Biomarkers to predict recurrent cardiovascular disease: the Heart and Soul Study

Purpose

The study purpose was to evaluate the ability of 6 biomarkers to improve the prediction of cardiovascular events among persons with established coronary artery disease.

Background

Cardiovascular risk algorithms are designed to predict the initial onset of coronary artery disease but are less effective in persons with preexisting coronary artery disease.

Methods

We examined the association of N-terminal prohormone brain natriuretic peptide (Nt-proBNP), cystatin C, albuminuria, C-reactive protein (CRP), interleukin-6, and fibrinogen with cardiovascular events in 979 Heart and Soul Study participants with coronary artery disease after adjusting for demographic, lifestyle, and behavior variables; cardiovascular risk factors; cardiovascular disease severity; medication use; and left ventricular ejection fraction. The outcome was a composite of stroke, myocardial infarction, and coronary heart disease death during an average of 3.5 years of follow-up.

Results

During follow-up, 142 participants (15%) developed cardiovascular events. The highest quartiles (vs lower 3 quartiles) of 5 biomarkers were individually associated with cardiovascular risk after multivariate analysis: Nt-proBNP hazard ratio (HR) = 2.13 (95% confidence interval [CI], 1.43-3.18); cystatin C HR = 1.72 (95% CI, 1.10-2.70); albuminuria HR = 1.71 (95% CI, 1.15-2.54); CRP HR = 2.00 (95% CI, 1.40-2.85); and interleukin-6 HR = 1.76 (95% CI, 1.22-2.53). When all biomarkers were included in the multivariable analysis, only Nt-proBNP, albuminuria, and CRP remained significant predictors of events: HR = 1.88 (95% CI, 1.23-2.85), HR = 1.63 (95% CI, 1.09-2.43), and HR = 1.82 (95% CI, 1.24-2.67), respectively. The area under the receiver operator curve for clinical predictors alone was 0.73 (95% CI, 0.68-0.78); adding Nt-proBNP, albuminuria, and CRP significantly increased the area under the receiver operator curve to 0.77 (95% CI, 0.73-0.82, P <.005).

Conclusion

Among persons with prevalent coronary artery disease, biomarkers reflecting hemodynamic stress, kidney damage, and inflammation added significant risk discrimination for cardiovascular events.     

Congenital hypofibrinogenemia: characterization of two missense mutations affecting fibrinogen assembly and secretion

Congenital hypofibrinogenemia is a rare bleeding disorder characterized by abnormally low levels of fibrinogen in plasma, generally due to heterozygous mutations in one of the three fibrinogen genes (FGA, FGB, and FGG, coding for Aα, Bβ, and γ chain, respectively). Hypofibrinogenemic patients are usually asymptomatic, whereas individuals bearing similar mutations in the homozygous or compound heterozygous state develop a severe bleeding disorder: afibrinogenemia. The mutational spectrum of these quantitative fibrinogen disorders includes large deletions, point mutations causing premature termination codons, and missense mutations affecting fibrinogen assembly or secretion, distributed throughout the 50-kb fibrinogen gene cluster. In this study, we report the mutational screening of two unrelated hypofibrinogenemic patients leading to the identification of two missense mutations, one hitherto unknown (αCys45Phe), and one previously described (γAsn345Ser). The involvement of αCys45Phe and γAsn345Ser in the pathogenesis of hypofibrinogenemia was investigated by in-vitro expression experiments. Both mutations were demonstrated to cause a severe impairment of intracellular fibrinogen processing, either by affecting half-molecule dimerization (αCys45Phe) or by hampering hexamer secretion (γAsn345Ser).     

结核性胸膜炎胸液中纤维蛋白原含量对胸膜肥厚及粘连形成的影响

目的　探讨结核性渗出性胸膜炎胸腔积液纤维蛋白原含量与胸膜肥厚、粘连的关系。方法117例初治结核性渗出性胸膜炎患者按胸腔积液纤维蛋白原含量从低到高分为A、B、C 3组 ,治疗过程中和治疗后测定胸膜厚度 ,评估胸膜粘连发生率。结果 治疗过程中胸膜厚度 :A组与B组比较 (t=2 .5 7,P<0.05 )有显著性差异 ,A组与C组比较 (t=7.15 ,P<0 .0 1)有显著差异性 ,B组与C组比较 (t=2.46 ,P<0 .0 5 )有显著性差异 ;胸膜粘连发生率 :A组与B组比较 (χ²=3.5 1,P>0.05 )无显著性差异 ,A组与C组比较 (χ²=9.87,P<0 .01)有显著性差异 ,B组与C组比较 (χ²=4 .5 1,P<0 .0 5 )有显著性差异。治疗结束时胸膜厚度 :A组与B组比较 (t=1.4 5 ,P>0 .0 5 )无显著性差异 ,A组与C组比较 (t=3.4 6 ,P<0.01)有显著性差异 ,B组与C组比较 (t=2 .89,P<0 .0 1)有显著性差异 ;胸膜粘连发生率 :A组与B组比较 (χ²=0 .10 ,P>0 .0 5 )无显著性差异 ,A组与C组比较 (χ²=4 .36 ,P<0.05)有显著性差异 ,B组与C组比较 (χ²=7.4 9,P<0 .0 1)有显著性差异。结论 胸液纤维蛋白原含量可影响胸膜肥厚度与胸膜粘连发生率。     

