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Objective@#To evaluate the efficacy and safety of ivabradine for the treatment of Chinese patients with chronic heart failure based on the Chinese subgroup data of the systolic heart failure treatment with the If inhibitor ivabradine trial (SHIFT).@*Method@#A total of 6 558 stable outpatients who presented symptoms of heart failure, with a left ventricular ejection fraction (LVEF) ≤35%, sinus rhythms with a heart rate ≥70 bpm participated in the randomized, double-blind, placebo-controlled, international multicenter clinical study.The subset of Chinese patients with heart rate ≥75 bpm was enrolled in the post-hoc subgroup analyses.Patients were randomly allocated by computer-generated assignment through a telephone interactive voice response system to ivabradine group (starting dose 5 mg bid, which was then uptitrated to the maximum 7.5 mg bid) or matched placebo group.The clinical baseline characteristics of participants were obtained and analyzed.The primary outcome endpoint was a composite endpoint of cardiovascular death or hospitalization resulting from worsening HF.The primary safety endpoint included total incidence of adverse events during the study, bradycardia, and adverse visual reaction (phosphenes).@*Results@#A total of 49 Chinese centers enrolled a total of 225 patients with chronic heart failure, of whom, 106 patients were randomized to the ivabradine group and the other 119 patients to the placebo group, and the mean follow-up time was (15.6±5.1) months.By the end of the study, mean heart rate (71.0 bpm vs. 80.3 bpm, P<0.05) and incidence of the primary endpoint events (18.9% (20/106) vs. 31.9%(38/119), HR=0.56, 95%CI 0.33-0.97, P=0.039) were significantly lower, while the percentage of patients with improvement in heart functional class NYHA (53.8% (56/106) vs. 34.5% (41/119), P=0.006 1) was significantly higher in the ivabradine group than in the placebo group.The total number of adverse events (129 events, 49.6% PY) in the ivabradine group was lower than that in the placebo group (203 events, 50.8% PY). In the ivabradine group and the placebo group, there were respectively 2 patients (1.9%) and 0 patients experienced bradycardia, 3 patients (2.9%) and 1 patient (0.8%) experienced adverse visual reaction (phosphenes).@*Conclusions@#Ivabradine significantly reduced heart rate and improved the clinical outcomes and NYHA function class in Chinese patients with chronic heart failure, these beneficial effects are achieved without inducing remarkable adverse reactions.The results of Chinese subgroup analysis were thus consistent with the overall results of the SHIFT study.@*Clinical Trial Registry@#International standard randomized controlled trials registry, ISRCTN 70429960.
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ABSTRACT:Objective To study the platelet changes in patients with unstable angina with different blood glucose ,and their related biochemical index changes ,and their relationship with global registry of acute coronary events (GRACE) score .Methods For this clinical study ,we enrolled 82 patients diagnosed with unstable angina , 47 of whom were male and 35 were female .Upon admission ,their random blood glucose was tested .According to different blood glucose values ,they were divided into normal blood glucose group (<6 .1 mmol/L) and high blood glucose (≥ 6 .1 mmol/L ) group . The following clinical data were compared between the two groups :age , hypertension ,diabetes ,smoking history ,and BMI .We detected EF (% ) ,HBA1C ,glucose ,LDL‐C ,HDL‐C ,TG , LPA ,CREA ,UA ,hsCRP ,BNP ,CKMB ,CTNI ,D‐Dimer ,and GRACE risk scores .We compared the platelet test results :PLT ,P‐LCR ,PDW ,and MPV .We also detected the relationship of MPV with hsCRP ,D‐Dimers and GRACE risk scores .Results MPV ,hsCRP ,and GRACE risk score differed significantly between normal blood glucose group and high blood glucose group (P<0 .05) .In the latter group ,MPV had significant correlation with hsCRP ,D‐Dimers and GRACE risk score ( r=0 .28 , r=0 .41 , r=0 .56 , P<0 .05) .Conclusion Hyperglycemia in patients with unstable angina causes the increase of MPV , change of the inflammatory marker hsCRP , and increase of clinical GRACE risk score .Abnormal MPV may predict the increased risk of unstable angina in patients with hyperglycemia upon hospitalization .
