值为10.51 mg/dl(敏感度为86.1%,特异度为51.7%)。结论在因胸痛接受冠状动脉CT检查的患者中,血清Lp(a)水平与CAC呈显著正相关。     

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.     

The Effect of Alcohol Withdrawal on Serum Concentrations of Lp(a), Apolipoproteins A-1 and B, and Lipids

Moderate alcohol consumption is associated with a decreased risk of coronary artery disease. The mechanism of the putative protective effect of alcohol intake, however, remains elusive. Recent studies suggest that a ratio of apolipoprotein A-I/apolipoprotein B and Lp(a) are better indicators of the risk of atherosclerosis than total cholesterol and high density lipoprotein cholesterol. To assess the effect of alcohol on these analytes, we determined the concentration of Lp(a), apolipoprotein A-I, apolipoprotein B, total cholesterol, and high-density lipoprotein cholesterol, and calculated low-density lipoprotein cholesterol in serum of 12 patients meeting DSM-III-R criteria for alcohol dependence at the time of admission for treatment of alcohol withdrawal (before). The analyses were repeated after 4 weeks of supervised abstinence on a locked research unit (after). With abstinence, there was a significant increase in the concentration of Lp(a), the atherogenic index and the ratio of low-density to high-density lipoprotein cholesterol but a significant decrease in total cholesterol, high-density lipoprotein cholesterol, apolipoprotein A-I, and the apolipoprotein A-I/B ratio. Apolipoprotein B and low-density lipoprotein cholesterol showed no significant changes before and after alcohol abstinence. Thus, decreased Lp(a) and increased high-density lipoprotein cholesterol and apolipoprotein A-I may be factors mediating the putative protective effect of alcohol in coronary artery disease.     

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.     

脂蛋白(a)及超敏C反应蛋白含量对冠脉病变程度的预测

目的:探讨脂蛋白(a)[Lp(a)]及超敏C反应蛋白(hs-CRP)水平对冠状动脉病变程度的预测价值。方法:入选行冠状动脉造影病例580例,根据冠状动脉病变程度分三组:A组(冠脉狭窄≤30%)154例;B组(冠脉狭窄31%～69%)243例;C组(冠脉狭窄≥70%)183例。对Lp(a)及hs-CRP水平与冠状动脉病变程度的相关性进行分析。结果:(1)随冠状动脉病变程度加重,总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、载脂蛋白B(ApoB)、Lp(a)及hs-CRP浓度逐渐增加。与A组比较,B组及C组各指标均有显著性增加(P<0.05或<0.01)。与B组比较,C组Lp(a)及hs-CRP有显著性增加(P<0.01);(2)多元逐步回归分析显示,按标准回归系数大小1.415～1.106顺序,相关因素为Lp(a)、hs-CRP、LDL-C和ApoB(P<0.05～<0.01),Lp(a)联合hs-CRP可使OR值进一步增高(P<0.05)。结论:Lp(a)及hs-CRP对冠状动脉病变程度的预测价值并不优于其他血脂指标,联合二者可提高其预测价值。     

Lack of association of lipoprotein(a) levels with coronary calcium deposits in asymptomatic postmenopausal women

OBJECTIVES: This study sought to determine the relationship of lipoprotein(a) (Lp(a)) and other cardiac risk factors to coronary atherosclerosis as measured by calcification of coronary arteries in asymptomatic postmenopausal women. BACKGROUND: Lipoprotein(a) is considered a risk factor for coronary heart disease. Coronary calcium deposition is believed to be a useful noninvasive marker of coronary atherosclerosis in women. However, to our knowledge, there are no reports of the relationship of Lp(a) to coronary calcium in postmenopausal women. METHODS: In 178 asymptomatic postmenopausal women (64 +/- 8 years), we measured Lp(a) and other cardiac risk factors: age, hypertension, diabetes, low-density lipoprotein cholesterol, smoking status, body mass index, physical activity level and duration of hormone replacement therapy. Electron-beam computed tomography was done to measure coronary calcium (calcium score). We analyzed the relationship between calcium score and cardiac risk factors using multivariate analysis. RESULTS: Although calcium score correlated with traditional risk factors of age, diabetes, hypertension and smoking, it did not correlate with Lp(a) in the asymptomatic postmenopausal women. Similar multivariate analyses were done in the subjects age >60 years and in the subjects with significant coronary calcium deposit (calcium score > or =50). These analyses also have failed to show an association of levels of Lp(a) with coronary calcium deposits. CONCLUSIONS: We conclude that in asymptomatic postmenopausal women, Lp(a) levels do not correlate with coronary atherosclerosis as measured by coronary calcium deposits.     

脂蛋白(a)水平与心血管疾病相关性研究进展

脂蛋白(a)是一种与低密度脂蛋白类似的脂蛋白,可以促进动脉粥样硬化及血栓形成,与冠状动脉粥样硬化性心脏病、脑血管病、糖尿病等多种疾病密切相关。流行病学资料及多个临床试验均显示脂蛋白(a)可以预测动脉硬化的风险,是冠状动脉粥样硬化性心脏病的独立危险因素之一;高浓度脂蛋白(a)还将加速动脉硬化的发展。随着对脂蛋白(a)的病理生理,致病机制等方面研究的进展,高脂蛋白(a)浓度的治疗方法也有了令人鼓舞的成果。现就脂蛋白(a)与心血管疾病的相关性作如下综述。     

New insights into the role of lipoprotein(a)-associated lipoprotein-associated phospholipase A2 in atherosclerosis and cardiovascular disease

