Cocaine unbalances endothelial tissue factor and tissue factor pathway inhibitor expression

Cocaine consumption can lead to myocardial infarction. Tissue factor (TF) has been implicated in acute coronary syndromes, and the balance of TF and tissue factor pathway inhibitor (TFPI) determines initiation of thrombus formation. This study was designed to investigate the effect of cocaine on endothelial TF and TFPI expression. Cocaine (10(-8)-10(-5) mol/l) increased thrombin-induced TF expression by 24% at 10(-7) mol/l (P < 0.001) without affecting basal TF expression. In contrast, cocaine reduced endothelial TFPI expression by 47% at 10(-7) mol/l (P < 0.01). Moreover, thrombin impaired endothelial TFPI expression, and cocaine (10(-8) mol/l) further reduced TFPI expression by 33% as compared to thrombin (P < 0.02). These effects occur at cocaine concentrations usually present in plasma of consumers. Given the importance of TF in the pathogenesis of acute coronary syndromes, TF induction in conjunction with TFPI suppression may be relevant for the increased frequency of myocardial infarction observed in cocaine consumers.     

A prospective study of biopsy-proven myocarditis: prognostic relevance of clinical and aetiopathogenetic features at diagnosis.

AIMS: Myocarditis may be idiopathic, viral, and/or immune; frequency of these forms and prognosis are ill-defined. We aimed at identifying aetiopathogenetic and prognostic markers in myocarditis, including viral genome on endomyocardial biopsy (EMB) by polymerase chain reaction (PCR) and serum anti-heart autoantibodies (AHA). METHODS AND RESULTS: We studied 174 patients, 110 males, aged 36 +/- 18 years, median follow-up 23.5 months, range 10-54; 85 patients had active myocarditis and 89 borderline myocarditis (no diffuse or severe inflammation) (Dallas criteria). Serum AHA were detected by indirect immunofluorescence. PCR was used to detect virus. Six-year actuarial survival was 73%. AHA were found in 56% of patients and positive PCR in 26%. Univariate predictors of death/transplantation were young age, longer symptom duration, giant cell myocarditis, NYHA II-IV, positive PCR, presentation with LV dysfunction, clinical signs/symptoms of heart failure, and echocardiographic and haemodynamic indexes of cardiac dysfunction. By Cox univariate analysis, highest risk was conferred by clinical signs/symptoms of left (HR = 4.3, CI 1.7-10.8, P = 0.002) and right heart failure (HR 3.4, CI 1.5-7.3, P = 0.002). CONCLUSION: In myocarditis, biventricular dysfunction at diagnosis was the main predictor of death/transplantation. AHA identified immune-mediated myocarditis in the majority of cases. Viral genome was a univariate predictor of adverse prognosis. Our approach of using AHA and positive PCR as aetiopathogenetic markers should help patient selection and recruitment in future studies on aetiological therapy.     

病毒性心肌炎患者血清一氧化氮和肿瘤坏死因子含量变化及意义

目的:探讨病毒性心肌炎(VMC)患者血清一氧化氮(NO),肿瘤坏死因子(TNF)含量的变化及其意义。方法:检测70例病毒性心肌炎患者血清一氧化氮和肿瘤坏死因子含量,选择30例健康体检者作对照组。结果:VMC患者血清NO和TNF水平明显高于对照组(P<0.01),且二者含量呈显著正相关(P<0.05)。结论:血清NO和TNF含量增加是VMC病理生理特征之一,且二者在VMC发病中具有协同作用。     

