Yuanhua Yang

Efficacy and Safety of Low Dose Recombinant Tissue-Type Plasminogen Activator for the Treatment of Acute Pulmonary Thromboembolism: A Randomized, Multicenter, Controlled Trial

Background Optimal dosing of the recombinant tissue-type plasminogen activator (rt-PA) is important in treating pulmonary thromboembolism (PTE). The aim of this study was to compare the efficacy and safety of a 50 mg/2 h rt-PA regimen with a 100 mg/2 h rt-PA regimen in patients with acute PTE. Methods A prospective, randomized, multicenter trial was conducted in which 118 patients with acute PTE and either hemodynamic instability or massive pulmonary artery obstruction were randomly assigned to receive a treatment regiment of either rt-PA at 50 mg/2 h (n = 65) or 100 mg/2 h (n = 53). The efficacy was determined by observing the improvements of right ventricular dysfunctions (RVDs) on echocardiograms, lung perfusion defects on ventilation perfusion lung scans, and pulmonary artery obstructions on CT angiograms. The adverse events, including death, bleeding, and PTE recurrence, were also evaluated. Results Progressive improvements in RVDs, lung perfusion defects, and pulmonary artery obstructions were found to be similarly significant in both treatment groups. This is true for patients with either hemodynamic instability or massive pulmonary artery obstruction. Three (6%) patients in the rt-PA 100 mg/2 h group and one (2%) in the rt-PA 50 mg/2 h group died as the result of either PTE or bleeding. Importantly, the 50 mg/2 h rt-PA regimen resulted in less bleeding tendency than the 100 mg/2 h regimen (3% vs 10%), especially in patients with a body weight < 65 kg (14.8% vs 41.2%, P = .049). No fatal recurrent PTE was found in either group. Conclusions Compared with the 100 mg/2 h regimen, the 50 mg/2 h rt-PA regimen exhibits similar efficacy and perhaps better safety in patients with acute PTE. These findings support the notion that optimizing rt-PA dosing is worthwhile when treating patients with PTE. Trial registration clinicaltrials.gov; Identifier: NCT00781378

Pulmonary Embolism Incidence and Fatality Trends in Chinese Hospitals from 1997 to 2008: A Multicenter Registration Study

Background There has not been sufficient evidence to support the Asians being less susceptible to pulmonary embolism (PE) than other ethnicities, because the prevalence of PE/deep venous thrombosis (DVT) in different racial and ethnic groups has not been carefully studied until recently except in Caucasians. To test the hypothesis that the Chinese population has a lower risk for PE, this study comprehensively assessed the hospital-based incidence and case fatality rates for PE during the 1997–2008 in China. Methods A registration study of patients with suspected PE syndromes admitted to 60 level-3 hospitals involved in the National Cooperative Project for the Prevention and Treatment of Venous Thromboembolism (NCPPT) was conducted from January 1997 to December 2008. The only exclusion criterion was an age of less than 18 years. Helical computed tomography scan, ventilation-perfusion lung scintigraphy or pulmonary angiography was carried out before or after hospitalization. All images were reviewed and evaluated independently by two specialists. Results A total of 18,206 patients were confirmed with PE from 16,972,182 hospital admissions. The annual incidence was 0.1% (95% CI: 0.1% to 0.2%). The overall incidence of PE in male patients (0.2%, 95% CI: 0.1% to 0.3%) was higher than that in female patients (0.1% and 95% CI: 0.0% to 0.1%). An increasing incidence gradient for PE was noticed from Southern to Northern China. In addition, the case fatality rate was apparently decreasing: 25.1% (95% CI: 16.2% to 36.9%) in 1997 to 8.7% (95% CI: 3.5% to 15.8%) in 2008. Conclusions Our findings suggest the relatively stable PE incidence and decreasing fatality trends in Chinese hospitals may be partially attributable to the implementation of the NCCPT and suggest the government should reevaluate the severity of PE so that health resources for the prevention, diagnosis and treatment of PE could be used to their fullest.

Molecular epidemiological analysis of methicillin-resistant Staphylococcus aureus isolates from Chinese pediatric patients.

