氯吡格雷通过上调miR-145表达抑制VSMC增殖的机制研究

目的 本研究旨在探究miR-145是否对血管平滑肌细胞(VSMC)的增殖起调控作用,以及氯吡格雷如何通过调控CD40来发挥其消炎作用,以期为氯吡格雷的药用作用发挥提供新的理论依据.方法 实验分组为①DMSO组,即溶剂对照组;②TNF-α组;③miR-145抑制剂对照组;④氯吡格雷组;⑤miR-145抑制剂+氯吡格雷组.并通过EdU标记检测细胞增殖;qRT-PCR用于检测miR-145,CD40和VSMC中Calponin mRNA的表达;Western blot检测CD40的蛋白表达水平;通过ELISA检测细胞培养物上清液中IL-6的水平.结果 与氯吡格雷组相比,miR-145抑制剂+氯吡格雷组的Calponin mRNA水平降低(P <0.01);与DMSO组相比,TNF-α组的miR-145 mRNA水平下降(P<0.01);与TNF-α组相比,氯吡格雷组的miR-145 mRNA水平上升(P<0.01);与氯吡格雷组相比,miR-145抑制剂+氯吡格雷组的miR-145 mRNA水平下降(P<0.01).miR-145抑制剂对照组不影响CD40的水平;与DMSO组相比,TNF-α组的CD40 mRNA水平上升(P<0.01);与TNF-α组相比,氯吡格雷组的CD40 mRNA水平下降(P<0.01);与氯吡格雷组相比,miR-145 抑制剂+氯吡格雷组的CD40 mRNA水平上升(P<0.01).TNF-α组上清液中IL-6的水平高于DMSO组(P<0.01);氯吡格雷组中IL-6水平低于TNF-α组(P<0.01);miR-145抑制剂+氯吡格雷组IL-6的水平高于氯吡格雷组(P<0.01).结论 氯吡格雷通过抑制CD40的表达,诱导miR-145抑制VSMC细胞增殖并发挥消炎作用.     

Antiplatelet therapy for postdischarge medical management of acute coronary syndrome

Postdischarge management of patients with acute coronary syndrome is often suboptimal, despite their high risk of a subsequent event. Updated American College of Cardiology/American Heart Association guidelines emphasize the need for aggressive modification of risk factors and treatment with antiplatelet, antihypertensive, and lipid-lowering agents commenced in-hospital and continued long-term. Antiplatelet therapy involving aspirin and clopidogrel is the mainstay of secondary risk reduction. Increased adherence to medication and risk factor modification at discharge has been demonstrated with acute care quality improvement initiatives. Extension of these initiatives to postdischarge care will provide data on medication adherence post acute coronary syndrome and functional outcomes in the community setting. Successful secondary prevention of cardiovascular events requires implementation of evidence-based guidelines by physicians, and adherence to pharmacotherapy and lifestyle modifications by patients. Primary care physicians are well placed to influence adherence through their ongoing relationships with patients and can save lives by implementing secondary risk reduction measures after discharge.     

替格瑞洛、氯吡格雷对急性冠脉综合征患者PCI术后血小板聚集率、血流动力学及免疫功能的影响

目的:探讨替格瑞洛、氯吡格雷对急性冠脉综合征（ACS）患者经皮冠状动脉介入治疗（PCI）术后血小板聚集率、血流动力学及免疫功能的影响。方法:选取本院心血管内科收治的124例ACS患者作为研究对象,随机分为观察组（n=62）和对照组（n =62）,观察组给予替格瑞洛治疗,对照组给予氯吡格雷治疗,观察比较两组患者治疗前后小板聚集率、血流动力学指标、免疫功能指标变化情况和出血情况。结果:治疗后,两组患者血小板聚集率（PAV）均低于治疗前（P＜0.05）,且观察组明显低于对照组（P＜0.05）;治疗后,两组患者全血黏度（BV）、血浆粘度（PV）均低于治疗前（P＜0.05）,观察组明显低于对照组（P＜0.05）,而收缩期血流速度峰值（SPV）,舒张期血流速度峰值（DPV）,冠脉血流储备（CFVR）均高于治疗前（P＜0.05）,且观察组明显高于对照组（P＜0.05）;治疗后,两组患者CD3+、CD4+水平均高于治疗前（P＜0.05）,观察组明显高于对照组（P＜0.05）,而CD8+水平低于治疗前（P＜0.05）,观察组低于对照组（P＜0.05）;两组患者总出血事件发生率比较差异无统计学意义（P＞0.05）。结论:替格瑞洛能有效抑制ACS患者PCI术后血小板凝集,改善血流动力学和免疫功能,安全性高。     

