Effects of Ulinastatin on Postoperative Renal Function in Patients Undergoing Cardiac Surgery with Cardiopulmonary Bypass: A Prospective Cohort Study with 10-Year Follow-Up.

INTRODUCTION:The present study aimed to explore the potential effect of ulinastatin on renal function and long-term survival in patients receiving cardiac surgery with cardiopulmonary bypass (CPB).METHODS:This prospective cohort study was conducted at Fuwai Hospital, Beijing, China. Ulinastatin was applied after induction anesthesia. The primary outcome was the rate of new-onset postoperative acute kidney injury (AKI). Moreover, a 10-year follow-up was conducted until January 2021.RESULTS:The rate of new-onset AKI was significantly lower in the ulinastatin group than in the control group (20.00 vs. 32.40%, p = 0.009). There was no significant difference in renal replacement therapy between the two groups (0.00 vs. 2.16%, p = 0.09). The postoperative plasma neutrophil gelatinase-associated lipocalin (pNGAL) and IL-6 levels were significantly lower in the ulinastatin group compared with the control group (pNGAL: p = 0.007; IL-6: p = 0.001). A significantly lower incidence of respiratory failure in the ulinastatin group compared with the control group (0.76 vs. 5.40%, p = 0.02). The nearly 10-year follow-up (median: 9.37, 95% confidence interval: 9.17-9.57) survival rates did not differ significantly between the two groups (p = 0.076).CONCLUSIONS:Ulinastatin significantly reduced postoperative AKI and respiratory failure in patients receiving cardiac surgery with CPB. However, ulinastatin did not reduce intensive care unit and hospital stays, mortality, and long-term survival rate.

Effect of Clemastine Fumarate on Perioperative Hemodynamic Instability Mediated by Anaphylaxis During Cardiopulmonary Bypass Surgery.

BACKGROUND Perioperative hemodynamic instability mediated by anaphylaxis is a life-threatening complication in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). This study aimed to evaluate the effect of clemastine fumarate in this specific patient population. MATERIAL AND METHODS We enrolled 100 participants who met the inclusion criteria and randomly allocated them to the treatment group and the placebo group. Participants in the treatment group and the placebo group were treated separately with an injection of clemastine fumarate and saline, respectively. Plasma histamine concentration and blood pressure were quantified at 5 timepoints during the perioperative period, and differences between the 2 groups were assessed by repeated-measures ANOVA. The postoperative complications and in-hospital mortality also were evaluated. All participants were followed up for 7 days after cardiac surgery. RESULTS Plasma histamine concentrations increased in both groups but were statistically significantly lower in the treatment group during the perioperative period (P=0.007). Diastolic blood pressure (P=0.014) and mean arterial pressure (P=0.024) in the treatment group were significantly higher than in the placebo group during the perioperative period. The coefficients of variation for systolic (13.9±4.2% vs 17.2±4.4%, P<0.01) and diastolic (12.9±4.9% vs 15.3±5.2%, P=0.02) blood pressure were significantly lower in the treatment group compared with the placebo group. CONCLUSIONS Pretreatment with clemastine fumarate restrains the increase in histamine concentration and provides safer hemodynamics in patients undergoing cardiac surgery with CPB.

High-glucose-induced apoptosis, ROS production and pro-inflammatory response in cardiomyocytes is attenuated by metformin treatment via PP2A activation.

Metformin has been shown to ameliorate diabetic cardiomyopathy. In the present research we investigated whether metformin would reduce cardiomyocyte apoptosis that was induced by high-glucose stimulation in vitro via activation of PP2A. Primary human and rat cardiomyocytes were subject to high-glucose stimulation. Okadaic acid was used to inhibit PP2A activity. Cell viability and apoptosis was assessed using CCK-8 and by flow cytometry, respectively. Release of HMGB1, TNFα or IL-6 was analyzed by ELISA. Oxidative stress was evaluated by measuring cellular ROS and mitochondrial superoxide level. PP2A activity was evaluated by Serine/ Threonine phosphatase assay system or analyzing Y307 phosphorylation level of PP2A catalytic domain (PP2Ac) by Western blot and the association between PP2Ac and α4 by co-immunoprecipitation. Activation of the NF-κB signaling pathway was assessed by detecting Ser32 phosphorylation level of IκBα as well as nuclear entry of p65 protein by Western blot. Activation of the GSK3β/MCL1 signaling pathway was assessed by detecting Ser9 phosphorylation level of GSK3 β and protein level of MCL1. We found Metformin pre-treatment attenuated human and rat cardiomyocytes apoptosis, HMGB1, TNFα and IL-6 release and ROS production that were induced by high-glucose stimulation, and these effects of metformin could be blocked by okadaic acid treatment. Metformin reduced the upregulation of PP2Ac pY307 and the PP2Ac-a4 association, which was not affected by okadaic acid treatment. Metformin pre-treatment reduced NF-κB activation in human and rat cardiomyocytes apoptosis that was elicited by high-glucose stimulation, and this effect of metformin could be blocked by okadaic acid treatment. GSK3 β/MCL1 is not part of metformin activating PP2A induced myocardial cell death inhibition. In conclusion, metformin reduced apoptosis, ROS production and inflammatory response in primary human and rat cardiomyocytes in vitro in a PP2A dependent manner.