To investigate the molecular epidemiological analysis of methicillin-resistant Staphylococcus aureus (MRSA) isolates from five pediatric hospitals in China. Seventy-three MRSA isolates were analyzed by a combination of different genotyping methods, including multilocus sequence typing (MLST), SCCmec and spa typing. Panton-Valentine Leukocin (PVL) gene was also detected. The prevalent strains were ST239-MRSA-III and ST1-MRSA clones in the northern region; ST239-MRSA-III, ST910-MRSA-IV and ST88-MRSA in the eastern region; and ST59-MRSA in the southern region. Only the ST910-MRSA-IV clone has been found in China until now, and it is closely related to ST30-MRSA-IV. All MRSA isolates were found to be resistant to penicillin and azithromycin, and multidrug resistance was observed. The cases of necrotic pneumonia, severe skin and subcutaneous tissue infection and lymphadenitis resulted from PVL gene-positive MRSA. There were several novel genetic types of MRSA. Antimicrobial susceptibility tests showed high resistance of many antimicrobials and multiple drugs.

Antimicrobial susceptibility of Staphylococcus aureus isolated from children with impetigo in China from 2003 to 2007 shows community-associated methicillin-resistant Staphylococcus aureus to be uncommon and heterogeneous

Background  The number of patients with impetigo caused by community‐associated methicillin‐resistant Staphylococcus aureus (CA‐MRSA) has been increasing.

Computed tomographic pulmonary angiography in the assessment of severity of chronic thromboembolic pulmonary hypertension and right ventricular dysfunction

PURPOSE The aim was to investigate the role of computed tomographic pulmonary angiography (CTPA) in the assessment of severity and right ventricular function in chronic thromboembolic pulmonary hypertension (CTEPH). MATERIALS AND METHODS Clinical and radiological data of 56 patients with CTEPH January 2006-October 2009 were retrospectively reviewed in the present study. All patients received CTPA with a 64-row CT using the retrospective ECG-Gated mode before digital subtraction pulmonary angiography and right-heart catheterization. CTPA findings including Right Ventricular diameter (RVd) and left ventricular diameter (LVd) were measured at the end diastole. CT Pulmonary Artery Obstruction Indexes including Qanadli Index and Mastora Index were used in the assessment of severity of pulmonary arterial obstruction. Hemodynamic parameters and pulmonary hypertension classification were evaluated by right-heart catheterization in all patients. Right ventricular function was measured with echocardiography in 49 patients. RESULTS Qanadli Index and Mastora Index respectively were (37.93±14.74)% and (30.92±16.91)%, which showed a significant difference (Z=-5.983, P=0.000) and a good correlation (r=0.881, P=0.000). Neither Qanadli nor Mastora Index correlated with pulmonary hypertension classification (r=-0.009, P=0.920) or New York Heart Association heart function classification (r=-0.031, P=0.756). Neither Qanadli nor Mastora Index correlated with any echocardiographic right ventricular parameters (P>0.05), while RVd/LVd by CTPA correlated with echocardiographic right ventricular functional parameters (P<0.05). Both Qanadli (r=-0.288, P=0.006) and Mastora Index (r=-0.203, P=0.032) demonstrated a weakly negative correlation with SPO2. CTPA findings correlated with hemodynamic variables. Backward linear regression analysis revealed that the RVd/LVd, Right Ventricular Anterior Wall Thickness (RVAWT), Main Pulmonary Artery trunk diameter (MPAd) were shown to be independently associated with mean Pulmonary Artery Pressure (mPAP) levels (model: r2=0.351, P=0.025; RVd/LVd: beta=11.812, P=0.000; RVAWT: beta=2.426, P=0.000; MPAd: beta=0.677, P=0.003). CONCLUSION Computed tomographic pulmonary angiography is a valuable tool to evaluate hemodynamics, right ventricular function of CTEPH, but neither Qanadli Index nor Mastora Index can reflect pulmonary arterial obstruction in CTEPH accurately.

