脂蛋白相关磷脂酶A2与冠心病的相关性研究进展

血浆脂蛋白相关磷脂酶A2(LP-PLA2)由成熟的巨噬细胞和淋巴细胞合成和分泌,又称血小板活化因子乙酰水解酶(PAF-AH),在血浆中主要与低密度脂蛋白结合.近年来,越来越多研究表明在冠心病的发病机制及预防性治疗上,LP-PLA2是一个新的有待研究的因子,其在循环中的含量和活性与冠状动脉事件风险存在正相关,可能成为冠心病治疗的新靶点.     

抑制脂蛋白相关性磷脂酶A2与冠心病关系的研究进展

大量流行病学研究证明脂蛋白相关性磷脂酶A2是冠心病的独立危险预测因子。脂蛋白相关性磷脂酶A2在动脉粥样硬化过程中所起的作用已引起广泛关注,认为抑制脂蛋白相关性磷脂酶A2的生物学活性可以抑制动脉粥样硬化的进展,从而预防并减少冠脉事件的发生。     

Comparative Pharmacodynamic Evaluation of Eptifibatide and Abciximab in Patients with Non-ST-Segment Elevation Acute Coronary Syndromes: The TAM2 Study

Background: The importance of the relationship between clinical outcome and degree of platelet aggregation inhibition (PAI) achieved with the dosing regimens of GPIIb-IIIa inhibitors used in large trials in patients with non-ST segment elevation (NSTE) acute coronary syndromes (ACS) is increasingly appreciated. In the PURSUIT trial, eptifibatide treatment that consistently provided >80% PAI was associated with clinical benefit at 30 days and 6 months. The GUSTO IV ACS trial, however, did not show any effect of abciximab on 30-day outcomes. This difference might be due to variability of antiplatelet effects of these drugs. As previous studies found, a 12 hr abciximab infusion had <80% PAI, particularly at 6 and 12 hr. These studies did not evaluate PAI with a longer, 24-hour infusion as used in GUSTO IV ACS.Methods: We conducted a prospective study in 40 patients with NSTE ACS prior to catheterization or coronary intervention at 3 centers using the PURSUIT dose of eptifibatide (180/0.2) and the GUSTO IV dose of abciximab (0.25, 0.125). Blood samples were collected at baseline, and during the infusion at 10 min, 1 hr, 6 hr, 8 hr, 12 hr, 18 hr, and 24 hr. Measurements of ex vivo light transmission aggregometry (LTA) were performed using PPACK anticoagulant and 20 M ADP agonist. Receptor Occupancy (RO) was also determined in a subset of patients.Results: Eptifibatide achieves higher PAI during the entire infusion period than abciximab (p < 0.01). At 10 min, average PAI with eptifibatide and abciximab was 88% and 80%, respectively, 95% and 79% at 6 hr, and 97% and 79% at 24 hr. There was also more variability in individual patient response to abciximab. Although average RO for eptifibatide was similar to that of abciximab at 10 min, 67% versus 69%, respectively, average RO was higher in the eptifibatide cohort at all subsequent timepoints. By 24 hr, average RO for eptifibatide was 86%, whereas abciximab averaged 67%.Conclusion: These data support the hypothesis that differences in clinical outcomes of large GPIIb-IIIa trials in patients with NSTE ACS may be related to the consistency and potency of antiplatelet effects of the dosing regimens used.Abbreviated abstract. We compared platelet aggregation inhibition (PAI) with the glycoprotein IIb-IIIa inhibitors eptifibatide and abciximab in patients with non–ST-segment elevation (NSTE) acute coronary syndromes (ACS), using light transmission aggregometry assays with D-phenylalanyl-L-propyl-L-arginine chloromethylketone (PPACK) as the anticoagulant and 20 mol adenosine diphosphate (ADP) as the platelet agonist. Mean PAI with eptifibatide during the entire 24-hour infusion period was >80%, and it was significantly higher than the mean PAI achieved with abciximab (p < 0.0001). Mean PAI with abciximab was <80% at 6, 8, 12, 18, and 24 hr. Most patients in the eptifibatide arm had >80% PAI at all time points, whereas many patients treated with abciximab had <80% PAI throughout the infusion period, particularly at later times (6 hr and beyond). Mean GPIIb-IIIa receptor occupancy with eptifibatide was also higher than with abciximab. These pharmacodynamic differences may have contributed to differing clinical effects of eptifibatide and abciximab in large clinical trials in patients with NSTE ACS.     

