The role of lipoprotein-associated phospholipase A2 as a marker for atherosclerosis

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme that belongs to the superfamily of phospholipase A2 enzymes. Although initial studies showed that Lp-PLA2 might be protective against atherosclerosis, emerging data seem to suggest that Lp-PLA2 may be proatherogenic, which is an effect thought to be mediated by lysophosphatidylcholine and oxidized nonesterified fatty acids, two mediators generated by Lp-PLA2. This article reviews the potential mechanisms by which Lp-PLA2 may participate in the pathogenesis of atherosclerosis and its clinical manifestations, namely, coronary artery disease and stroke.     

Role of lipoprotein-associated phospholipase A2 in atherosclerosis

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) is a biomarker that can be used to assess the risk for cardiovascular disease and events. In addition to being a useful marker of a risk factor, several studies suggest that Lp-PLA₂ has a pathophysiologic role in the atherosclerotic disease process. In this article, we review this aspect and its therapeutic implications.     

氧化应激、氧化低密度脂蛋白和脂蛋白相关磷脂酶A2与动脉粥样硬化

氧化应激是动脉粥样硬化早期的一个重要危险因素,涉及线粒体损伤、自由基释放,脂质过氧化、磷脂酶激活以及炎症介质释放等多种病理生理学过程.越来越多的研究表明,氧化应激、氧化低密度脂蛋白和脂蛋白相关磷脂酶A2在动脉粥样硬化的发生和发展中起着重要的作用.因此,探讨其相互关系,有助于加深动脉粥样硬化的认识,并采取针对性预防.     

An evolving story of lipoprotein-associated phospholipase A2 in atherosclerosis and cardiovascular risk prediction.

Over the past 50 years, the age-adjusted mortality rate fromcardiovascular disease has decreased substantially. Despitethe improved mortality rate, there is evidence that actual cardiovascularevent rates remain relatively unchanged (i.e. more people aresurviving acute events), and heart disease and stroke continueto be leading causes of death in Western societies.¹ Intensiveresearch efforts are currently under way with the goal of furtherreducing the global burden of cardiovascular disease. An improvedunderstanding of vascular biology and the pathogenesis of atherosclerosis—includingthe role of inflammatory processes—may prove helpful inachieving this goal. Atherosclerosis is a condition involving numerous complex processeswithin the vessel wall that can be characterized as an inflammatoryresponse to injury.     

The role of lipoprotein-associated phospholipase A(2) in the metabolic syndrome and diabetes

OBJECTIVES: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a novel inflammation marker. We investigated its association with other coronary risk factors and evaluated its role as a comprehensive marker of the metabolic syndrome in individuals with type 2 diabetes. METHODS: Our cross-sectional study evaluated 92 insulin-treated subjects with type 2 diabetes. Biochemical measurements of Lp-PLA(2), glycemic control, lipid profiles, and C-reactive protein were carried out. Seventy-seven subjects were diagnosed as having the metabolic syndrome, which was defined according to the American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. RESULTS: Lp-PLA(2) was significantly correlated with waist-hip ratio (r=.25), triglycerides (r=.50), high-density lipoprotein cholesterol (r=-.31), and low-density lipoprotein cholesterol (LDL-C; r=.27; all P<.02). In a multiple-regression model, triglycerides and LDL-C levels were the significant predictors of Lp-PLA(2). Lp-PLA(2) was significantly higher in subjects with the metabolic syndrome than in those without it (268+/-23.4 vs. 127+/-15.8 ng/ml, P<.001). There was a linear increase in Lp-PLA(2) with an increment of the number of the metabolic syndrome criteria (P(trend)=.041). Another multiple-regression model showed that the hypertriglyceridemia component was the only predictor of Lp-PLA(2). CONCLUSIONS: Our findings suggest that Lp-PLA(2) assay potentially facilitates a more comprehensive assessment of the metabolic syndrome in patients with type 2 diabetes on insulin.     

Effect of low-density lipoprotein apheresis on lipoprotein-associated phospholipase A2

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a proinflammatory participant in atherosclerosis and a potential biomarker for coronary heart disease. The effects of low-density lipoprotein (LDL) apheresis on Lp-PLA(2) levels were evaluated in 8 patients with cardiovascular disease. Each patient received 5 LDL apheresis treatments over a 3-month period. The mean direct LDL cholesterol level reduction was 60% (252 to 100 mg/dl). LDL apheresis acutely reduced Lp-PLA(2) by 21.4%. Over the course of treatment, Lp-PLA(2) levels were reduced by 29%. Chronic LDL apheresis significantly reduces Lp-PLA(2) independent of LDL cholesterol, which may be a potential mechanism by which LDL apheresis diminishes coronary heart disease risk.     