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OBJECTIVE:To provide reference for performing quality control and protecting the subjects’rights and interests. METHODS:233 severe adverse events (SAE) cases reported by our hospital during Jan. 2012-Jun. 2015 were collected and ana-lyzed statistically in respects of subjects’gender and age,department,drug/equipment types,SAE types,relationship of SAE with drug/equipment,comorbidities,etc. RESULTS:The incidence of SAE in male was higher than female(71.2% vs. 28.8%);SAE mainly occurred in people over the age of 50(189 cases,81.1%);the incidence of SAE in cardiology department was the highest (137 cases,58.8%);main SAE type was hospitalization(183 cases,78.5%);most of SAE had nothing to do with studied drugs (164 cases,70.4%);more than half of the subjects suffered from other comorbidities(128 cases,54.9%). CONCLUSIONS:In order to ensure the quality of drug clinical trial data and safety of subjects,the investigator should strengthen the management of the elderly subjects and those suffering from comorbidities,to ensure that each SAE case is timely processed and accurately record-ed and reported.
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Combined with work experience, this paper described the project process of clinical research pro-jects and ethical review points, and pointed out that clinical research projects should be submitted to peer reviewers prior to ethical review. The ethics committee would review the projects in accordance with legality, scientificity, feasibility, ethics, and other points in detail. Accurately grasp of the balance between innovations and ethics ensure the standardized development of clinical research.
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<p><b>OBJECTIVE</b>To investigate the pathologies of aortic root atherosclerotic lesion in uremic apoE-/- mice and explore the effect of serum from patients with chronic renal insufficiency (CRI) and the uremic toxin, indoxyl sulfate (IS), on the expression of cholesterol transporting receptors and lipid accumulation in macrophages in vitro.</p><p><b>METHODS</b>The uremic apoE-/- mouse model was established by surgical operation. Frozen sections of the aortic root were collected from uremic apoE-/- mice, sham-operated apoE-/- mice and C57BL/6J mice and stained with oil red O to calculate the relative area of atherosclerotic plaque. Murine macrophage RAW264.7 cell line was treated for 12 h with different concentrations of IS or serum samples from CRI patients and healthy individuals, and the mRNA expressions of cholesterol transporting receptors (SR-A1, CD36, ABCA1, ABCG1 and SR-B1) were detected. After treatment for 24 h, the cells were induced into foam cells to determine lipid contents using oil red O staining.</p><p><b>RESULTS</b>The relative area of the atherosclerotic plaques in the aortic root increased significantly in uremic apoE-/- mice compared with that in sham-operated apoE-/- mice. CRI serum (5%) and IS (250 µmol/L) obviously increased the mRNA expression of CD36 and lipid accumulation in the macrophages, but did not affect the mRNA expression of other cholesterol transporting receptors.</p><p><b>CONCLUSION</b>CRI can accelerate the progression of atherosclerosis through the mechanism that IS in CRI serum promotes lipid accumulation in macrophages by enhancing the mRNA expression of CD36, which contributes to the formation of foam cells.</p>
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Animals , Humans , Mice , Apolipoproteins E , Cell Line , Foam Cells , Chemistry , Indican , Pharmacology , Lipids , Chemistry , Macrophages , Chemistry , Mice, Inbred C57BL , Plaque, Atherosclerotic , Pathology , Renal Insufficiency, Chronic , BloodABSTRACT
ABSTRACT:Objective To observe the effect of curcumin on RAW264.7 macrophages induced with LPS and IFNγ(M1)and the mechanisms involved.Methods Curcumin of different concentrations (6.25 μmol/L,12.5μmol/L and 25 μmol/L)was used to treat RAW264.7 macrophages induced with LPS and IFNγ(M1)for 12 h,and RAW264.7 macrophages induced with LPS and IFNγ(M1)were incubated with 20μmol/L GW9662 and 25 μmol/L curcumin for 12 h.Using Real-time PCR,ELISA and Western blotting analysis,we examined the expressions of IL-1β,IL-6,PPARγand phenotype markers M2 (KLF4,FIZZ1,and MGL1 )and the expressions of KLF4 and FIZZ1 when PPARγwas inhibited.Results Curcumin of different concentrations all could inhibit the expressions of IL-1βand IL-6 in RAW264.7 macrophages induced with LPS and IFNγ(M1).Curcumin of different concentra-tions could upregulate the expression of M2 markers (KLF4,FIZZ1 and MGL1)and PPARγin RAW264.7 macro-phages induced with LPS and IFNγ(M1).When M1 macrophages were incubated with curcumin and GW9662,the expression of the M2 phenotype markers was reduced.Conclusion Curcumin polarized the M1 phenotype macro-phages derived from RAW264.7 macrophages to become M2 phenotype through activating PPARγ.