稳定期冠心病患者中医证候演变规律的研究

目的探讨稳定期冠心病患者发生急性心血管事件的中医证候演变规律及其与随访发生急性心血管事件的关系。方法纳入稳定期冠心病患者303例,详细记录入选时、半年、1年的中医证候情况及2年随访时事件发生情况。应用频数分布法,观察两组患者整体的证候分布。应用多因子降维(MDR)数据挖掘方法探讨中医证候的演变规律。结果频数法显示3个时间点(两个时间段)的演变趋势:两组的气滞、寒痰(第2时段)均呈现降低趋势,痰热证在事件组呈现逐渐增加。阴虚、气虚的变化趋势基本相同,而阳虚的变化两组则呈现相反的方向。应用MDR来研究证候之间的转化,结果提示,第2个时点的阳虚转化为第3个时点的痰热、第2个时点的气虚转化为第3个时点的痰热与发生心血管事件呈正相关。结论证候演变中以气虚—痰热、阳虚—痰热的转化易引发心血管事件。     

冠心病合并2型糖尿病病人中医证型与冠状动脉病变的关系探讨

目的探讨冠心病合并2型糖尿病病人中医证型与冠状动脉病变支数、狭窄程度及Gensini积分的关系。方法选取2012年1月—2016年12月在安徽中医药大学第一附属医院心内科行冠状动脉造影检查确诊为冠心病,同时经临床证实合并有2型糖尿病的病人共300例,分析冠状动脉病变程度(包括病变支数、狭窄程度分级、Gensini积分)与中医证型的关系。结果冠心病合并2型糖尿病病人同一冠状动脉狭窄程度的中医证型分布差异有统计学意义(P<0.05)。冠状动脉轻度狭窄病人以气阴两虚证(55.3%)为主;冠状动脉病变程度较重病人以气虚痰瘀证(中度狭窄占50.5%,重度狭窄占37.2%,完全闭塞占56.1%)及阳虚血瘀证(重度狭窄占35.9%)为主,且与气阴两虚证比较差异均有统计学意义(P<0.05)。冠状动脉单支病变病人以气阴两虚证为主,双支及多支病变病人以气虚痰瘀证为主,并且不同冠状动脉病变支数的气阴两虚证、气虚痰瘀证、阳虚血瘀证分布差异有统计学意义(P<0.01)。阳虚血瘀证的Gensini积分最高,与气阴两虚证、阳虚血瘀证比较差异均有统计学意义(P<0.05)。结论冠心病合并2型糖尿病病人的冠状动脉病变特点与中医证型之间具有一定的关联性。     