A prospective evaluation of lipoprotein-associated phospholipase A(2) levels and the risk of future cardiovascular events in women.

OBJECTIVES: We sought to determine prospectively whether lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) was a predictor of future cardiovascular risk in women. BACKGROUND: Inflammatory markers may help predict cardiovascular risk. Lp-PLA(2) levels have recently been hypothesized to be an independent predictor of cardiovascular risk in hypercholesterolemic men. METHODS: We conducted a prospective, nested case-control study among 28,263 apparently healthy middle-aged women to assess the risk of death from coronary heart disease, non-fatal myocardial infarction, and stroke associated with baseline levels of Lp-PLA(2) over a mean follow-up of three years. RESULTS: In univariate analysis, mean levels of Lp-PLA(2) correlated strongly with low-density lipoprotein cholesterol (r = 0.51; p = 0.0001), were lower among women currently using hormone replacement therapy (mean 0.98 mg/l vs. 1.23 mg/l; p = 0.0001) and were significantly higher at baseline among cases (n = 123) than controls (n = 123) (mean 1.20 mg/l vs. 1.05 mg/l; p = 0.016). However, the predictive value of Lp-PLA(2) was markedly attenuated after adjustment for these and other cardiovascular risk factors. Specifically, the multivariate relative risks of future cardiovascular events for women in the lowest (referent) to highest quartiles of Lp-PLA(2) were 1.00, 0.75, 0.64 and 1.17, respectively (all p values non-significant). In contrast, the adjusted relative risks of future cardiovascular events for each increasing quartile of C-reactive protein (another marker of low-grade inflammation) were 1.00, 1.78, 2.02 and 4.66, respectively (p-value for trend = 0.002). Inclusion of Lp-PLA(2) levels did not significantly attenuate this latter observation. CONCLUSIONS: In contrast to prior data among hyperlipidemic men, the current data suggest that Lp-PLA(2) is not a strong predictor of future cardiovascular risk among unselected women.     

脂蛋白相关磷脂酶A2在颈动脉粥样硬化和缺血性卒中中的作用

脂蛋白相关磷脂酶A2(lipoprotein-associated phospholipase A2,Lp-PLA2)是磷脂酶A2超家族的一个亚型,主要由巨噬细胞和淋巴细胞产生.Lp-PLA2选择性水解低密度脂蛋白颗粒表面的氧化型磷脂,产生溶血磷脂胆碱和氧化型游离脂肪酸.Lp-PLA2表达于动脉粥样硬化斑块和不稳定斑块纤维帽内的巨噬细胞.研究表明,缺血性卒中患者血浆Lp-PLA2活性显著增高,而Lg-PLA2可能成为预测缺血性脑血管事件的独立危险因素.选择性LP-PLA2抑制剂可减轻炎症反应,增强斑块稳定性,抑制动脉粥样硬化斑块形成,有可能成为抗动脉粥样硬化斑块形成的一类新型药物.     

脂蛋白相关磷脂酶A2与临床冠心病的关系

目的探讨冠心病患者血清脂蛋白相关磷脂酶A2(Lp-PLA2)与冠状动脉(冠脉)炎症反应程度的关系。方法102例经冠脉造影证实的患者纳入冠心病(CHD)组,其中稳定型心绞痛(SAP)41例,不稳定型心绞痛(UAP)30例,急性心肌梗死(AMI)31例,对照组38例为冠脉造影正常的非冠心病者。所有对象造影前采集血标本以检测Lp-PLA2、C反应蛋白(CRP)和白细胞介素6(IL-6)。结果(1)冠心病组血清Lp-PLA2、CRP和IL-6均高于对照组(P<0.01);(2)AMI组与UAP组血清Lp-PLA2、CRP、IL-6比较差异无显著性(P>0.05),但均高于SAP组(P<0.01),在校正了心血管危险因素后差异仍有统计学意义;(3)经双变量相关性分析,血清Lp-PLA2水平与CRP、IL-6水平呈显著相关(r=0.722、0.665,P<0.01)。结论血清Lp-PLA2水平能反映冠脉炎症活动性状况,对冠心病的病情判断有一定价值。     

Apo E4 and lipoprotein-associated phospholipase A2 synergistically increase cardiovascular risk