小儿病毒性心肌炎与扩张型心肌病临床特征与鉴别

目的:探讨小儿病毒性心肌炎(VMC)与扩张型心肌病(DCM)的不同临床特征。方法:对63例小儿 VMC和23例小儿DCM的临床资料进行对比分析。结果:与VMC相比,DCM患儿发病年龄在2岁以下者 (4.3%)少见,病程较长(>2个月者占61.0%),心脏增大和心力衰竭发生率高(均P<0.05),心脏增大明显,中 重度二尖瓣反流(82.6%)多见,心力衰竭较严重,心脏收缩功能减退显著(P<0.05);与DCM相比,VMC患儿 多有新近病毒感染史(79.4%),血清病毒 IgM阳性(77.1%)及CK MB升高(77.8%)(均P<0.05),治疗3个月 后VMC患儿轻度增大的心脏恢复正常。结论:小儿VMC与DCM在发病年龄、病程、有无新近病毒感染史,CK MB升高、心脏增大、心力衰竭和心脏收缩功能减退的发生率及程度,治疗效应方面均有不同,但两者的差异是相 对的,必须综合判断才能做出正确诊断,其中超声心动图和治疗效应对鉴别诊断尤为重要。     

ApoE-/-小鼠动脉粥样硬化病变中稳定斑块组织因子的表达

目的:研究稳定斑块组织因子(TF)活化表达及在血栓形成中的作用。方法:建立ApoE-/-小鼠动脉粥样硬化病变的动物模型,一期凝固法检测小鼠血浆TF特异性的促凝活性,光镜和电镜观察稳定斑块病变,免疫组化SP法检测小鼠稳定斑块TF的蛋白表达,原位杂交法检测小鼠稳定斑块TF mRNA表达。结果:ApoE-/-小鼠血浆促凝活性显著增加(P<0.01),并随着诱发斑块时间的延长呈上升趋势,抗TF单抗能显著抑制血浆促凝活性(P<0.01);实验小鼠的病变为稳定斑块,电镜下,ApoE-/-小鼠可见完整的血管内皮细胞,在内皮完整的血管内有血小板的聚集;不同狭窄程度的ApoE-/-小鼠动脉粥样硬化病变部位TF的表达差异有统计学意义(P<0.01),TF的表达随着粥样硬化病变的进展而增强,TFmRNA与TF蛋白表达一致。结论:TF可能通过活化和释放启动凝血过程,导致血栓的形成;TF不仅是粥样硬化导致动脉损伤的结果,还可能是促进动脉粥样硬化病变的重要原因。     

Clinical significance of expression of tissue factor and tissue factor pathway inhibitor in ulcerative colitis

AIM: To investigate the clinical significance of expression of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in ulcerative colitis (UC).METHODS: Thirty UC specimens taken by colonoscopy from patients with active UC treated at the Department of Pathology, Central Hospital Affiliated to Shenyang Medical College from February 2010 to January 2012 were included in an experimental group, and 30 normal colon tissue samples taken by colonoscopy from non-UC patients were included in a control group. Expression of TF and TFPI in UC and normal colon tissue samples was detected by immunohistochemistry.RESULTS: The positive rate of TF in UC was significantly higher than that in normal colon tissue (63% vs 33%, χ² = 5.41, P < 0.05). The positive rate of TFPI in UC was also significantly higher than that in normal colon tissue (43% vs 17%, χ² = 5.08, P < 0.05).CONCLUSION: Positive rates of TF and TFPI expression in UC are significantly higher than those in normal colon tissue. TF and TFPI may play an important role in the pathogenesis of UC.     

冠心病患者血浆组织因子和组织因子途径抑制物的变化

目的 :通过检测不同类型冠心病 (CHD)患者血浆组织因子 (TF)和组织因子途径抑制物 (TFPI)水平变化 ,探讨其在CHD发病过程中的作用。方法 :以酶联免疫吸附测定法测定CHD患者血浆中TF和TFPI抗原水平。结果 :不稳定型心绞痛 (UAP)和急性心肌梗死 (AMI)患者的血浆TF和TFPI水平与正常对照者和稳定型心绞痛 (SAP)患者相比均有显著性增高 (P <0 .0 5 ) ,以AMI患者尤为明显 (P <0 .0 1) ;UAP和AMI患者的TF PI/TF比值显著降低 (P <0 .0 5 ) ,而SAP患者的上述指标与正常对照者相比 ,其差异均无显著性意义 (P >0 .0 5 )。结论 :UAP和AMI患者TFPI/TF系统失衡 ,标志高凝状态的存在 ;TF和TFPI在这两种类型CHD的发病机制中可能起着重要的作用     