脂蛋白相关磷脂酶A2与冠心病患者踝臂指数、心率变异性的相关性研究

背景踝臂指数(ABI)可预测冠状动脉狭窄,心率变异性(HRV)降低与冠心病(CHD)的进展有关,脂蛋白相关磷脂酶A2(Lp-PLA2)是CHD患者冠状动脉狭窄的危险因素,但三者之间的关系目前尚不明确。目的分析Lp-PLA2与CHD患者ABI、HRV的相关性,并分析Lp-PLA2对CHD患者ABI及HRV异常的预测价值。方法选取2016年4月-2019年1月汕头大学附属粤北人民医院心血管内科确诊的非CHD患者292例作为A组,同期确诊的CHD患者389例作为B组。比较两组患者一般资料、实验室检查指标、血脂指标及ABI、HRV;变量间的相关性分析采用Pearson偏相关及多元线性回归分析;绘制ROC曲线以评价Lp-PLA2对CHD患者ABI及HRV异常的预测价值。结果 (1)两组患者高血压病史、体质指数(BMI)、三酰甘油(TG)、载脂蛋白B (ApoB)比较,差异无统计学意义(P>0.05);B组患者年龄、有2型糖尿病病史者所占比例、同型半胱氨酸(Hcy)、Lp-PLA2、糖化血红蛋白(HbA1c)、超敏C反应蛋白(hs-CRP)、脂蛋白a[LP (a)]高于A组,总胆固醇(TC)、载脂蛋白A (ApoA)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、ABI及全部窦性心搏RR间期的标准差(SDNN)低于A组(P<0.05)。(2) Lp-PLA2未进入多元线性回归方程。Pearson偏相关分析结果显示,ABI与CHD (r=-0.147)、Hcy (r=-0.082)呈负相关,与BMI (r=0.119)、SDNN (r=0.157)呈正相关(P<0.05)。多元线性回归分析结果显示,ABI与CHD (β=-0.50)和Hcy (β=-0.01)呈负相关,与BMI (β=0.004)和SDNN (β=0.001)呈正相关(P<0.05)。(3)Pearson偏相关分析结果显示,SDNN与Lp-PLA2 (r=-0.098)、hs-CRP (r=-0.123)呈负相关(P<0.05)。多元线性回归分析结果显示,SDNN与CHD患者LP-PLA2 (β=-0.040)、hs-CRP (β=-4.388)负相关,与ABI (β=43.301)呈正相关(P<0.05)。(4)ROC曲线显示,Lp-PLA2预测CHD患者ABI异常的曲线下面积(AUC)为0.583[95%CI(0.480,0.687)],灵敏度为0.84、特异度为0.38;Lp-PLA2预测CHD患者SDNN异常的AUC为0.656[95%CI(0.600,0.712)],灵敏度为0.76,特异度为0.48。结论 CHD患者Lp-PLA2升高,ABI、HRV降低;Lp-PLA2与CHD患者HRV呈负相关且对CHD患者HRV异常有一定的预测价值,但其与CHD患者ABI无关,而ABI与CHD患者HRV呈正相关。     

Associations and interaction effects of maternal smoking and genetic polymorphisms of cytochrome P450 genes with risk of congenital heart disease in offspring: A case–control study

To assess associations and interactions of maternal smoking and cytochrome P450 (CYP450) genetic variants with the developments of congenital heart disease (CHD) and specific subtypes.A case–control study of 654 cases and 666 controls was conducted from November 2017 to March 2020. The exposures of interest were maternal active and passive smoking before/in the early pregnancy and CYP450 genetic polymorphisms. Data were analyzed using the Chi-square test and logistic regression analysis.After adjusting for the potential confounding factors, our study showed maternal active (OR_adj = 2.34, 95%CI: 1.19–4.60) or passive (OR_adj = 1.76, 95%CI: 1.34–2.31) smoking before pregnancy, passive smoking in the early pregnancy (OR_adj = 3.05, 95%CI: 2.26–4.12), as well as polymorphisms of CYP450 at rs1065852 (G/A vs G/G: OR_adj = 1.46, 95%CI: 1.07–1.99; A/A vs G/G: OR_adj = 1.63, 95%CI: 1.15–2.33) and rs16947 (A/A vs G/G: OR_adj = 3.61, 95%CI: 2.09–6.23), were significantly associated with risk of total CHD in offspring. Similar results were also found for some subtypes of CHD. Additionally, significant interactions between maternal smoking and CYP450 genes on the risk of CHD were observed.Maternal smoking and CYP450 genetic variants were associated with increased risk of CHD and specific subtypes in offspring. And the effects of CYP450 genes on CHD may be modified by maternal smoking.     