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<p><b>OBJECTIVE</b>To examine the changes in the expression of pro-inflammatory and anti-inflammatory cytokines in the peripheral blood mononuclear cells (PBMCs) and elucidate the inflammatory status of apparently healthy subjects.</p><p><b>METHODS</b>Peripheral blood samples (5 ml) were collected after fasting for more than 8 h from 14 healthy control subjects and 14 apparently healthy subjects with elevated serum high-sensitivity CRP (hsCRP) level (≥ 2.0 mg/L). PBMCs were separated by Ficoll density gradient centrifugation and the total RNA was extracted for real-time quantitative PCR analysis of the inflammatory cytokines, and plasma was separated for ELISA analysis of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) expressions.</p><p><b>RESULTS</b>The gene expressions of TNF-α and MCPIP were significantly increased in PBMCs of apparently healthy subjects, while IL-6 and MCP-1 only showed slight elevations; IL-10 expression in PBMCs decreased significantly in apparently healthy subjects as compared to that in the control group. The results of ELISA showed significantly elevated TNF-α level without significant changes of plasma IL-6 level in apparently healthy subjects.</p><p><b>CONCLUSION</b>In apparently healthy subjects with normal lipid levels, chronic low-grade inflammation has occurred shown by elevated expressions of the pro-inflammatory cytokines and lowered expressions of the anti-inflammatory cytokines.</p>
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Humans , Enzyme-Linked Immunosorbent Assay , Gene Expression , Healthy Volunteers , Inflammation , Allergy and Immunology , Interleukin-10 , Blood , Interleukin-6 , Blood , Leukocytes, Mononuclear , Allergy and Immunology , Tumor Necrosis Factor-alpha , BloodABSTRACT
Objective To evaluate the correlation between plasma high sensitivity C reactive protein (hs-CRP) level and global registry of acute coronary events (GRACE) scores,and its predictive value for long-term (5 years) cardiovascular events in middle-aged and elderly patients with acute coronary syndrome (ACS).Methods 138 middle aged and elderly patients with ACS were divided into three groups according to GRACE scores:low risk group,middle risk group,high risk group.And based on quartiles of hs-CRP levels,subjects were segregated into 4 groups (Q1 to Q4).All subjects were followed up for about 5 years and adverse cardiovascular disease events were recorded.Results The hs-CRP level was gradually increased along with increasing risk according to GRACE risk stratification (hs-CRP low risk group,0.09 ± 0.22 ; middle risk group,0.21 ± 0.04 ;high risk group,0.43±0.23,P＜0.001).Meantime,GRACE risk scores were gradually increased along with increasing hs-CRP levels from Q1 to Q4 (Q1:133.0 ± 43.6; Q2:161.9 ± 60.2; Q3:169.3±52.6; Q4:188.4±47.5; all P＜0.001).Regression analysis showed that hs-CRP level was positively correlated with GRACE risk scores (r=0.576,P＜0.001).During a follow-up period of about 5 years,96 cardiovascular events were recorded.Receiver operating characteristic(ROC) curve analysis showed that area under the ROC curve (AUC) of hs-CRP was 0.821 (95 ％CI:0.749-0.892,P＜0.001) and AUC of GRACE risk score was 0.869 (95％CI:0.801 0.938,P＜0.001) in the evaluation of the long-term risk of incident cardiovascular events.The differences in prediction of long-term cardiovascular events in middle-aged and elderly patients with ACS were not significant (P =0.237) between GRACE risk score and hs CRP level.Conclusions Plasma hs-CRP level is positively associated with GRACE score.Both of them can predict long-term adverse cardiovascular events in middle-aged and elderly patients with acute coronary syndrome.