ObjectiveApolipoprotein E (apoE) has been implicated as conveying increased risk for coronary artery disease (CAD). Previous studies suggest a role of apoE as a modulator of immune response and inflammatory properties. We hypothesized that the presence of apo E4 is associated with an increased inflammatory burden in subjects with CAD as compared to subjects without CAD.MethodsApoE genotypes, systemic (C-reactive protein [CRP], fibrinogen, serum amyloid-A [SAA]) and vascular inflammatory markers (Lipoprotein-associated phospholipase A₂ [Lp-PLA₂] and pentraxin-3 [PTX-3]) were assessed in 324 Caucasians and 208 African Americans, undergoing coronary angiography.ResultsFor both ethnic groups, Lp-PLA₂ index, an integrated measure of Lp-PLA₂ mass and activity, increased significantly and stepwise across apoE isoforms (P = 0.009 and P = 0.026 for African Americans and Caucasians respectively). No differences were found for other inflammatory markers tested (CRP, fibrinogen, SAA and PTX-3). For the top cardiovascular score tertile, apo E4 carriers had a significantly higher level of Lp-PLA₂ index in both ethnic groups (P = 0.027 and P = 0.010, respectively).ConclusionThe presence of the apo E4 isoform was associated with a higher level of Lp-PLA₂ index, a marker of vascular inflammation. Our results suggest that genetic variation at the apoE locus may impact cardiovascular disease risk through enhanced vascular inflammation.     

New insights into the role of HDL as an anti-inflammatory agent in the prevention of cardiovascular disease

Several known functions of high-density lipoproteins (HDLs) may contribute to their ability to protect against atherosclerosis. The best known of these functions is the ability to promote cholesterol efflux from cells in a process that may minimize the accumulation of foam cells in the artery wall. However, HDLs have additional properties, including antioxidant, anti-inflammatory, and antithrombotic effects, that may also be anti-atherogenic. Recent in vivo studies in several animal models have demonstrated that HDLs can inhibit acute and chronic vascular inflammation. The fact that these effects can be achieved with very low doses of reconstituted discoidal HDL or even lipid-free apolipoprotein A-I suggests that they may reflect activity of a minor, highly active HDL subpopulation. These results have potentially important clinical implications in regard to managing the acute vascular inflammation states that accompany acute coronary syndrome and acute ischemic stroke.     

脂蛋白相关性磷脂酶A2活性与冠心病的关系

目的:探讨血浆脂蛋白相关性磷脂酶A2(Lp-PLA2)活性与冠心病(CHD)传统危险因素的关系及与CHD发病的关系。方法:测定经冠状动脉造影证实的87例CHD患者和58例对照组的血浆Lp-PLA2活性、总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)水平并进行比较;同时调查年龄、性别、高血压史、糖尿病史、高脂血症史及吸烟史等CHD危险因素,研究它们与Lp-PLA2活性的关系。结果:①CHD组血浆Lp-PLA2活性显著高于对照组(P<0.01)。②CHD组中男性并高脂血症者Lp-PLA2活性显著升高。血浆Lp-PLA2活性与TC、LDL-C呈正相关,与HDL-C呈负相关,而与年龄、高血压、糖尿病、吸烟、TG无关。③非条件Logistic多元回归分析显示,调整其他危险因素后,Lp-PLA2活性仍与CHD独立相关。结论:CHD患者血浆Lp-PLA2活性显著增高,与TC、LDL-C呈正相关,与HDL-C呈负相关,是CHD的独立危险因素。     

Interpretation of lipoprotein-associated phospholipase A2 levels is influenced by cardiac disease,comorbidities, extension of atherosclerosis and treatments

Purpose

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory biomarker secreted in the atherosclerotic plaque. Blood levels of Lp-PLA2 predict future cardiovascular events in patients with ischemic disease and heart failure. This association seems to be independent of traditional cardiovascular risk factors.The aims of our study were (1) to assess relationships between Lp-PLA2 levels, cardiac disease and treatments; (2) to evaluate the association of Lp-PLA2 level with the severity of angiographic coronary artery disease (CAD) and the extracoronary atherosclerosis.

Methods

Between December 2009 and June 2010, 494 subjects were recruited from a population scheduled for diagnostic coronary angiography. Routine clinical (age, gender, BMI and treatment), cardiac (echocardiography, coronarography, carotid ultrasonography) and biochemical parameters were recorded for all patients. Lp-PLA2 mass concentration was assessed in serum with a Plac®-test turbidimetric immunoassay. Control Lp-PLA2 values were specifically obtained in 61 healthy subjects aged 44.5 ± 17.6 years (range: 25 to 59 years) without known cardiovascular risk factors (diabetes, smoking, hypertension, dyslipidemia) or cardiac treatment.