血浆脂蛋白相关磷脂酶A2在急性冠脉综合征患者危险分层及近期预后评估中的作用

目的探讨血浆脂蛋白相关磷脂酶A2(lipoprotein-associated phospholipase A2,LP-PLA2)在急性冠脉综合征患者危险分层中的价值以及其在近期预后评估中的作用。方法选取入住茂名市人民医院的急性冠脉综合征患者100例(含ST段抬高型心肌梗死、非ST段抬高型心肌梗死、不稳定型心绞痛等类型患者),另以稳定型心绞痛患者为对照组。根据全球急性冠状动脉事件注册(global registry of acute coronary events,GRACE)评分将急性冠脉综合征患者分高危、中危、低危组。所有患者治疗前抽血测定血浆LP-PLA2等指标。随访患者自住院至6个月内发生的主要心血管事件。结果 (1)急性冠脉综合征组患者血浆LP-PLA2浓度显著高于对照组,差异有统计学意义(P<0.05)。(2)据GRACE评分,高危组中血浆LP-PLA2浓度显著高于中危组和低危组,差异有统计学意义(P<0.01)。(3)随访观察6个月,高危组血浆LP-PLA2浓度显著高于中、低危组,差异有统计学意义(P<0.01);血浆LP-PLA2浓度在主要心血管事件发生组中较未发生组明显升高,差异有统计学意义[(192.4±8.3)ng·m L-1vs.(168.6±9.3)ng·m L-1,P<0.05]。结论血浆LP-PLA2浓度可用于急性冠脉综合征危险分层。血浆LP-PLA2浓度联合GRACE评分预测冠状动脉事件风险,对于急性冠脉综合征患者近期预后评估有意义。     

A prospective survey of the characteristics, treatments and outcomes of patients with acute coronary syndromes in Europe and the Mediterranean basin; the Euro Heart Survey of Acute Coronary Syndromes (Euro Heart Survey ACS).

AIMS: To better delineate the characteristics, treatments, and outcomes of patients with acute coronary syndromes (ACS) in representative countries across Europe and the Mediterranean basin, and to examine adherence to current guidelines. METHODS AND RESULTS: We performed a prospective survey (103 hospitals, 25 countries) of 10484 patients with a discharge diagnosis of acute coronary syndromes. The initial diagnosis was ST elevation ACS in 42.3%, non-ST elevation ACS in 51.2%, and undetermined electrocardiogram ACS in 6.5%. The discharge diagnosis was Q wave myocardial infarction in 32.8%, non-Q wave myocardial infarction in 25.3%, and unstable angina in 41.9%. The use of aspirin, beta-blockers, angiotensin converting enzyme inhibitors, and heparins for patients with ST elevation ACS were 93.0%, 77.8%, 62.1%, and 86.8%, respectively, with corresponding rates of 88.5%, 76.6%, 55.8%, and 83.9% for non-ST elevation ACS patients. Coronary angiography, percutaneous coronary interventions, and coronary bypass surgery were performed in 56.3%, 40.4%, and 3.4% of ST elevation ACS patients, respectively, with corresponding rates of 52.0%, 25.4%, and 5.4% for non-ST elevation ACS patients. Among patients with ST elevation ACS, 55.8% received reperfusion treatment; 35.1% fibrinolytic therapy and 20.7% primary percutaneous coronary interventions. The in-hospital mortality of patients with ST elevation ACS was 7.0%, for non-ST elevation ACS 2.4%, and for undetermined electrocardiogram ACS 11.8%. At 30 days, mortality was 8.4%, 3.5%, and 13.3%, respectively. CONCLUSIONS: This survey demonstrates the discordance between existing guidelines for ACS and current practice across a broad region in Europe and the Mediterranean basin and more extensively reflects the outcomes of ACS in real practice in this region.     