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<p><b>OBJECTIVE</b>To investigate the effect of diclofenac on the expression of Kv1.3 and Kir2.1 channels in human macrophages and the membrane potential and foaming process of the macrophages.</p><p><b>METHODS</b>The effect of diclofenac on the expression of Kv1.3 and Kir2.1 channels in cultured human monocyte-derived macrophages was investigated using real-time RT-PCR and Western blotting, and its effect on the membrane potential was analyzed with optical mapping of the membrane potential with voltage-sensitive dyes. The ratio of cholesterol ester (CE) in the macrophages following intake of oxidized low-density lipoprotein (OxLDL) was analyzed by an enzymatic fluorometric method.</p><p><b>RESULTS</b>The expression of Kv1.3 and Kir2.1 channels in the macrophages were down-regulated by diclofenac (1.5 µmol/L and 15 µmol/L). Compared with those in the control group, Kv1.3 mRNA expression was reduced by over 80% and 90% (P<0.05), and Kir2.1 mRNA by over 20% and 30% (P>0.05), respectively; both their protein expression was reduced by over 10% and 60% with a dose- dependent effect (P<0.05). Diclofenac at the two doses dose-dependently reduced the surface fluorescence intensity of the macrophage, and the membrane potential was decreased by 28% and 54%, respectively (P<0.05). Incubation of the macrophages with 30 mg/L OxLDL for 60 h caused an obvious enlargement of the cell volume and deposition of numerous lipid granules in cytoplasm, resulting also in a CE/TC ratio over 50% (P<0.05). Diclofenac at 1.5 and 15 µmol/L both significantly decreased the CE/TC ratio to (23.624∓3.34)% and (13.601∓2.916)% (P<0.05), respectively, but this effect did not show a dose-response relationship (P>0.05).</p><p><b>CONCLUSION</b>Diclofenac can significant down-regulate the expression of Kv1.3 and Kir2.1 channels in human macrophages, lower their membrane potential and inhibit the process of foam cell formation.</p>
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Humans , Cells, Cultured , Diclofenac , Pharmacology , Foam Cells , Cell Biology , Metabolism , Macrophages , Metabolism , Physiology , Membrane Potentials , Potassium Channels, Inwardly Rectifying , MetabolismABSTRACT
Objective To establish a uremic apoE-/- mouse model to observe serum biochemical parameters and features of aortic root atherosclerosis (AS) in the model. Methods A uremic model was induced surgically in apoE-/- mice: electrocautery of the right kidney at 8 weeks of age and nephrectomy (NX) of the left one 2 weeks later. Control mice were sham-operated. Two weeks after NX, renal functions were detected in the uremic and control mice to evaluate the efficiency of the model. After 10 weeks of NX, blood samples were taken to determine serum biochemical parameters, and aortic root was collected for frozen sections to investigate the lesion features of AS. Results Two weeks after NX, renal functions declined significantly in the uremic mice compared with the control ones, and remained stable 8 weeks later either in males or in females. Ten weeks after NX, serum levels of TCH, TG and LDL-C were dramatically higher in the uremic mice than in the controls, whereas no differences in serum HDL-C or glucose concentration were found between the two groups. Aortic root plaque relative area increased significantly in the uremic mice compared with the controls either in males or in females; more-over, the lesion area was larger in female mice than in male ones. Conclusion We established a uremic apoE-/- mouse model successfully, and this model is characterized by accelerated atherogenesis which is associated with an increase in serum lipid profile. This experimental model can be a useful tool to study the pathogenesis and therapeutic strategies of uremic AS.
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<p><b>OBJECTIVE</b>To examine the procoagulant effects of thrombolytic agent on hemostasis and study the role of hemostatic markers as predictors of clinical outcomes.</p><p><b>METHODS</b>In the present study, eighteen patients with acute myocardial infarction (AMI) received 1.5 or 2.0 million U nonspecific urokinase (UK), or 70 approximately 80 mg fibrin-specific recombinant tissue plasminogen activator (rt-PA) and did not use heparin until 8 hours after intravenous injection of the above agents. Eight patients with AMI and without thrombolytic therapy were enrolled as controls. Coagulant and thrombolytic activity markers included thrombin-antithrombin III complex (TAT), D-dimer, fibrinogen (Fg), FMPV/Amax. All markers were determined before, immediately, 1, 2, 4 and 8 hours after the administration of thrombolytic agents respectively.