病毒性心肌炎与扩张型心肌病心肌线粒体DNA缺失的定量分析

目的对比研究病毒性心肌炎(VMC)与扩张型心肌病(DCM)患者活检心肌组织线粒体DNA(mtDNA)缺失突变情况及其与外周淋巴细胞mtDNA缺失程度的相关性.方法用定量PCR法检测20例VMC患者、12例DCM患者心肌细胞及其外周血淋巴细胞mtDNA4977碱基对(mtDNA4977)和mtDNA7436碱基对(mtDNA)缺失率.取12例健康意外死亡者心肌和23例献血员外周血淋巴细胞作正常对照.结果正常对照者、VMC和DCM患者心肌细胞均存在mtDNA4977及mtDNA7436缺失,合计缺失率分别为0.175%、0.385%和3.004%;外周淋巴细胞mtDNA缺失程度与心肌细胞呈一致性改变,且有良好的相关性(r=0.960,P＜0.001).结论mtDNA缺失可能是VMC发病及其向DCM演变的一个重要心肌损伤机制;外周淋巴细胞在研究心肌细胞mtDNA缺失中的作用值得进一步探讨.     

特莫普利上调心肌硫氧化还原蛋白表达减轻心肌炎

目的 特莫普利是否能通过加强氧化还原调节机制减轻心肌炎。方法 Lewis大鼠自身免疫性心肌炎及离体培养的心肌细胞,免疫杂交检测特莫普利治疗前后硫氧化还原蛋白(TRX)表达,及其对心肌炎的影响。结果 特莫普利加强心肌细胞胞质定位的TRX表达,但对线粒体定位的TRX2表达则无明显改变。超氧化物歧化酶表达也无明显变化。特莫普利治疗从第1。21天,可减轻心肌炎的严重程度和降低氧化蛋白含量;但治疗从第15-21天,则无明显效果。本组心肌炎模型炎症大致从第15天开始,到21d达高峰,特莫普利从第1-21天治疗,可看做有2周的预治疗来上调心肌细胞TRX表达,通过加强TRX表达减轻心肌炎症。结论 TRX和经TRX修饰的氧化还原状态在自身免疫性心肌炎的发病中起重要作用,特莫普利治疗通过加强心肌TRX表达减轻心肌炎症。     

Myocardial deformation measures by cardiac magnetic resonance tissue tracking in myocarditis: Relationship with systolic function and myocardial damage

Introduction and ObjectivesCardiac magnetic resonance (CMR)-based tissue tracking (TT) enables quantification of myocardial deformation and may be used as an objective measure of myocardial involvement in myocarditis. The aims of this study were to characterize myocardial deformation alterations in myocarditis and to determine their relationship with the extent of late gadolinium enhancement (LGE), regional wall motion abnormalities (WMA) and left ventricular ejection fraction (LVEF).MethodsA single-center, retrospective study was conducted by identifying patients with clinically suspected myocarditis who underwent CMR between 2012 and 2016. The myocardial deformation parameters were derived by TT and correlated with LVEF, LGE and WMA, through Spearman's coefficient.ResultsA cohort of 78 patients with myocarditis (aged 42.7±17.2 years) were included. CMR characteristics including morphologic parameters (LVEF 52.1±12.8%), extent of WMA (29.3±41.0%) and of LGE (30.5±21.8%) were assessed. Significant correlations were found between all deformation parameters (strain, strain rate, velocity and displacement) and both LVEF and extent of WMA. LGE was significantly correlated with systolic radial strain (r: -0.32, p=0.004), strain rate (r: -0.27, p=0.017) and displacement (r: -0.32, p=0.004) as well as systolic circumferential strain (r: 0.28, p=0.013).ConclusionDeformation parameters are an objective method for quantification of myocardial function in myocarditis. They correlate with LVEF, extent of WMA and degree of myocardial damage. Further studies are needed to assess their incremental beneficial value for the diagnosis and risk stratification of myocarditis.     