Results

In healthy controls, mean Lp-PLA2 level was 163 ± 43 μg/L (166 ± 45 μg/L in men and 159 ± 39 μg/L in women, non significant difference).In our cohort of 494 patients (69.8% men) aged 64.2 ± 16.7 years, the main etiologies of cardiomyopathies were ischemic (40%), valvular (22%), cardiac failure with left ventricular (LV) dysfunction (14%), infection (5%) and aortic aneurysm (7%). Mean Lp-PLA2 levels were 216 ± 17 μg/L. Lp-PLA2 correlated with age, BMI, current smoking, history of hypertension but not with diabetes and gender. The bivariate analysis showed a significant correlation between Lp-PLA2, and BMI (p = 0.001) but no correlation with serum creatinine or NYHA status. A multivariate correlation showed that Lp-PLA2 was associated with total cholesterol, LDL-cholesterol and apoB (r = 0.95, p < 0.0001) but not with Lp(a). We observed that Lp-PLA2 was significantly associated with treatments such as statins and ACEi/ARA2 but not with β-blockers, antiaggregant drugs or diuretics.Lp-PLA2 levels were significantly higher in patients with CAD than in patients without CAD (223 ± 54 vs. 208 ± 52 μg/L, respectively; p < 0.007). Moreover, Lp-PLA2 levels were significantly higher in patients with the most extensive angiographic CAD [single (n = 24) = 215.2 ± 52 μg/L; two (n = 55) = 222 ± 53 μg/L and three vessels (n = 140) = 251.9 ± 53.7 μg/L, respectively; p < 0.0001]. Patients with heart failure, sepsis or aortic aneurysm had increased Lp-PLA2 levels: 256.2 ± 46.8; 226.7 ± 47.3; 218.1 ± 38.9 μg/L, respectively, as compared to controls (p < 0.0001).In patients with carotid artery disease, Lp-PLA2 significantly increased with the severity of atherosclerosis. Mean Lp-PLA2 levels were 218.8 ± 51 μg/L in the group without any stenosis (n = 108), 224 ± 51 μg/L in the group with mild stenosis (n = 101), and 231 ± 46 μg/L in the group with severe stenosis (n = 22); p = 0.004.

Conclusion

This study clearly shows that interpretation of Lp-PLA2 levels needs a good assessment of cardiac parameters and treatments, especially statins and ACEi/ARA2. Lp-PLA2 levels are significantly associated with coronary heart disease and with the extension of extra coronary disease after adjustment for age and gender.     

脂蛋白相关磷脂酶A2对老年颈动脉粥样硬化患者斑块稳定性的预测价值

目的 探讨血清脂蛋白相关磷脂酶A2 (Lp-PLA2)对老年颈动脉粥样硬化患者斑块稳定性的预测价值。方法 回顾性分析2016年6月—2021年5月江苏省荣军医院收治的82例老年颈动脉粥样硬化患者的临床资料。根据颈动脉超声检查结果,将研究对象分为不稳定斑块组（n=49）和稳定斑块组（n=33）。比较2组的临床资料,分析影响老年颈动脉粥样硬化患者斑块稳定性的危险因素。结果 不稳定斑块组的高脂血症占比、脑梗死家族史占比、C反应蛋白（CRP）水平、斑块积分、动脉内-中膜厚度（IMT）及血清Lp-PLA2水平均高于稳定性斑块组（均P<0.05）。Logistic回归分析显示,斑块积分（OR=2.735,P=0.015）及血清Lp-PLA2 (OR=3.380,P=0.001)是老年颈动脉粥样硬化患者斑块稳定性的危险因素。受试者操作特征曲线显示,血清Lp-PLA2对老年颈动脉粥样硬化患者不稳定性斑块进行预测的最佳截断点为251.42ng/mL,敏感度和特异度分别为83.67%(41/49)和66.67%(22/33),曲线下面积为0.842(95%CI:0.745～0.913)。结论 血清L...     

脂蛋白相关磷脂酶A2水平与冠状动脉病变严重程度的关系

目的 探讨脂蛋白相关磷脂酶A2(Lp-PLA2)水平与冠状动脉(冠脉)病变严重程度的相关性.方法 检测344例疑诊为冠状动脉疾病(CAD)患者血浆Lp-PLA2,并行冠脉造影,以病变支数及评分评价冠脉病变程度,并分析与Lp-PLA2水平之间的关系.结果 无CAD者(冠脉评分=0分)与CAD者Lp-PLA2水平差异有统计学意义[(211±47)ng/ml与(245+59)ng/m1](u=5.99,P＜0.05);不同冠脉病变支数、冠脉评分与Lp-PLA2水平闻差异有统计学意义,3支病变和2支病变组均高于1支病变组[(254±66)ng/ml、(247+57)ng/ml和(230±50)ng/m1](F=9.98、H=29.09,均P＜0.05);在排除影响因素后,经多元逐步回归分析显示,Lp-PLA2是冠脉病变的危险因子.结论 血浆Lp-PLA2水平与冠状动脉病变呈正相关.