Differentially Expressed Plasma MicroRNAs and the Potential Regulatory Function of Let-7b in Chronic Thromboembolic Pulmonary Hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease characterized by misguided thrombolysis and remodeling of pulmonary arteries. MicroRNAs are small non-coding RNAs involved in multiple cell processes and functions. During CTEPH, circulating microRNA profile endued with characteristics of diseased cells could be identified as a biomarker, and might help in recognition of pathogenesis. Thus, in this study, we compared the differentially expressed microRNAs in plasma of CTEPH patients and healthy controls and investigated their potential functions. Microarray was used to identify microRNA expression profile and qRT-PCR for validation. The targets of differentially expressed microRNAs were identified in silico, and the Gene Ontology database and Kyoto Encyclopedia of Genes and Genomes pathway database were used for functional investigation of target gene profile. Targets of let-7b were validated by fluorescence reporter assay. Protein expression of target genes was determined by ELISA or western blotting. Cell migration was evaluated by wound healing assay. The results showed that 1) thirty five microRNAs were differentially expressed in CTEPH patients, among which, a signature of 17 microRNAs, which was shown to be related to the disease pathogenesis by in silico analysis, gave diagnostic efficacy of both sensitivity and specificity >0.9. 2) Let-7b, one of the down-regulated anti-oncogenic microRNAs in the signature, was validated to decrease to about 0.25 fold in CTEPH patients. 3) ET-1 and TGFBR1 were direct targets of let-7b. Altering let-7b level influenced ET-1 and TGFBR1 expression in pulmonary arterial endothelial cells (PAECs) as well as the migration of PAECs and pulmonary arterial smooth muscle cells (PASMCs). These results suggested that CTEPH patients had aberrant microRNA signature which might provide some clue for pathogenesis study and biomarker screening. Reduced let-7b might be involved in the pathogenesis of CTEPH by affecting ET-1 expression and the function of PAECs and PASMCs.

Efficacy and safety of 2-hour urokinase regime in acute pulmonary embolism: a randomized controlled trial

BackgroundsUrokinase (UK) 2 200 U/kg·h for 12 hours infusion(UK-12 h)is an ACCP recommended regimen in treating acute pulmonary embolism (PE). It is unclear whether this dose and time can be reduced further. We compared the efficacy and safety of 20, 000 U/kg for 2 hours (UK-2 h) with the UK-12 h regime in selected PE patients.MethodsA randomized trial involving 129 patients was conducted. Patients with acute PE were randomly assigned to receive either UK-12 h (n = 70), or UK-2 h (n = 59). The efficacy was determined by the improvement of right heart dysfunction and perfusion defect at 24 h and 14 d post UK treatment. The bleeding incidence, death rate and PE recurrence were also evaluated.ResultsSimilarly significant improvements in right heart dysfunction and lung perfusion defects were observed in both groups. Overall bleeding incidents were low in both groups. Major bleeding directly associated with UK infusion occurred in one patient in the UK-2 h group and one in the UK-12 h group. Mortality rates were low, with one reported fatal recurrent in the UK-12 h group and none in the UK-2 h group. When the rate of bleeding, death and PE recurrence were compared separately in the hemodynamic instability and the massive anatomic obstruction subgroups, no significant difference was found.ConclusionsThe UK-2 h regimen exhibits similar efficacy and safety as the UK-12 h regimen for acute PE.Trial RegistrationClinical trial registered with http://clinicaltrials.gov/ct2/show/NCT00799968 (Identifier: NCT 00799968)

Prevalence and Associations of VTE in Patients With Newly Diagnosed Lung Cancer

BACKGROUND The risk of VTE before anticancer therapy in patients with lung cancer is not well defined. METHODS A total of 673 hospitalized patients with newly diagnosed lung cancer were examined for VTE within 1 week after admission at five hospitals between January 2009 and January 2011. Additionally, VTE diagnoses within the last 3 months were reviewed. All VTE events were confirmed with imaging studies. Blood cell count and serum carcinoembryonic antigen (CEA) levels were measured before initial treatment. RESULTS VTE events occurred in 89 of the 673 patients (13.2%) enrolled in this study. Forty-two patients (6.2%) developed lower extremity DVT alone, 33 patients (4.9%) developed pulmonary embolism (PE) alone, and 14 patients (2.1%) developed both DVT and PE. By multivariate logistic regression analysis, distant metastasis (OR, 2.2; 95% CI, 1.2-3.9) and leukocytosis (OR, 2.8; 95% CI, 1.5-5.4) were significantly associated with DVT, adenocarcinoma (OR, 2.1; 95% CI, 1.1-4.4) and anemia (OR, 4.6; 95% CI, 1.4-14.5) were significantly associated with PE, and an elevated CEA level in tertiles was linearly associated with PE (P for trend = .06). The area under the receiver operating characteristic curve for the prognostic or diagnostic CEA values was 0.68 (95% CI, 0.59-0.76; P < .001). CONCLUSIONS The prevalence of VTE was high in patients with newly diagnosed lung cancer. In patients with lung cancer, the factors associated with DVT might be different from those associated with PE. An elevated CEA level might facilitate the identification of patients at a higher risk of developing PE.