Ulinastatin reduces postoperative bleeding and red blood cell transfusion in patients undergoing cardiac surgery: A PRISMA-compliant systematic review and meta-analysis.

BACKGROUND:Ulinastatin is a type of glycoprotein and a nonspecific wide-spectrum protease inhibitor like antifibrinolytic agent aprotinin. Whether Ulinastatin has similar beneficial effects on blood conservation in cardiac surgical patients as aprotinin remains undetermined. Therefore, a systematic review and meta-analysis were performed to evaluate the effects of Ulinastatin on perioperative bleeding and transfusion in patients who underwent cardiac surgery.METHODS:Electronic databases were searched to identify all clinical trials comparing Ulinastatin with placebo/blank on postoperative bleeding and transfusion in patients undergoing cardiac surgery. Primary outcomes included perioperative blood loss, blood transfusion, postoperative re-exploration for bleeding. Secondary outcomes include perioperative hemoglobin level, platelet counts and functions, coagulation tests, inflammatory cytokines level, and so on. For continuous variables, treatment effects were calculated as weighted mean difference (WMD) and 95% confidential interval (CI). For dichotomous data, treatment effects were calculated as odds ratio and 95% CI. Statistical significance was defined as P < .05.RESULTS:Our search yielded 21 studies including 1310 patients, and 617 patients were allocated into Ulinastatin group and 693 into Control (placebo/blank) group. There was no significant difference in intraoperative bleeding volume, postoperative re-exploration for bleeding incidence, intraoperative red blood cell transfusion units, postoperative fresh frozen plasma transfusion volumes and platelet concentrates transfusion units between the 2 groups (all P > .05). Ulinastatin reduces postoperative bleeding (WMD = -0.73, 95% CI: -1.17 to -0.28, P = .001) and red blood cell (RBC) transfusion (WMD = -0.70, 95% CI: -1.26 to -0.14, P = .01), inhibits hyperfibrinolysis as manifested by lower level of postoperative D-dimer (WMD = -0.87, 95% CI: -1.34 to -0.39, P = .0003).CONCLUSION:This meta-analysis has found some evidence showing that Ulinastatin reduces postoperative bleeding and RBC transfusion in patients undergoing cardiac surgery. However, these findings should be interpreted rigorously. Further well-conducted trials are required to assess the blood-saving effects and mechanisms of Ulinastatin.

Survey on Anesthesia Services in Fuwai Hospital.

Effect of ulinastatin on post-operative blood loss and allogeneic transfusion in patients receiving cardiac surgery with cardiopulmonary bypass: a prospective randomized controlled study with 10-year follow-up.