Expression of tissue factor in pancreatic adenocarcinoma is associated with activation of coagulation

AIM: To study expression of tissue factor (TF) in pancreatic cancer and its role in the development of thromboembolism. METHODS: TF expression was studied in eight human pancreatic carcinoma cell lines by Northern blot and indirect immunofluorescence. Expression of alternatively spliced TF (asTF) was assessed by RT-PCR. In addition, TF expression was determined by immunofluorescence in pancreatic tissues of 19 patients with pancreatic adenocarcinoma (PCa), 9 patients with chronic pancreatitis (CP) and 20 normal controls. Plasma samples (30 PCa-patients, 13 CP-patients and 20 controls) were investigated for soluble TF levels and coagulation activation markers [thrombin-antithrombin III complex (TAT), prothrombin fragment 1 2 (F1 2)]. RESULTS: All pancreatic carcinoma cell lines expressed TF (8/8) and most of them expressed asTF (6/8). TF expression at the protein level did not correlate with the differentiation of the carcinoma cell line. All but two pancreatic cancer tissue samples stained positive for TF (17/19). In all samples of CP weak staining was restricted to pancreatic duct cells, whereas only a few subendothelial cells were positive in 9/20 of normal controls. TF and TAT levels in PCa patients were significantly elevated compared to controls whereas elevated F1 2 levels did not reach statistical significance compared to controls. In CP patients TAT and F1 2 levels proved to be significantly elevated compared to controls, although TAT elevation was less pronounced than in PCa patients. CONCLUSION: We conclude that in addition to the upregulated expression of TF on the cell membrane, soluble TF might contribute to activation of the coagulation system in pancreatic cancer.     

Decreased fibrinolytic capacity and increased von Willebrand factor levels as indicators of endothelial cell dysfunction in patients with lupus anticoagulant

Summary Over a 6-year period, 10 patients with lupus anticoagulant activity were seen. A history of thrombotic disease was found in 6 patients, but only 3 had systemic autoimmune disease. Reduced fibrinolytic activity after venous occlusion was found in 9 subjects, but only 4 had high von Willebrand factor levels. These changes were unrelated to inflammatory activity, which was ruled out by normal serum protein electrophoresis in all but one case. Human brain thromboplastin dilution test was pathological in all subjects with depressed fibrinolytic activity. These two tests may prove to be of value to single out those LA patients with highest risk for development of thromboembolic disease.     

TIMP-1 mRNA表达在病毒性心肌炎小鼠心肌胶原重构中的作用及其与TGF-β1的关系

目的探讨TIMP-1mRNA表达在病毒性心肌炎小鼠心肌胶原重构中的作用及其与转化生长因子(TGF-β1)的关系。方法4周龄雄性BALB/c鼠腹腔接种0.1ml100TCID50CVB3m,周龄、性别相同小鼠为对照,分别于接种后3、7、9、14、21、28、56d断脊处死小鼠,心肌标本经常规制片,VG染色观察心肌组织胶原的改变,原位杂交观察TIMP-1mRNA和TGF-β1mRNA的表达,免疫组织化学观察TGF-β1的表达。结果感染后28d小鼠心肌组织血管周围胶原明显沉积,感染后56d心肌组织血管周围及心肌细胞间隙胶原沉积均明显增加;感染后7d可见TIMP-1mRNA表达,14～21d最为明显,此后减弱,直到56d。感染后3d可见TGF-β1mRNA及TGF-β1表达,7～21d最为明显,此后减弱,持续至感染后56d;TIMP-1mRNA和TGF-β1表达等级间存在正相关关系(P<0.001)。结论TGF-β1表达增加及其上调TIMP-1mRNA的表达可能在病毒性心肌炎心肌胶原重构中起重要作用。     