急性脑梗死患者颈动脉硬化与C反应蛋白及纤维蛋白原的相关性

目的探讨急性脑梗死患者高敏C反应蛋白和纤维蛋白原的变化与颈动脉粥样硬化超声指标之间的关系。方法应用高频多普勒超声检测颈动脉内膜—中膜厚度、斑块总计分和血流速度;同时检测其血C反应蛋白和纤维蛋白原浓度;连续观察103例,其中急性脑梗死组33例,慢性脑梗死组34例,年龄相匹配的正常对照组36例。各项数据用SPSS10软件统计分析。结果颈动脉内膜—中膜厚度和斑块发生率急性组和慢性组较对照组增加(P均<0.01),而急性组和慢性组间差异无显著性(P>0.05);慢性组颈动脉斑块积分较急性组显著增加(P>0.05);C反应蛋白浓度急性组(19.54±37.96mg/L)较慢性组(4.01±7.22mg/L)和对照组(1.66±1.17mg/L)增高(P均<0.01);慢性组较对照组增高但差异无显著性(P>0.05)。急性组、慢性组和对照组间C反应蛋白浓度95%的可信范围分别为1.24～2.08mg/L、4.52～34.56mg/L和1.42～6.62mg/L。急性组血浆纤维蛋白原浓度依次大于慢性组和对照组,但差异无显著性(P>0.05)。多元逐步回归分析表明:血C反应蛋白浓度与纤维蛋白原和斑块总计分呈正相关,与血流阻力指数呈负相关。血纤维蛋白原浓度与高密度脂蛋白胆固醇浓度呈负相关。结论脑梗死患者急性期纤维蛋白原血浓度变化不敏感;C反应蛋白血浓度升高与颈动脉内膜—中膜厚度无关,与纤维蛋白原血浓度和斑块总计分关系密切。     

Blood hyperviscosity and its relationship to progressive renal failure in patients with diabetic nephropathy

Blood rheology was investigated in patients with diabetic nephropathy and progressive renal insufficiency, and compared with similar non-diabetic patients and healthy control subjects. Plasma viscosity and whole blood viscosity at standardized haematocrit were elevated to a comparable degree in the two patient groups, but erythrocyte deformability was normal. In diabetic patients, the rate of progression of renal failure showed weak, but significant, correlations with plasma viscosity (rs = 0.50, p = 0.005), standardized whole blood viscosity (rs = 0.41, p = 0.021), plasma fibrinogen (rs = 0.46, p = 0.010), C reactive protein (rs = 0.40, p = 0.023), and proteinuria (rs = 0.52, p = 0.003). Both plasma viscosity and plasma fibrinogen correlated significantly with proteinuria (rs = 0.45, p = 0.012 and 0.40, p = 0.027, respectively). Rheological abnormality is probably a manifestation of increased acute phase proteins, but it remains to be determined whether these are the cause or the effect of the renal injury. Abnormal blood rheology may be a risk factor for the progression of renal failure in diabetic nephropathy.     

碱性电解水对大鼠抗氧化及抗纤维蛋白原作用的实验研究

目的　探讨碱性电解水抗氧化及抗纤维蛋白原的作用。方法　W istar雄性大鼠 36只 ,分三组 ,每组 1 2只。A组 :空白对照 ,B组 :高脂模型组。 C组 :高脂 +碱性电解水组。实验结束后 ( 30 d) ,乙醚麻醉 ,腹主动脉取血 ,采用硫代巴比妥酸比色法在日本岛津 UV— 36 0分光光度计上测定丙二醛 ( MDA) ;上海斯隆纤维蛋白原测定仪测定纤维蛋白原。结果　 A、B、C三组 M DA分别为 3.39± 0 .50 ( nmol/ m1 )、4 .1 0± 0 .37及 3.6 8±0 .4 6 ;纤维蛋白原分别为 1 94 .6 3± 2 3.6 3( mg/ d1 )、2 0 1 .2 2± 2 4 .32及 1 6 9.50± 1 1 .1 7。 C组比 B组显著下降 ( P<0 .0 5)。结论　碱性电解水具有一定抗氧化及降低纤维蛋白原的功能。     