BACKGROUND:Major bleeding and allogeneic transfusion leads to negative outcomes in patients receiving cardiac surgery with cardiopulmonary bypass (CPB). Ulinastatin, a urine trypsin inhibitor, relieves systemic inflammation and improves coagulation profiles with however sparse evidence of its effects on blood loss and allogeneic transfusion in this specific population.METHODS:In this prospective randomized controlled trial, 426 consecutive patients receiving open heart surgery with CPB were randomly assigned into three groups to receive ulinastatin (group U, n = 142), tranexamic acid (group T, n = 143) or normal saline (group C, n = 141). The primary outcome was the total volume of post-operative bleeding and the secondary outcome included the volume and exposure of allogeneic transfusion, the incidence of stroke, post-operative myocardial infarction, renal failure, respiratory failure and all-cause mortality. A ten-year follow-up was carried on to evaluate long-term safety.RESULTS:Compared with placebo, ulinastatin significantly reduced the volume of post-operative blood loss within 24 h (688.39 ± 393.55 ml vs 854.33 ± 434.03 ml MD - 165.95 ml, 95%CI - 262.88 ml to - 69.01 ml, p < 0.001) and the volume of allogeneic erythrocyte transfusion (2.57 ± 3.15 unit vs 3.73 ± 4.21 unit, MD-1.16 unit, 95%CI - 2.06 units to - 0.26 units, p = 0.002). The bleeding and transfusion outcomes were comparable between the ulinastatin group and the tranexamic acid group. In-hospital outcomes and 10-year follow-up showed no statistical difference in mortality and major morbidity among groups.CONCLUSIONS:Ulinastatin reduced post-operative blood loss and allogeneic erythrocyte transfusion in heart surgery with CPB. The mortality and major morbidity was comparable among the groups shown by the 10-year follow-up.TRIAL REGISTRATION:The trial was retrospectively registered on February 2, 2010.TRIAL REGISTRATION NUMBER:https://www.clinicaltrials.gov Identifier: NCT01060189.

Long non-coding RNA CASC2 suppresses pulmonary artery smooth muscle cell proliferation and phenotypic switch in hypoxia-induced pulmonary hypertension.

BACKGROUND:In this study, we aimed to investigate whether and how lncRNA CASC2 was involved in hypoxia-induced pulmonary hypertension (PH)-related vascular remodeling.METHODS:The expression of lncRNAs or mRNAs was detected by qRT-PCR, and western blot analysis or immunochemistry was employed for detecting the protein expression. Cell number assay and EdU (5-ethynyl-2'-deoxyuridine) staining were performed to assess cell proliferation. Besides, flow cytometry and wound healing assay were employed for assessments of cell apoptosis and cell migration, respectively. Rat model of hypoxic PH was established and the hemodynamic measurements were performed. Hematoxylin and eosin (HE) and Masson's trichrome staining were carried out for pulmonary artery morphometric analysis.RESULTS:The expression of lncRNA CASC2 was decreased in hypoxia-induced rat pulmonary arterial tissues and pulmonary artery smooth muscle cells (PASMCs). Up-regulation of lncRNA CASC2 inhibited cell proliferation, migration yet enhanced apoptosis in vitro and in vivo in hypoxia-induced PH. Western blot analysis and immunochemistry showed that up-regulation of lncRNA CASC2 greatly decreased the expression of phenotype switch-related marker α-SMA in hypoxia-induced PH. Furthermore, it was indicated by the pulmonary artery morphometric analysis that lncRNA CASC2 suppressed vascular remodeling of hypoxia-induced rat pulmonary arterial tissues.CONCLUSION:LncRNA CASC2 inhibited cell proliferation, migration and phenotypic switch of PASMCs to inhibit the vascular remodeling in hypoxia-induced PH.

Mir-455-3p-1 represses FGF7 expression to inhibit pulmonary arterial hypertension through inhibiting the RAS/ERK signaling pathway.

OBJECTIVE:To analyze the effects of miR-455-3p-1 and its possible mechanisms in pulmonary arterial hypertension (PAH).METHODS:A microarray assay was used to examine the expressed genes between normal and PAH. The expressed genes in PAH was assessed by qRT-PCR. The targeted interaction between miRNAs and FGF7 was confirmed using a dual luciferase reporter assay. A CCK-8 assay and cell count were used to analyze the pulmonary artery smooth muscle cells (PASMCs) activity and proliferation level, respectively. Apoptotic PASMCs were detected by flow cytometry. In addition, the mRNA and protein expression levels of RAS/ERK signaling pathway were determined by qRT-PCR and a Western blot assay, respectively. A PAH rat model was used to identify the effects of miR-455-3p-1 in vivo.RESULTS:FGF7 was upregulated in PAH. MiR-455-3p-1 was downregulated in PAH. MiR-455-3p-1 targeted FGF7. MiR-455-3p-1 decreased the expression of FGF7. Moreover, the effect of FGF7 on PASMCs was suppressed by miR-455-3p-1. MiR-455-3p-1 upregulation was associated with reduced mRNA and protein levels of core RAS/ERK signal genes, suggesting the inhibition of the RAS/ERK pathway. Furthermore, miR-455-3p-1 upregulation improved the RVSP, mPAP, ratio of RV/LV + S, CO and RV function of PAH rat model in vivo.CONCLUSION:Our findings illustrate a role for miR-455-3p-1 in modulating FGF7-RAS/ERK signaling and suggest that an agomir of miR-455-3p-1 could inhibit the proliferation of PASMCs and mitigate PAH in vivo.

