Study On The Roles Of Plateled-related Factors In Cardiovascular System Diseases

Part Ⅰ.The effects of BaP on platelet-derived thrombosis GoalTo investigate the effect of BaP on platelet aggregation, activation, thrombosis, and the potential underlying mechanisms.Methods1. To assess the effect of BaP on different agonists-induced (ADP, collagen, and thrombin) platelet aggregation.2. To assess the effect of BaP on platelet adhesion using flow chamber system under different shear rates.3. To identify the target molecules of BaP in ADP-induced platelet signaling pathway using Western blotting, and confirmed the results with relevant inhibitors; to assess the effect of BaP on platelet activation (the expression of P-selection, Fibrinogen binding)with whole blood flow cytometry.4. To confirm the effect of BaP on acute thrombosis in an acute thrombosis model (C57BL/6J wild type mouse).Results1. BaP enhanced platelet aggregation induced by ADP in a dose-dependent manner, but had no effect on platelet aggregation induced by collagen and thrombin;2. BaP increased platelet adhesion on collagen surfaces under shear rates of1000s-1; 3. Western blot analysis showed that BaP could increase P38MAPK phosphorylation during ADP-induced platelet aggregation, but had no significant influence on other critical signaling proteins such as AKT, ERK,and Src;4. BaP could augment ADP-induced expression of P-selection and Fibrinogen binding;5. Compared to the control group, BaP could shorten the time of thrombosis in acute thrombosis models significantly.Conclusion:Bap augmented platelet activation via the up-regulation of P38MAPK phosphorylation during ADP-induced platelet aggregation, and enhanced arterial thrombus formation in vivo. Our data suggest that BaP could contribute to atherothrombogenesis by influencing the platelet signaling pathways.Part Ⅱ.Predictive value of three platelet function-related biomarkers in coronary diseasesGoalTo identify and confirm several independent and effective predictors for theshort-term and long-term prognosis of CAD patients.MethodsTo investigate the predictive value of three biomarkers which were still controversial (admission platelet count, fibrinogen level, and lymphocyte percentage), combined with several classic predictors (such as CRP, white blood cell count, and admission fasting glucose), the study was performed at long-term follow-up and cooperated with several studies in Western countries (more than40,000patients were included). Logistic regression and meta analyse were conducted to assess the predictive value of the candidate prognositic markers.Results1. Higher PLT (>350×109/L) at baseline increases the relative risk of mortality and MACE in ACS patients at short-term and long-term follow-up, U-shaped relationship between platelet count and risk estimates of adverse events was established.2. Plasma fibrinogen levels (FBG) were significantly higher in the patients with acute coronary syndromes (302±90mg/dL) than in the patients with stable coronary heart disease (274±61mg/dL) and the control group (243±55mg/dL)(both P<0.05). We also found significantly higher plasma fibrinogen levels in patients who developed clinical events than in those who did not, at30days and2years (P<0.05). Cox regression analysis showed that plasma fibrinogen levels≥350mg/dL were predictors of poor long-term prognosis. The adjusted odds ratio (95%confidence interval) for patients who had higher levels of plasma fibrinogen was5.207. Plasma fibrinogen level can be used as an independent predictor of major adverse cardiac events during short-and long-term follow-up (P<0.01). The association is independent of other classical risk factors.3. Univariate analyses showed that ACS patients had significantly lower L%compared with those with stable CHD or control. Multivariate analysis and logistic regression analysis revealed that L%was an independent significant risk factor for one year major adverse cardiac events (MACE) in ACS patients.ConclusionThree important biornarkers for cardiovascular diseases, including admission PLT, FBG level, and L%were identified, and their independent predictive value in ACS patients was confirmed.Part Ⅲ.Efficacy and safety of abciximab in diabetic patients who underwent percutaneous coronary intervention with thienopyridines loadingGoalIt has been controversial whether abciximab offered additional benefits for diabeticpatients who underwent percutaneous coronary intervention (PCI) with thienopyridines loading.MethodsMEDLINE, EMBASE, the Cochrane library clinical trials registry, ISI Science Citation Index, ISI Web of Knowledge and China National Knowledge Infrastructure (CNKI)_were searched and original data of ISAR trials and BRAVE trial were extracted. Quantitative meta-analyses were performed to assess differences between abciximab groups and controls with respect to post-PCI risk of major cardiac events (MACEs), angiographic restenosis and bleeding complications.Results9trials were identified, involving2607diabetic patients receiving PCI for coronary artery diseases. Among those patients who underwent elective PCI or primary PCI, pooling results showed that abciximab did not significantly reduce risks of MACEs (for elective-PCI patients:RR1-month:0.93,95%CI:0.60-1.44; RR1-year:0.95,95%CI:0.81-1.11; for primary-PCI patients:RR1-momh:1.05,95%CI:0.70-1.57; RR1-year:0.98,95%CI:0.80-1.21), nor all-cause mortality, re-infarction and angiographic restenosis in either group. The only beneficial effect by abciximab appeared to be a decrease1-year TLR (target lesion revascularization) risk in elective-PCI patients (RR1-year:0.83,95%CI:0.70-0.99). Moreover, occurrence of minor bleeding complications increased in elective-PCI patients treated with abciximab (RR:2.94,95%CI:1.68-5.13, P<0.001), whereas major bleedings rate was similar (RR:0.83,95%CI:0.27-2.57).ConclusionsConcomitant dosing of abciximab and thienopyridines provides no additional benefit among diabetic patients who underwent PCI; this conculsion, though, needs further confirmation in larger studies.