Lipoprotein(a) [Lp(a)] plays an important role in atherosclerosis. The biological effects of Lp(a) have been attributed either to apolipoprotein(a) or to its low-density lipoprotein-like particle. Lp(a) contains platelet-activating factor acetylhydrolase, an enzyme that exhibits a Ca2+-independent phospholipase A2 activity and is complexed to lipoproteins in plasma; thus, it is also referred to as lipoprotein-associated phospholipase A2. Substrates for lipoprotein-associated phospholipase A2 include phospholipids containing oxidatively fragmented residues at the sn-2 position (oxidized phospholipids; OxPLs). OxPLs may play important roles in vascular inflammation and atherosclerosis. Plasma levels of OxPLs present on apolipoprotein B-100 particles (OxPL/apolipoprotein B) are correlated with coronary artery, carotid, and peripheral arterial disease. Furthermore, OxPL/apolipoprotein B levels in plasma are strongly correlated with Lp(a) levels, are preferentially sequestered on Lp(a), and thus are potentially subjected to degradation by the Lp(a)-associated lipoprotein-associated phospholipase A2. The present review article focuses specifically on the characteristics of the lipoprotein-associated phospholipase A2 associated with Lp(a) and discusses the possible role of this enzyme in view of emerging data showing that OxPLs in plasma are preferentially sequestered on Lp(a) and may significantly contribute to the increased atherogenicity of this lipoprotein.     

Inheritability of atherosclerosis and the role of lipoproteins as risk factors in the development of atherosclerosis in WHHL rabbits: risk factors related to coronary atherosclerosis are different from those related to aortic atherosclerosis.

Inheritability of atherosclerosis and the influences of serum lipids on atherosclerosis were examined by following its progression in selectively bred WHHL rabbits. Our studies indicate (1) coronary atherosclerosis is clearly inherited from parents by offspring whereas inheritability of aortic atherosclerosis is uncertain; (2) coronary stenosis is positively correlated to serum cholesterol level, although the correlation coefficient is markedly low: in contrast, no relationship between serum lipid levels and aortic atherosclerosis was observed; (3) cholesterol-rich VLDL showed atherogenicity in aorta, but not in coronary arteries; (4) an unknown lipoprotein detected by 3.6% polyacrylamide gel electrophoresis was related to coronary atherosclerosis, although no relationship between the unknown lipoprotein and aortic atherosclerosis was observed. These findings suggest that there are two types of genetic factors involved in atherosclerosis, one of which is unique to coronary atherosclerosis whereas the other is related to only aortic atherosclerosis.     

Lipid and apolipoprotein predictors of atherosclerosis in youth: apolipoprotein concentrations do not materially improve prediction of arterial lesions in PDAY subjects. The PDAY Research Group

We compared serum lipid and apolipoprotein predictors of atherosclerosis in cases from the multicenter study, Pathobiological Determinants of Atherosclerosis in Youth (PDAY). The lipid measures included HDL cholesterol (HDL-C) and non-HDL-C, and the apolipoprotein measures included concentrations of apoA1, apoB, and Lp(a), and sizes of the apo(a) proteins. We tested whether the apolipoprotein measures predicted atherosclerotic lesions as well as the more traditional lipid measures. We estimated extent of lesions as fatty streaks or raised lesions (fibrous plaques, complicated or calcified lesions) in 3 sites: thoracic aorta, abdominal aorta, and right coronary artery. Neither apoA1 nor apoB measures were as strongly or consistently correlated with extent of lesions as the corresponding lipid measure (HDL-C and non-HDL-C, respectively). Beyond the basic model that included sex, age, race, smoking status, hypertension, and the lipid measures, apoA1 and apoB added only an average 1.3% increased explanatory ability to the model, whereas HDL-C plus non-HDL-C added an average 2.5%. The results suggest that the traditional lipid measures are more useful than apolipoprotein measures for detecting young persons at high risk of precocious atherosclerosis. Because of large racial differences, the two Lp(a)-related measures, Lp(a) concentrations and apo(a) size, were evaluated in blacks and whites separately. Under these circumstances, neither of the Lp(a)-related measures was strongly or consistently correlated with extent of lesions.     

Lipoprotein predictors of the severity of coronary artery disease in men and women

In this study we examined the relationships between levels of several components of plasma lipoproteins and severity of coronary artery disease in 65 men and 42 women who underwent coronary arteriography for suspected coronary disease. Severity of coronary atherosclerosis was scored as the extent of disease seen at arteriography. Univariate analyses of the relationships between the plasma lipoprotein parameters and score for severity of atherosclerosis revealed a marked difference between men and women. In men, the score for severity of atherosclerosis was strongly related to the low-density lipoprotein (LDL) cholesterol and apolipoprotein B concentrations, whereas in women it was related to the triglyceride concentrations in plasma intermediate-density lipoprotein (IDL) and LDL and to the cholesterol and apolipoprotein B concentrations in IDL. The significance of these correlations was not negated by possible confounding factors such as alcohol intake, diabetes, and treatment with thiazides and beta-adrenergic blockers. Stepwise regression analyses of data adjusted for weight and age indicated that 22% of the variation in the score for severity of atherosclerosis could be accounted for by levels of LDL cholesterol in men. No other lipoprotein parameter could account for any further variation. In contrast, cholesterol did not account for any variation in the score for severity of atherosclerosis in women, whereas plasma triglyceride accounted for 16% of the observed variation in this group. No relationships were found between score for severity of atherosclerosis and high-density lipoprotein cholesterol or plasma apolipoprotein A-I concentrations in either group.(ABSTRACT TRUNCATED AT 250 WORDS)