Efficacy and Safety of Tranexamic Acid in Pediatric Patients Undergoing Cardiac Surgery: A Single-Center Experience.

Aims: This study evaluated the efficacy and safety of tranexamic acid (TXA) undergoing cardiac surgery. Methods: Using a retrospective cohort study design, 2,026 consecutive pediatric patients who underwent surgical repair of atrial or ventricular septal defect or complete repair of Tetralogy of Fallot were included, and divided into a control group and a TXA group. Results: Compared with that in the control group, there were statistically significant reduction of both the 12-h and total postoperative blood loss in the TXA group [6.573 ± 0.144 vs. 5.499 ± 0.133 ml kg-1, mean difference (MD) 1.074 ml kg-1, p < 0.001; 12.183 ± 0.298 vs. 9.973 ± 0.276 ml kg-1, MD, 2.210 ml kg-1, p < 0.001]. There was a statistically significant reduction of the MD of 12-h postoperative blood loss due to TXA in patients aged < 1 year compared with that in patients aged ≥1 year (MD, 1.544 vs. 0.681 ml kg-1, P = 0.007). There were statistically significant reduction of the MD of both the 12-h and total postoperative blood loss due to TXA in patients weighing < 10 kg compared with that in patients weighing ≥10 kg (MD, 1.542 vs. 0.456 ml kg-1, P < 0.001, and MD, 2.195 vs. 0.929 ml kg-1, P = 0.036, respectively). There was a statistically significant reduction of the MD of total postoperative blood loss due to TXA in cyanotic patients compared with that in acyanotic patients (MD, 3.381 vs. 1.038 ml kg-1, P = 0.002). There was no significant difference in the postoperative volume or exposure of allogeneic transfusion, in-hospital morbidity or mortality between the groups. Conclusions: TXA took effects in reduction of postoperative blood loss but not the allogeneic transfusion requirement in pediatric patients undergoing cardiac surgery, particularly in infants weighing < 10 kg and cyanotic children. Moreover, the study suggested the use of TXA was safe in pediatric cardiac surgery.

Effects of tranexamic acid on short-term and long-term outcomes of on-pump coronary artery bypass grafting: Randomized trial and 7-year follow-up.

AIMS:Safety evaluations of tranexamic acid (TXA) remain sparse, especially with respect to its impact on long-term outcomes in patients undergoing on-pump coronary artery bypass grafting (CABG). We hypothesized that the effects of TXA on perioperative bleeding and allogeneic transfusion and its impact on long-term clinical outcomes of patients receiving on-pump CABG are superior to those in the control group.METHODS:In this prospective, randomized, placebo-controlled trial, 210 patients undergoing primary and isolated on-pump CABG were randomly assigned to receive TXA or a corresponding volume of saline solution. Randomly assigned patients were followed up at 1, 3, 5, and 7 years after hospital discharge. Finally, 163 patients fulfilled the 7-year follow-up. The primary outcome was allogeneic red blood cell (RBC) transfusion. Long-term mortality and morbidity were also evaluated.RESULTS:Compared with placebo, TXA reduced the allogeneic RBC requirement in terms of the volume transfused (4.20 ± 4.06 vs 6.25 ± 4.86 units; P < 0.01), ratio exposed (52.0% vs 71.6%; P < 0.01), and blood loss volume (879.0 ± 392.5 vs 1154.0 ± 582.8 mL; P < 0.01). Except for myocardial infarction, there were no significant differences in mortality or morbidity between the two groups during the 7-year follow-up. The TXA group had a lower rate of myocardial infarction than did the placebo group (0.0% vs 4.9% at 84 months; P = 0.03).CONCLUSIONS:Tranexamic acid significantly decreased postoperative bleeding and allogeneic transfusion in patients undergoing on-pump CABG. The 7-year follow-up suggested that the use of TXA was safe and might play a potential role in the prevention of long-term myocardial infarction.