The Effect of Common Variants in SLC44A2 on the Contribution to the Risk of Deep Cein Thrombosis after Orthopedic Surgery

Aim: Deep vein thrombosis (DVT) is a common complication of orthopedic surgery. Multiple lines of evidence indicate that genetic factors play an important role in the development of DVT following orthopedic surgery (DVTFOS). Recent evidence suggested that the solute carrier family 44 member 2 (SLC44A) gene may contribute to the risk of DVT. In this study, we aimed to investigate the associations of SLC44A2 and DVTFOS in Chinese Han individuals.Methods: In the study, 2,655 subjects, including 689 DVTFOS patients and 1,966 controls, were recruited. Eighteen SNPs were genotyped in the study. Genetic association analyses were performed at both the single marker and haplotype levels. Bioinformatics analyses were conducted to predict the functional consequences of significant SNPs.Results: SNP rs2288904 of SLC44A2 was identified as being significantly associated with DVTFOS (P = 0.0003, OR [95%CI]= 1.28[1.12–1.46]). Allelic analyses showed that the G allele of this SNP significantly elevated the risks of DVTFOS, which was replicated in the genotypic association analyses. Moreover, a two-SNP haplotype, including rs2288904, was found to be strongly correlated with the risk of DVTFOS (P = 4.15 × 10⁻¹¹). Widespread effects in the expression quantitative trait loci were identified for rs2288904 in multiple tissues.Conclusion: In summary, our results provide further supportive evidence of the association of SLC44A2 with the risk of DVTFOS, which also provide clues for understanding the important roles of the SLC44A2 gene in the pathogenesis of DVTFOS and in the development of preventive strategies.     

Role of Phospholipase A2 in Cholesterol Gallstone Formation Is Associated with Biliary Phospholipid Species Selection at the Site of Hepatic Excretion

Phospholipase A₂ plays a role in cholesterol gallstone development by hydrolyzing bile phospholipids into lysolecithin and free fatty acids. Lysolecithin and polyunsaturated free fatty acids are known to stimulate the synthesis and/or secretion of gallbladder mucin via a prostanoid pathway, leading to enhancing cholesterol crystal nucleation and growth, and therefore, the action of phospholipase A₂ is associated, in part, with bile phospholipid fatty acid. To clarify this hypothesis, we evaluated the effect on bile lipid metastability in vitro of replacing phospholipids with lysolecithin and various free fatty acids. Supersaturated model biles were created with an identical composition (cholesterol saturation index, 1.8; egg yolk lecithin, 34 mM; taurocholate, 120 mM; cholesterol, 25 mM) except for 5%, 10%, or 20% replacement of egg yolk lecithin with a combination of palmitoyl–lysolecithin and a free fatty acid (palmitate, stearate, oleate, linoleate, or arachidonate), followed by time-sequentially monitoring of vesicles and cholesterol crystals using spectrophotometer and video-enhanced differential contrast microscopy. Replacement with hydrophilic fatty acids (linoleate and arachidonate) reduced vesicle formation and promoted cholesterol crystallization, whereas an enhanced cholesterol-holding capacity was evident after replacement with hydrophobic fatty acids (palmitate and stearate). These results indicate that the effect of phospholipase A₂ on bile lithogenecity is modulated by the fatty acid species in bile phospholipids, and therefore, that the role of phospholipase A₂ in cholesterol gallstone formation is dependent, in part, on biliary phospholipid species selection at the site of hepatic excretion.     

The recent effects of small dose of folic acid on lipoprotein-associated phospholipase A2 and systolic blood pressure variability in coronary heart disease patients with hyperhomocysteinemia: A single-center prospective cohort study