复方丹参注射液抗脂多糖诱导的兔弥漫性血管内凝血

目的: 研究复方丹参注射液对脂多糖(LPS)诱导的兔弥漫性血管内凝血(DIC)的作用。方法: 用LPS诱导兔DIC模型。凝固法测定纤维蛋白原含量,全自动凝血分析仪检测活化部分凝血活酶时间(APTT)、凝血酶原时间(PT)和纤维蛋白原含量;全自动血细胞分析仪进行血小板计数;全自动血浆分析仪测定谷丙转氨酶(ALT)以及血尿素氮(BUN);发色底物法测定蛋白C及抗凝血酶Ⅲ的活性。观察复方丹参注射液对LPS诱导的兔DIC的拮抗作用。结果: 兔耳缘静脉持续滴注LPS,观察到:APTT和PT显著延长;血小板计数和纤维蛋白原含量明显减少;ALT和BUN显著升高;蛋白C和抗凝血酶Ⅲ的活性明显降低。给予复方丹参注射液后,APTT和PT的延长明显缩短;血小板计数和纤维蛋白原的含量均明显恢复;ALT和BUN显著下降;蛋白C及抗凝血酶Ⅲ的活性显著改善。结论: 复方丹参注射液对LPS诱导的兔DIC有良好的拮抗作用。     

冠心病患者的牙周状况与Fg和hs-CRP相关性的研究

目的：通过牙周临床检查和血生化指标检测,观察冠心病患者的牙周状况,探讨纤维蛋白原和高敏C反应蛋白在两者间的相关关系。方法：按照冠心病及慢性牙周炎临床诊断标准随机选择200名研究对象,年龄35～80岁,分为急性冠脉综合征（ACS）组50人,慢性冠脉病（CAD）组50人,单纯慢性牙周炎（CP）组50人,健康（H）对照组50人,每组都进行牙周探诊深度（PD）、临床附着丧失度（CAL）、龈沟出血指数（SBI）和简化卫生指数（OHI-S）检查,采集清晨静脉血检测Fg和hs-CRP水平。结果：PD、CAL、OHI-S在ACS组中最高,与CP组比较有显著性差异（P〈0.001）;SBI在CAD组中最高,ACS组与CP组比较有显著性差异（P〈0.001）;Fg和hs-CRP在ACS组中测定值最高,与CP组比较有显著性差异（P〈0.05）;血生化指标Fg和hs-CRP的水平与牙周临床指标PD、CAL、SBI、OHI-S比较呈正相关（P〈0.01）。结论：冠心病患者无论是急性期还是稳定期牙周状况都比单纯慢性牙周炎患者严重;PD、CAL、OHI-S的升高可引起血清中Fg和hs-CRP水平的变化,牙周临床指标的改变可能与冠心病的急性发作和加重冠心病病程有关。     

肝硬化患者凝血、抗凝及纤溶指标的变化与Child-Pugh分级的关系

目的 探讨肝硬化患者凝血、抗凝及纤溶指标的变化及其与Child-Pugh分级的关系。 方法肝硬化患者43例,Child-Pugh分级A级13例,B级15例,C级15例。正常对照组16例,男11例,女5例。均检测凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、纤维蛋白原(Fib)、凝血因子Ⅱ、Ⅴ、Ⅶ、Ⅷ、Ⅸ、Ⅹ、血管性假性血友病因子(vWF)、抗凝血酶-Ⅲ(AT-Ⅲ)、蛋白-C(PC)、D-二聚体(D-d)、组织纤溶酶原激活物(t-PA)抗原和组织纤溶酶原激活物抑制剂(PAI)。 结果 PT、APTT随病情加重而显著延长,F值分别为32.828和18.743,P值均<0.01;Fib随病情加重逐渐降低,F=4.747,P<0.01。凝血因子Ⅱ、Ⅴ、Ⅶ、Ⅸ、Ⅹ随病情加重活性逐渐降低,F值分别为43.129、12.677、36.405、9.380和21.988,P值均<0.01。Ⅷ、vWF因子随病情加重活性逐渐增高,F值分别为16.672和14.657,P值均<0.01。AT-Ⅲ、PC随病情加重活性逐渐降低,F值分别为22.602和15.430,P值均<0.01。D-d、t-PA抗原随病情加重逐渐增高,F=5.957,P<0.05。PAI活性正常对照组和3组患者检测结果近似,差异无统计学意义。 结论 肝硬化患者存在明显的凝血、抗凝血以及纤溶机制的异常,且与肝硬化程度密切相关。在防治肝硬化患者出血时,不仅要纠正患者的凝血因子异常,还要给予一定的抗纤溶治疗。