Effects of Ulinastatin on Postoperative Renal Function in Patients Undergoing Cardiac Surgery with Cardiopulmonary Bypass: A Prospective Cohort Study with 10-Year Follow-Up.

INTRODUCTION:The present study aimed to explore the potential effect of ulinastatin on renal function and long-term survival in patients receiving cardiac surgery with cardiopulmonary bypass (CPB).METHODS:This prospective cohort study was conducted at Fuwai Hospital, Beijing, China. Ulinastatin was applied after induction anesthesia. The primary outcome was the rate of new-onset postoperative acute kidney injury (AKI). Moreover, a 10-year follow-up was conducted until January 2021.RESULTS:The rate of new-onset AKI was significantly lower in the ulinastatin group than in the control group (20.00 vs. 32.40%, p = 0.009). There was no significant difference in renal replacement therapy between the two groups (0.00 vs. 2.16%, p = 0.09). The postoperative plasma neutrophil gelatinase-associated lipocalin (pNGAL) and IL-6 levels were significantly lower in the ulinastatin group compared with the control group (pNGAL: p = 0.007; IL-6: p = 0.001). A significantly lower incidence of respiratory failure in the ulinastatin group compared with the control group (0.76 vs. 5.40%, p = 0.02). The nearly 10-year follow-up (median: 9.37, 95% confidence interval: 9.17-9.57) survival rates did not differ significantly between the two groups (p = 0.076).CONCLUSIONS:Ulinastatin significantly reduced postoperative AKI and respiratory failure in patients receiving cardiac surgery with CPB. However, ulinastatin did not reduce intensive care unit and hospital stays, mortality, and long-term survival rate.

Effect of Clemastine Fumarate on Perioperative Hemodynamic Instability Mediated by Anaphylaxis During Cardiopulmonary Bypass Surgery.

BACKGROUND Perioperative hemodynamic instability mediated by anaphylaxis is a life-threatening complication in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). This study aimed to evaluate the effect of clemastine fumarate in this specific patient population. MATERIAL AND METHODS We enrolled 100 participants who met the inclusion criteria and randomly allocated them to the treatment group and the placebo group. Participants in the treatment group and the placebo group were treated separately with an injection of clemastine fumarate and saline, respectively. Plasma histamine concentration and blood pressure were quantified at 5 timepoints during the perioperative period, and differences between the 2 groups were assessed by repeated-measures ANOVA. The postoperative complications and in-hospital mortality also were evaluated. All participants were followed up for 7 days after cardiac surgery. RESULTS Plasma histamine concentrations increased in both groups but were statistically significantly lower in the treatment group during the perioperative period (P=0.007). Diastolic blood pressure (P=0.014) and mean arterial pressure (P=0.024) in the treatment group were significantly higher than in the placebo group during the perioperative period. The coefficients of variation for systolic (13.9±4.2% vs 17.2±4.4%, P<0.01) and diastolic (12.9±4.9% vs 15.3±5.2%, P=0.02) blood pressure were significantly lower in the treatment group compared with the placebo group. CONCLUSIONS Pretreatment with clemastine fumarate restrains the increase in histamine concentration and provides safer hemodynamics in patients undergoing cardiac surgery with CPB.

High-glucose-induced apoptosis, ROS production and pro-inflammatory response in cardiomyocytes is attenuated by metformin treatment via PP2A activation.

Metformin has been shown to ameliorate diabetic cardiomyopathy. In the present research we investigated whether metformin would reduce cardiomyocyte apoptosis that was induced by high-glucose stimulation in vitro via activation of PP2A. Primary human and rat cardiomyocytes were subject to high-glucose stimulation. Okadaic acid was used to inhibit PP2A activity. Cell viability and apoptosis was assessed using CCK-8 and by flow cytometry, respectively. Release of HMGB1, TNFα or IL-6 was analyzed by ELISA. Oxidative stress was evaluated by measuring cellular ROS and mitochondrial superoxide level. PP2A activity was evaluated by Serine/ Threonine phosphatase assay system or analyzing Y307 phosphorylation level of PP2A catalytic domain (PP2Ac) by Western blot and the association between PP2Ac and α4 by co-immunoprecipitation. Activation of the NF-κB signaling pathway was assessed by detecting Ser32 phosphorylation level of IκBα as well as nuclear entry of p65 protein by Western blot. Activation of the GSK3β/MCL1 signaling pathway was assessed by detecting Ser9 phosphorylation level of GSK3 β and protein level of MCL1. We found Metformin pre-treatment attenuated human and rat cardiomyocytes apoptosis, HMGB1, TNFα and IL-6 release and ROS production that were induced by high-glucose stimulation, and these effects of metformin could be blocked by okadaic acid treatment. Metformin reduced the upregulation of PP2Ac pY307 and the PP2Ac-a4 association, which was not affected by okadaic acid treatment. Metformin pre-treatment reduced NF-κB activation in human and rat cardiomyocytes apoptosis that was elicited by high-glucose stimulation, and this effect of metformin could be blocked by okadaic acid treatment. GSK3 β/MCL1 is not part of metformin activating PP2A induced myocardial cell death inhibition. In conclusion, metformin reduced apoptosis, ROS production and inflammatory response in primary human and rat cardiomyocytes in vitro in a PP2A dependent manner.