血栓弹力图评价血小板花生四烯酸途径抑制率对血凝块形成的影响

目的了解血小板花生四烯酸途径抑制率对血凝块形成的影响及其与ADP受体途径抑制率的关系。方法联用阿司匹林和氯吡格雷的急性冠脉综合征80例,血栓弹力图测定血小板抑制率和花生四烯酸通道的α角、K时间、MA、TMA。结果花生四烯酸途径抑制率为（81.7±20.7）%,ADP受体抑制率为（65.9±25.3）%,α角为（48.2±15.9）°,MA为（20.8±14.2）mm,TMA为（13.8±7.5）min。随花生四烯酸途径抑制率增高,α角缩小,MA降低,TMA缩短,ADP受体抑制率增高（P〈0.05）,K时间延长并且无K时间病例增多。结论抑制血小板花生四烯酸途径不利于血凝块形成,随抑制率增高,血凝块形成减慢、强度变小;二条途径抑制率呈正相关。     

氯吡格雷反应性差异的分子机制研究进展

临床观察到有一部分患者不能从氯吡格雷治疗中获益,从而提出氯吡格雷反应性差异的问题。目前研究主要集中在基因多态性和药物的相互作用上,关于氯吡格雷反应差异的基因多态性研究可根据氯吡格雷在人体内代谢、作用过程分为吸收环节(ABCB1)、转化环节(CYP2C19、CYP3A4、CYP3A5)、作用位点环节(P2Y12)等。现就以上几个环节的最新的研究成果予以综述,力求反映相关研究的趋势与方向。     

Vitamin D levels and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor

Background: Suboptimal platelet inhibition still represents an important challenge, especially for patients undergoing percutaneous coronary interventions (PCIs). However, very few are known so far on the predictors of high-residual platelet reactivity (HRPR) despite antiplatelet strategies. Increasing attention has been paid in the last years to the role of vitamin D in atherothrombosis. Therefore, the aim of our study was to evaluate the impact of vitamin D levels on platelet function in patients treated with dual antiplatelet therapy (DAPT). Patients treated with DAPT (ASA and clopidogrel or ticagrelor) after a recent acute coronary syndrome (ACS) or elective PCI were scheduled for platelet function assessment at 30–90 days post-discharge. Platelet function was assessed by whole blood impedance aggregometry (Multiplate®-Roche Diagnostics AG), HRPR was considered for ASPI test values > 862 AU*min (for ASA) and adenosine diphosphate (ADP) test values ≥417 AU*min (for ADP-antagonists). Fasting samples were obtained for main chemistry parameters and vitamin D level assessment.

Our population is represented by 503 patients, who were divided according to vitamin D quartiles (≤9.1; 9.2–14.4; 14.5–21.7; >21.7 ng/ml). Lower vitamin D levels related with age (p = 0.04), diabetic status (p = 0.05), and previous coronary surgery (p = 0.007), therapy with beta-blockers and statins (p = 0.01 and p = 0.02). Vitamin D inversely related to the levels of total cholesterol (p = 0.01), triglycerides (p < 0.001), hemoglobin (p = 0.05), and HbA1c (p < 0.001). Significantly higher platelet reactivity was observed after platelet stimulation with ADP (p = 0.01), but not with other platelet activators. The prevalence of HRPR for ASA was low (1.2%) and not conditioned by Vitamin D levels (adjusted OR[95%CI] = 1.56[0.71–3.5], p = 0.27). HRPR with ADP-antagonists was observed in 26% of patients, and the rate increased with lower vitamin D quartiles (37.3% vs 22.2% vs 24.4% vs 20.2%, p = 0.005, adjusted OR[95%CI] = 1.23[1.02–1.49], p = 0.04).

An absolute increase in HRPR with lower vitamin D levels was similarly observed among patients receiving ticagrelor (adjusted OR[95% CI] = 1.40[0.95–2.06], p = 0.08), and those on clopidogrel (adjusted OR[95%CI] = 1.31[0.99–1.75], p = 0.06).

Thus, lower vitamin D levels are associated with higher platelet reactivity and impaired effectiveness of ADP-antagonists, while not influencing the effectiveness of ASA. Future studies will tell whether vitamin D supplementation can reduce platelet reactivity, overcoming the phenomenon of resistance to antiplatelet agents.     

Inhibition of the antithrombotic effects of clopidogrel by proton pump inhibitors: Facts or fancies?