Fibrinogen Aα Thr312Ala Polymorphism Specifically Contributes to Chronic Thromboembolic Pulmonary Hypertension by Increasing Fibrin Resistance

Background Polymorphisms are associated with chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary thromboembolism (PTE), but no polymorphism specific to CTEPH but not PTE has yet been reported. Fibrin resistance is associated with CTEPH, but the mechanism has not been elucidated. Methods Polymorphisms were analyzed in 101 CTEPH subjects, 102 PTE subjects and 108 healthy controls by Massarray or restriction fragment length polymorphism (RFLP). Plasmin-mediated cleavage of fibrin was characterized in 69 subjects (29 with CTEPH, 21 with PTE and 19 controls). Results Genotype frequencies and allele frequencies of fibrinogen Aα Thr312Ala were significantly higher in CTEPH subjects than in controls and PTE subjects, while there was no difference between PTE subjects and controls. The odd ratio (OR 2.037) and 95% confidence interval (95% CI, 1.262–3.289) showed that Thr312Ala polymorphism was a risk factor for CTEPH but not PTE. Fibrin from CTEPH subjects was more resistant to lysis than that from PTE subjects and controls. Fibrin resistance was significantly different between Aα Thr312Ala (A/G) genotypes within CTEPH subjects, and the fibrin with GG genotype was more resistant than that with AA and AG genotype. Conclusions Fibrinogen Aα Thr312Ala (A/G) polymorphism was associated with CTEPH, but not PTE, suggesting that the fibrinogen Aα Thr312Ala polymorphism may act as a potential biomarker in identifying CTEPH from PTE. GG genotype polymorphism contributes to CTEPH through increasing fibrin resistance, implying that PTE subjects with fibrinogen Aα GG genotype may need long-term anticoagulation therapy.

Cardiovascular parameters of computed tomographic pulmonary angiography to assess pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension

OBJECTIVES The purpose is to identify the role of cardiovascular parameters of computed tomographic pulmonary angiography (CTPA) to assess pulmonary vascular resistance (PVR) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). BACKGROUND The assessment of PVR is of great importance in the management of patients with CTEPH. The role of CPTA in assessment of PVR of CTEPH remains to be explored. METHODS Clinical and radiological data of 90 patients (55 men, age 17-84 years) with CTEPH were retrospectively reviewed in this study. All patients received CTPA before right-heart catheterization. Cardiovascular parameters and Pulmonary Artery Obstruction Indices including Qanadli Index and Mastora Index were evaluated on CTPA. Hemodynamic PVR was calculated with the standard formula according to data from right-heart catheterization. The correlation of cardiovascular parameters of CTPA and PVR was analyzed. RESULTS In Cardiovascular parameters, neither Qanadli Index(r=0.134, p=0.208) nor Mastora Index (r=0.149, p=0.90) did correlate with PVR. Cobb angle(r=0.613, p=0.000), the ratio of right to left ventricular area(r=0.422, p=0.000)and the ratio of right to left ventricular transverse diameter (r=0.410, p=0.000) respectively correlated with PVR. By receiver operating characteristic curve analysis, a Cobb angle cutoff value of 67.55° had a sensitivity of 72.5% and a specificity of 84.0% to determine PVR ≥1000 (dyn.sec/cm(5)) and its Area Under Curve is (0.800 ± 0.048). By stepwise linear regression analysis, Cobb angle was only one variable (R=0.601) shown to be independently associated with PVR, leading to the following equation: PVR=25.796 × Cobb angle-585.935(F=37.929, p=0.000). CONCLUSION The analysis of CTPA-derived cardiovascular parameters, especially the Cobb angle, is a reliable tool for estimating PVR in patients with CTEPH, but Pulmonary Artery Obstruction Indices do not correlate with PVR.