Ulinastatin reduces postoperative bleeding and red blood cell transfusion in patients undergoing cardiac surgery: A PRISMA-compliant systematic review and meta-analysis.

BACKGROUND:Ulinastatin is a type of glycoprotein and a nonspecific wide-spectrum protease inhibitor like antifibrinolytic agent aprotinin. Whether Ulinastatin has similar beneficial effects on blood conservation in cardiac surgical patients as aprotinin remains undetermined. Therefore, a systematic review and meta-analysis were performed to evaluate the effects of Ulinastatin on perioperative bleeding and transfusion in patients who underwent cardiac surgery.METHODS:Electronic databases were searched to identify all clinical trials comparing Ulinastatin with placebo/blank on postoperative bleeding and transfusion in patients undergoing cardiac surgery. Primary outcomes included perioperative blood loss, blood transfusion, postoperative re-exploration for bleeding. Secondary outcomes include perioperative hemoglobin level, platelet counts and functions, coagulation tests, inflammatory cytokines level, and so on. For continuous variables, treatment effects were calculated as weighted mean difference (WMD) and 95% confidential interval (CI). For dichotomous data, treatment effects were calculated as odds ratio and 95% CI. Statistical significance was defined as P < .05.RESULTS:Our search yielded 21 studies including 1310 patients, and 617 patients were allocated into Ulinastatin group and 693 into Control (placebo/blank) group. There was no significant difference in intraoperative bleeding volume, postoperative re-exploration for bleeding incidence, intraoperative red blood cell transfusion units, postoperative fresh frozen plasma transfusion volumes and platelet concentrates transfusion units between the 2 groups (all P > .05). Ulinastatin reduces postoperative bleeding (WMD = -0.73, 95% CI: -1.17 to -0.28, P = .001) and red blood cell (RBC) transfusion (WMD = -0.70, 95% CI: -1.26 to -0.14, P = .01), inhibits hyperfibrinolysis as manifested by lower level of postoperative D-dimer (WMD = -0.87, 95% CI: -1.34 to -0.39, P = .0003).CONCLUSION:This meta-analysis has found some evidence showing that Ulinastatin reduces postoperative bleeding and RBC transfusion in patients undergoing cardiac surgery. However, these findings should be interpreted rigorously. Further well-conducted trials are required to assess the blood-saving effects and mechanisms of Ulinastatin.

Survey on Anesthesia Services in Fuwai Hospital.

Effect of ulinastatin on post-operative blood loss and allogeneic transfusion in patients receiving cardiac surgery with cardiopulmonary bypass: a prospective randomized controlled study with 10-year follow-up.