Clopidogrel plus aspirin is considered the antiplatelet treatment of choice in patients with acute coronary syndrome, whether or not they are undergoing a percutaneous coronary intervention (PCI). The same treatment is mandatory in all patients undergoing a PCI with stent implantation. Clopidogrel is a pro-drug that needs metabolic activation through a cytochrome P450-dependent pathway, with an extensive involvement of the CYP 2C19 isoenzyme. Proton pump inhibitors (PPIs) reduce the risk of gastrointestinal bleeding in patients receiving dual antiplatelet therapy. In the past two years some scientific evidences have suggested a possible negative interference of PPIs on antiplatelet effect of clopidogrel because of the competitive inhibition of the CYP 2C19 isoenzyme. Few studies testing platelet reactivity in patients receiving both clopidogrel and a PPI have demonstrated a reduced inhibitory effect of the association on platelet aggregation. Moreover, results from retrospective observational studies have shown a higher incidence of major cardiovascular events in patients receiving both clopidogrel and PPIs. These data have not been confirmed neither by the only prospective randomized study comparing clopidogrel plus omeprazole with clopidogrel alone, nor by the retrospective analysis of the TRITON TIMI 38 trial, where PPIs did not affect the clinical outcome of patients given clopidogrel or prasugrel. Nevertheless both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) have discouraged the concomitant use of clopidogrel and PPIs. Important questions concerning a true interference between the two classes of drugs still remain unanswered and need to be addressed by adequately powered studies.     

Aspirin and clopidogrel resistance: an emerging clinical entity.

Antiplatelet therapy is a cornerstone of cardiovascular medicine. Aspirin and clopidogrel have emerged as critical therapies in the treatment of cardiovascular disease. Despite their efficacy, patients on these medications continue to suffer complications. Millions of patients are currently on low-dose antiplatelet therapy but it is unknown how many of these patients are under-treated or on the wrong medication. Aspirin and clopidogrel resistance are emerging clinical entities with potentially severe consequences such as recurrent myocardial infarction, stroke, or death. The mechanism of resistance remains incompletely defined, but there are specific clinical, cellular, and genetic factors that influence therapeutic failure. These factors range from physicians who fail to prescribe these medications despite appropriate indications to polymorphisms of platelet membrane glycoproteins. Rapid and accurate diagnosis of antiplatelet resistance also remains an issue as new bedside tests are developed. By understanding the mechanism of therapeutic failure and by improving the diagnosis of this clinical entity, a new era of individualized antiplatelet therapy may arise with routine measurements of platelet activity in the same way that cholesterol, blood pressure, and blood sugar are followed, thus improving the care for millions of people.     

Clopidogrel administration prior to coronary artery bypass grafting surgery: the cardiologist's panacea or the surgeon's headache?

AIMS: Thrombotic complications after percutaneous coronary intervention procedures have decreased in past years mainly due to the use of clopidogrel antiplatelet therapy. However, the risk of bleeding due to enhanced and irreversible platelet inhibition in patients who will require surgical coronary revascularization instead has not been adequately addressed in the literature. The purpose of this study was to evaluate the effect of pre-operative clopidrogel exposure in haemorrhage-related re-exploration rates, peri-operative transfusion requirements, morbidity, and mortality in patients undergoing coronary artery bypass grafting (CABG) surgery. METHODS AND RESULTS: A study population of 2359 patients undergoing isolated CABG between January 2000 and June 2002 was reviewed. Of these, 415 (17.6%) received clopidogrel prior to CABG surgery, and 1944 (82.4%) did not. A risk-adjusted logistic regression analysis was used to assess the association between clopidogrel pre-medication (vs. no) and haemostatic re-operation, intraoperative and post-operative blood transfusion rates, and multiple transfusions received. Haemorrhage-related pre-operative risk factors identified from the literature and those found significant in a univariate model were used. Furthermore, a sub-cohort, matched-pair by propensity scores analysis, was also conducted. The clopidogrel group had a higher likelihood of haemostatic re-operation [OR = 4.9, (95% CI, 2.63-8.97), P < 0.01], an increase in total packed red blood cell transfusions [OR = 2.2, (95% CI, 1.70-2.84), P < 0.01], multiple unit blood transfusions [OR = 1.9, (95% CI, 1.33-2.75), P < 0.01] and platelet transfusions [OR = 2.6, (95% CI, 1.95-3.56), P < 0.01]. Surgical outcomes and operative mortality [OR = 1.5, (95% CI, 0.36-6.51), P = 0.56] were not significantly different. CONCLUSION: Pre-operative clopidogrel exposure increases the risk of haemostatic re-operation and the requirements for blood and blood product transfusion during, and after, CABG surgery.     

三联疗法治疗急性ST段抬高型心肌梗死的疗效观察

目的:观察氯吡格雷联合阿司匹林和尿激酶治疗急性ST段抬高型心肌梗死的临床疗效。方法:将2009年6月-2010年6月我院60例确诊的急性ST段抬高型心肌梗死患者随机均分为观察组(氯吡格雷联合阿司匹林和尿激酶治疗)和对照组(阿司匹林和尿激酶治疗),比较2组治疗急性ST段抬高型心肌梗死的临床疗效。结果:观察组总有效率为93.33%,对照组为63.33%,观察组疗效明显高于对照组,2组比较差异有统计学意义(P<0.01)。对照组不良反应发生率(33.33%)高于观察组(3.33%),2组比较差异有统计学意义(P<0.05)。结论:氯吡格雷联合阿司匹林和尿激酶治疗急性ST段抬高型心肌梗死疗效确切,不良反应少。