To Investigate the recent effects of small dose of folic acid on lipoprotein-associated phospholipase A2 (LP-PLA2) and systolic blood pressure variability in coronary heart disease (CHD) patients with hyperhomocysteinemia.In this prospective cohort study, a total of 167 CHD patients with hyperhomocysteinemia were consecutively enrolled, and they were divided into Group A (without folic acid intervention, n = 99), Group B (with 0.4 mg of folic acid intervention, n = 34), Group C (0.8 mg of folic acid intervention, n = 34). General information, fasting blood glucose, and blood lipid, folic acid, homocysteine, Lp-PLA2, and blood pressure variability were compared among 3 groups. The above indicators were reviewed after 3 months of treatment.There were no statistically significant differences of age, gender, blood pressure, incidence of type 2 diabetes mellitus, fasting blood glucose, folic acid, homocysteine, Lp-PLA2, total cholesterol, 3 acyl glycerin, apolipoprotein B, lipoprotein (a), high density lipoprotein cholesterol, and low density lipoprotein cholesterol were found among 3 groups (P > .05); however, after being treated for 3 months, there was statistically significant difference in folic acid among 3 groups (P < .05), there was statistically significant difference in apolipoprotein A between Group A and Group B (t = 0.505, P = .039), and also between Group A and Group C (t = 0.052, P = .017). There were statistically significant differences in Lp-PLA2 (t = 24.320, P = .016) and systolic blood pressure variability (t = 0.154, P = .018) between Group A and Group C.For CHD patients with hyperhomocysteinemia, the higher dose (0.8 mg) of folic acid supplement was beneficial for increasing the apolipoprotein A, reducing the Lp-PLA2, and improving the systolic blood pressure variation, which might help to improve the prognosis in these patients.     

急性冠脉综合症患者MEF2A与MMP-8血清水平的相关性分析

目的：检测急性冠脉综合症(ACS)患者和健康对照组血清MEF2A及MMP-8水平的变化,观察MEF2A与MMP-8变化及对急性冠脉综合症患者的影响。方法：采用ELISA法检测ACS患者及健康对照组血液MEF2A及MMP-8水平的变化。结果：1.ACS组患者血液MEF2A水平与对照组相比明显降低(P<0.05);2.ACS组患者血液MMP-8水平与对照组相比明显升高(P<0.05);3.在ACS组中MEF2A水平与MMP-8水平变化呈负相关(r =-0.853,P <0.01)。结论：ACS患者血液MEF2A水平明显降低,且与MMP-8水平变化呈明显负相关。血液MEF2A、MMP-8水平变化对AS炎症反应和斑块的稳定程度评价具有重要的临床意义。     

血清Lp-PLA2 GGT与冠心病及冠状动脉病变严重程度的相关性分析

目的分析血清脂蛋白相关磷脂酶A2(Lp-PLA2)、γ-谷氨酰转移酶(GGT)与冠心病(CHD)及冠状动脉病变严重程度的相关性。方法选择2018-06~2019-06于郑州大学第二附属医院心内科首次就诊的170例疑似CHD患者的临床资料,根据冠状动脉造影检查结果分为CHD组(103例)和非CHD组(67例)。检测患者血清Lp-PLA2、GGT水平,分析血清Lp-PLA2、GGT与CHD及冠状动脉病变严重程度的关系。结果CHD组Lp-PLA2、GGT、甘油三酯(TG)、低密度脂蛋白(LDL)、Gensin积分水平以及合并高血压、糖尿病人数比例显著高于非CHD组(P<0.05),而高密度脂蛋白(HDL)水平显著低于非CHD组(P<0.05)。Spearman相关分析结果显示,CHD患者血清Lp-PLA2、GGT水平与冠状动脉病变支数呈正相关(rs=0.681,P=0.000;rs=0.603,P=0.000)。Pearson相关分析结果显示,CHD患者血清Lp-PLA2、GGT水平与Gensin积分呈正相关(r=0.799,P=0.000;r=0.621,P=0.000)。多因素logistic分析结果显示,较高水平的Lp-PLA₂、GGT和LDL,以及合并高血压是促进CHD发生的危险因素(P<0.05);而较高水平的HDL是抑制CHD发生的保护因素(P<0.05)。结论较高水平的血清Lp-PLA2、GGT是促进CHD发生的危险因素,可较好地反映冠状动脉病变严重程度,可作为评估CHD发生、进展的可靠指标。     

Impact of Pre-Diabetes on Coronary Plaque Composition and Clinical Outcome in Patients With Acute Coronary Syndromes: An Analysis From the PROSPECT Study

Objectives

The aim of this study was to investigate the impact of pre-diabetes (pre-DM) on coronary plaque characteristics and ischemic outcomes in patients with acute coronary syndromes (ACS).