BACKGROUND:Major bleeding and allogeneic transfusion leads to negative outcomes in patients receiving cardiac surgery with cardiopulmonary bypass (CPB). Ulinastatin, a urine trypsin inhibitor, relieves systemic inflammation and improves coagulation profiles with however sparse evidence of its effects on blood loss and allogeneic transfusion in this specific population.METHODS:In this prospective randomized controlled trial, 426 consecutive patients receiving open heart surgery with CPB were randomly assigned into three groups to receive ulinastatin (group U, n = 142), tranexamic acid (group T, n = 143) or normal saline (group C, n = 141). The primary outcome was the total volume of post-operative bleeding and the secondary outcome included the volume and exposure of allogeneic transfusion, the incidence of stroke, post-operative myocardial infarction, renal failure, respiratory failure and all-cause mortality. A ten-year follow-up was carried on to evaluate long-term safety.RESULTS:Compared with placebo, ulinastatin significantly reduced the volume of post-operative blood loss within 24 h (688.39 ± 393.55 ml vs 854.33 ± 434.03 ml MD - 165.95 ml, 95%CI - 262.88 ml to - 69.01 ml, p < 0.001) and the volume of allogeneic erythrocyte transfusion (2.57 ± 3.15 unit vs 3.73 ± 4.21 unit, MD-1.16 unit, 95%CI - 2.06 units to - 0.26 units, p = 0.002). The bleeding and transfusion outcomes were comparable between the ulinastatin group and the tranexamic acid group. In-hospital outcomes and 10-year follow-up showed no statistical difference in mortality and major morbidity among groups.CONCLUSIONS:Ulinastatin reduced post-operative blood loss and allogeneic erythrocyte transfusion in heart surgery with CPB. The mortality and major morbidity was comparable among the groups shown by the 10-year follow-up.TRIAL REGISTRATION:The trial was retrospectively registered on February 2, 2010.TRIAL REGISTRATION NUMBER:https://www.clinicaltrials.gov Identifier: NCT01060189.

Long non-coding RNA CASC2 suppresses pulmonary artery smooth muscle cell proliferation and phenotypic switch in hypoxia-induced pulmonary hypertension.

BACKGROUND:In this study, we aimed to investigate whether and how lncRNA CASC2 was involved in hypoxia-induced pulmonary hypertension (PH)-related vascular remodeling.METHODS:The expression of lncRNAs or mRNAs was detected by qRT-PCR, and western blot analysis or immunochemistry was employed for detecting the protein expression. Cell number assay and EdU (5-ethynyl-2'-deoxyuridine) staining were performed to assess cell proliferation. Besides, flow cytometry and wound healing assay were employed for assessments of cell apoptosis and cell migration, respectively. Rat model of hypoxic PH was established and the hemodynamic measurements were performed. Hematoxylin and eosin (HE) and Masson's trichrome staining were carried out for pulmonary artery morphometric analysis.RESULTS:The expression of lncRNA CASC2 was decreased in hypoxia-induced rat pulmonary arterial tissues and pulmonary artery smooth muscle cells (PASMCs). Up-regulation of lncRNA CASC2 inhibited cell proliferation, migration yet enhanced apoptosis in vitro and in vivo in hypoxia-induced PH. Western blot analysis and immunochemistry showed that up-regulation of lncRNA CASC2 greatly decreased the expression of phenotype switch-related marker α-SMA in hypoxia-induced PH. Furthermore, it was indicated by the pulmonary artery morphometric analysis that lncRNA CASC2 suppressed vascular remodeling of hypoxia-induced rat pulmonary arterial tissues.CONCLUSION:LncRNA CASC2 inhibited cell proliferation, migration and phenotypic switch of PASMCs to inhibit the vascular remodeling in hypoxia-induced PH.

Mir-455-3p-1 represses FGF7 expression to inhibit pulmonary arterial hypertension through inhibiting the RAS/ERK signaling pathway.

OBJECTIVE:To analyze the effects of miR-455-3p-1 and its possible mechanisms in pulmonary arterial hypertension (PAH).METHODS:A microarray assay was used to examine the expressed genes between normal and PAH. The expressed genes in PAH was assessed by qRT-PCR. The targeted interaction between miRNAs and FGF7 was confirmed using a dual luciferase reporter assay. A CCK-8 assay and cell count were used to analyze the pulmonary artery smooth muscle cells (PASMCs) activity and proliferation level, respectively. Apoptotic PASMCs were detected by flow cytometry. In addition, the mRNA and protein expression levels of RAS/ERK signaling pathway were determined by qRT-PCR and a Western blot assay, respectively. A PAH rat model was used to identify the effects of miR-455-3p-1 in vivo.RESULTS:FGF7 was upregulated in PAH. MiR-455-3p-1 was downregulated in PAH. MiR-455-3p-1 targeted FGF7. MiR-455-3p-1 decreased the expression of FGF7. Moreover, the effect of FGF7 on PASMCs was suppressed by miR-455-3p-1. MiR-455-3p-1 upregulation was associated with reduced mRNA and protein levels of core RAS/ERK signal genes, suggesting the inhibition of the RAS/ERK pathway. Furthermore, miR-455-3p-1 upregulation improved the RVSP, mPAP, ratio of RV/LV + S, CO and RV function of PAH rat model in vivo.CONCLUSION:Our findings illustrate a role for miR-455-3p-1 in modulating FGF7-RAS/ERK signaling and suggest that an agomir of miR-455-3p-1 could inhibit the proliferation of PASMCs and mitigate PAH in vivo.