</p><p><b>RESULTS</b>Molecular marker of thrombin generation--TAT showed an activated coagulant state immediately after thrombolytic therapy. Level of TAT showed no significant changes between every two observed phases in controls. However, level of TAT increased significantly from 4.95 +/- 1.75 microg/L ( 4.63 +/- 1.37 microg/L) to 14.71 +/- 3.31 microg/L (14.25 +/- 2.53 microg/L) before and immediately after administration of thrombolytic agents UK (or rt-PA). There was significant difference between level of serum TAT of patients with and without thrombolytic therapy (P < 0.05). Patients achieving clinical reperfusion had lower TAT level than those failing in thrombolytic therapy, and higher FMPV/Amax level than controls. D-dimer, a surrogate of thrombolytic activity increased markedly and Fg significantly declined after thrombolytic therapy (P < 0.05).</p><p><b>CONCLUSIONS</b>Thrombin generation occurred in plasma in response to excess fibrinolysis induced by thrombolytic therapy. Both urokinase and rt-PA had procoagulant action. This transient activation of the coagulant system might contribute to early reocclusion. These data provided the theoretical support for simultaneous administration of anticoagulant therapy with thrombolytic agents. These results also suggested that TAT might be useful in predicting clinical outcomes of patients treated with thrombolytic therapy for AMI.</p>
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Aged , Female , Humans , Male , Middle Aged , Antithrombin III , Biomarkers , Blood , Fibrin Fibrinogen Degradation Products , Metabolism , Fibrinogen , Metabolism , Fibrinolytic Agents , Therapeutic Uses , Myocardial Infarction , Blood , Drug Therapy , Peptide Hydrolases , Blood , Recombinant Proteins , Therapeutic Uses , Thrombolytic Therapy , Tissue Plasminogen Activator , Therapeutic Uses , Urokinase-Type Plasminogen Activator , Therapeutic UsesABSTRACT
Objective To investigate the protective effect of felodipine on reactive oxygen species (ROS) generation,mRNA level of inflammatory factors such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1),in human umbilical vein endothelial cells (HUVECs) injured by oxidized low-density lipoprotein (ox-LDL) so as to explore felodipine's anti-atherosclerosis mechanism independent of its anti-hypertensive effect. Methods Isolated HUVECs were treated with ox-LDL at different concentrations (6,12.5 and 25 mg/L) for 24 hours so that the optimal concentration and time of ox-LDL treatment were selected. Then the cells were incubated with ox-LDL and treated with felodipine at different concentrations (0.1,1 and 10 ?mol/L). Intracellular ROS level was determined by flow cytometry (FCM). Expressions of inflammatory factors ICAM-1 and VCAM-1 were measured by real time-polymerase chain reaction (real time-PCR). Results ROS generation was increased in HUVECs after treatment with different concentrations (6,12.5 and 25 mg/L) of ox-LDL for 24 hours and there was a significant difference at 25 mg/L ox-LDL (P
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Objective To investigate the protective effects of felodipine on mRNA levels of endothelial nitricoxide synthase (eNOS) and inducible nitricoxide synthase (iNOS) as well as the level of nitrogen monoxidum (NO) from human umbilical vein endothelial cells (HUVECs) injuryed by oxidized low density lipoprotein (ox-LDL). Methods Isolated HUVECs were divided into blank control group,ox-LDL injury group treated with ox-LDL of different concentrations (6,12.5 and 25 mg/L),and intervention group of felodipine (0.1,1.0 and 10 ?mol/L)+ox-LDL (25 mg/L). Then eNOS and iNOS expressions were measured by real time-polymerase chain reaction and the level of NO in the supernatants of the cultures was assayed by nitrate reductase method. Results The mRNA expressions of eNOS and iNOS in HUVECs and NO level in the supernatants during treatment with different ox-LDL concentrations were higher than those in control group. However,felodipine significantly down-regulated the expression of iNOS in HUVECs injured by ox-LDL and inceased NO generation. Conclusion Felodipine has protective effects on endothelial cells. The mechanism may be related to its lowering the mRNA expression of iNOS induced by low ox-LDL concentration and increasing NO production.
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Objective To study the effects of chronic ouabain treatment on Na+-K+-ATPase activity and the expression of dopamine D1 receptor in rat kidney cortex. Methods A total of 28 male Sprague-Dawley (SD) rats were randomly divided into ouabain group and control group,which were treated with ouabain or saline for 5 weeks; rat tail systolic blood pressure (SBP) was recorded weekly. Rats were sacrificed after 3 and 5 weeks,respectively. Then Na+-K+-ATPase activity and the expression of dopamine D1 receptor in rat kidney cortex were measured by colorimetric assay and real-time PCR,respectively. Results After 3 weeks of ouabain treatment,the mean SBP did not change significantly,but the Na+-K+-ATPase activity increased (P