Microparticles in atrial fibrillation: A link between cell activation or apoptosis,tissue remodelling and thrombogenicity

Microparticles (MPs) are small membrane vesicles that are shed from virtually all cells in response to stress. Widely described in atherothrombotic diseases, recent data suggest a role for circulating MPs in the hypercoagulable state associated with supraventricular tachyarrhythmia. During atrial fibrillation, several mechanisms, such as high ventricular heart rate, low or oscillatory shear stress, stretch, hypoxia, inflammation and oxidative stress, are potent inducers of apoptotic cell death, which leads to the shedding of procoagulant MPs within the vasculature. As key regulators of cell–cell cross-talk and important mediators of inflammatory, thrombogenic and proteolytic pathways, MPs directly or indirectly contribute to the amplification loops involved in atrial fibrillation. Because high levels of platelets and endothelial-derived MPs are identified during stroke and are associated with infarct size and clinical outcome, they are proposed to be a potent marker of ischaemic risk. During pulmonary vein isolation, the additional increases of platelet and leukocyte MP levels suggest the extent of tissue damage and reflect a transient activation of the coagulation cascade that could favour ischaemic stroke. Conversely, the observed decreases of several apoptotic markers some months after the restoration of sinus rhythm suggest that the extent of apoptotic processes is reversible and might enable restoration of haemostasis. In this review, we will summarise the current evidence supporting the roles of apoptosis and cell activation in the development of the prothrombotic state observed in atrial fibrillation, with a particular focus on procoagulant MPs.     

Von willebrand factor antigen in assessment of vasculitis in patients with connective tissue diseases

Summary Von Willebrand factor antigen (vWF:Ag) is synthesized and secreted by endothelial cells. In the present study we tried to assess the relationship between plasma level of vWF:Ag and vascular damage in patients with vasculitis. The study was carried out on 59 patients with connective tissue diseases. Vasculitis was diagnosed by biopsies of the skin. The patients with vasculitis had a significantly elevated level of vWF: Ag; however, no significant correlation between the amount of plasma vWF:Ag and the degree of vasculitis was found. The obtained results show that the plasma level of vWF: Ag may reflect the presence of vascular, especially endothelial, damage in patients with connective tissue diseases.     

Eosinophilic myocarditis: case series and review of literature

Although the etiology of eosinophilic myocarditis (EM) is not always apparent, several causes are identified, including hypersensitivity to a drug or substance, with the heart as the target organ. However, symptoms and signs of hypersensitivity are not found in all patients. EM can lead to progressive myocardial damage with destruction of the conduction system and refractory heart failure. The present report describes three cases of biopsy-proven EM with different presentations, including acute coronary syndrome, cardiogenic shock and newly diagnosed heart failure. In one patient, hypersensitivity to sumatriptan was suspected to be the underlying cause. All patients responded well to treatment with steroids, angiotensin-converting enzyme inhibitors and beta-blockers. There was a complete recovery of the ventricular function in all cases.     

The relationship between gender and age with monocyte tissue factor expression

Background In normal healthy individuals, the level of tissue factor (TF) expression on monocytes is low. However, studies have shown that patients with cardiovascular disease (CVD) have elevated levels of TF. As the risk of CVD increases with age and is more prominent in the male population, it is postulated that TF expression may be positively correlated with these factors. However, very few studies have examined the relationship between age and gender on TF expression. Methods This study evaluated the influence of age and gender on TF expression using data obtained from female (n = 44) and male (n = 27) subjects. We also examined the influence of BMI and total fat intake on TF expression in the same subjects. Results The results of our study found no significant difference in TF expression between the male and female subgroups. No correlation was found between TF and age, BMI or total fat intake in the male or female groupings. Conclusion It may be postulated that the risk of CVD development in such populations may not be due to increases in TF expression with increasing age or gender differences.