Efficacy and Safety of Tranexamic Acid in Pediatric Patients Undergoing Cardiac Surgery: A Single-Center Experience.

Aims: This study evaluated the efficacy and safety of tranexamic acid (TXA) undergoing cardiac surgery. Methods: Using a retrospective cohort study design, 2,026 consecutive pediatric patients who underwent surgical repair of atrial or ventricular septal defect or complete repair of Tetralogy of Fallot were included, and divided into a control group and a TXA group. Results: Compared with that in the control group, there were statistically significant reduction of both the 12-h and total postoperative blood loss in the TXA group [6.573 ± 0.144 vs. 5.499 ± 0.133 ml kg-1, mean difference (MD) 1.074 ml kg-1, p < 0.001; 12.183 ± 0.298 vs. 9.973 ± 0.276 ml kg-1, MD, 2.210 ml kg-1, p < 0.001]. There was a statistically significant reduction of the MD of 12-h postoperative blood loss due to TXA in patients aged < 1 year compared with that in patients aged ≥1 year (MD, 1.544 vs. 0.681 ml kg-1, P = 0.007). There were statistically significant reduction of the MD of both the 12-h and total postoperative blood loss due to TXA in patients weighing < 10 kg compared with that in patients weighing ≥10 kg (MD, 1.542 vs. 0.456 ml kg-1, P < 0.001, and MD, 2.195 vs. 0.929 ml kg-1, P = 0.036, respectively). There was a statistically significant reduction of the MD of total postoperative blood loss due to TXA in cyanotic patients compared with that in acyanotic patients (MD, 3.381 vs. 1.038 ml kg-1, P = 0.002). There was no significant difference in the postoperative volume or exposure of allogeneic transfusion, in-hospital morbidity or mortality between the groups. Conclusions: TXA took effects in reduction of postoperative blood loss but not the allogeneic transfusion requirement in pediatric patients undergoing cardiac surgery, particularly in infants weighing < 10 kg and cyanotic children. Moreover, the study suggested the use of TXA was safe in pediatric cardiac surgery.

Effects of tranexamic acid on short-term and long-term outcomes of on-pump coronary artery bypass grafting: Randomized trial and 7-year follow-up.

AIMS:Safety evaluations of tranexamic acid (TXA) remain sparse, especially with respect to its impact on long-term outcomes in patients undergoing on-pump coronary artery bypass grafting (CABG). We hypothesized that the effects of TXA on perioperative bleeding and allogeneic transfusion and its impact on long-term clinical outcomes of patients receiving on-pump CABG are superior to those in the control group.METHODS:In this prospective, randomized, placebo-controlled trial, 210 patients undergoing primary and isolated on-pump CABG were randomly assigned to receive TXA or a corresponding volume of saline solution. Randomly assigned patients were followed up at 1, 3, 5, and 7 years after hospital discharge. Finally, 163 patients fulfilled the 7-year follow-up. The primary outcome was allogeneic red blood cell (RBC) transfusion. Long-term mortality and morbidity were also evaluated.RESULTS:Compared with placebo, TXA reduced the allogeneic RBC requirement in terms of the volume transfused (4.20 ± 4.06 vs 6.25 ± 4.86 units; P < 0.01), ratio exposed (52.0% vs 71.6%; P < 0.01), and blood loss volume (879.0 ± 392.5 vs 1154.0 ± 582.8 mL; P < 0.01). Except for myocardial infarction, there were no significant differences in mortality or morbidity between the two groups during the 7-year follow-up. The TXA group had a lower rate of myocardial infarction than did the placebo group (0.0% vs 4.9% at 84 months; P = 0.03).CONCLUSIONS:Tranexamic acid significantly decreased postoperative bleeding and allogeneic transfusion in patients undergoing on-pump CABG. The 7-year follow-up suggested that the use of TXA was safe and might play a potential role in the prevention of long-term myocardial infarction.