miR-432-5p Inhibits the Ferroptosis in Cardiomyocytes Induced by Hypoxia/Reoxygenation via Activating Nrf2/SLC7A11 Axis by Degrading Keap1.

Early reperfusion into the myocardium after ischemia causes myocardial ischemia-reperfusion (I/R) injury and ferroptosis was involved. Ischemia activates the expression of a series of oxidative stress genes and their downstream regulatory genes, including ferroptosis-related genes such as nuclear factor E2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and SLC7A11. This study adopted primary cardiomyocytes and I/R in rats to evaluate the ferroptosis and changing of Nrf2-SLC7A11/heme oxygenase-1 (HO-1) in vitro and in vivo. Online analysis tools were used to predict the possible target Kelch-like ECH-associated protein 1 (Keap1) of miR-432-5p. The mimic of miR-432-5p plasmid was constructed to verify the effect of miR-432-5p on ferroptosis. We found that hypoxia/reoxygenation (H/R) in cardiomyocytes and I/R in rats induced lipid peroxidation and ferroptosis in cardiomyocytes. The activation of the Nrf2-SLC7A11/HO-1 pathway protects cardiomyocytes from ferroptosis. Downregulation of miR-432-5p has been confirmed in H/R cardiomyocytes (in vitro) and cardiomyocytes in myocardial infarction rats (in vivo). Upregulation of miR-432-5p inhibited ferroptosis of cardiomyocytes induced by RAS-selective lethal 3 (RSL3), an inhibitor of GPX4 and ferroptosis inducer through decreasing the binding protein of Nrf2, Keap1, which was confirmed by bioinformatics and mutation assay. Knockdown Nrf2 attenuates the protection effect of miR-432-5p on H/R cardiomyocytes. Intravenous delivery of liposome carriers of miR-432-5p remarkably ameliorated cardiomyocyte impairment in the I/R animal model. In conclusion, miR-432-5p inhibits the ferroptosis in cardiomyocytes induced by H/R by activating Nrf2/SLC7A11 axis by degrading Keap1 and is a potential drug target for clinical myocardial infarction treatment.

The effect and mechanism of dl-3-n-butylphthalide on angiogenesis in a rat model of chronic myocardial ischemia.

OBJECTIVE: To assess the effect of dl-3-n-butylphthalide (NBP) on angiogenesis and its underlying mechanism in a rat model of chronic myocardial ischemia (CMI). METHODS: Forty Sprague-Dawley rats were randomly divided into four groups: model, low-dose NBP (L-NBP), middle-dose NBP (M-NBP), or high-dose NBP (H-NBP) (n=10/group). All groups received intraperitoneal injections of isoprinosine hydrochloride daily for 14 days. Additionally, the L-NBP, M-NBP, and H-NBP groups received NBP at 3, 6, and 12 mg per kg body weight, respectively, by intraperitoneal injection. An additional 10 rats (control group) received 0.9% sodium chloride via intraperitoneal injection for 14 consecutive days. Echocardiography was used for the measurement of heart function. Immunohistochemical staining for factor VIII-related antigen and microvascular density determination were performed. The protein and mRNA expression of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) in CMI areas were measured by western blot and RT-PCR, respectively. RESULTS: Electrocardiograms showed that NBP improved cardiac function by regulating left ventricular end-diastolic and end-systolic diameters, ejection fraction, and fractional shortening. Compared with the control and model groups, the L-NBP, M-NBP, and H-NBP groups showed increased mRNA and protein expression of VEGFA and HIF-1α in myocardial tissue. The mRNA and protein expression of VEGFA and HIF-α in the H-NBP group were the highest. CONCLUSION: NBP treatment promotes VEGF and HIF-1α protein expression during myocardial ischemia, which may represent useful biomarkers for coronary collateral establishment and offer potential targets for therapeutic induction of angiogenesis in patients with CMI.

Different dosage regimens of nifedipine, labetalol, and hydralazine for the treatment of severe hypertension during pregnancy: a network meta-analysis of randomized controlled trials.

OBJECTIVES: This network meta-analysis aimed to compare the efficacy and safety of intravenous (IV) hydralazine, oral nifedipine, and IV labetalol with different dosage regimens in the treatment of severe hypertension during pregnancy. METHODS: A comprehensive literature search was performed on PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov for randomized controlled trials (RCTs) exploring the effects of hydralazine, nifedipine, and labetalol in the treatment of severe hypertension during pregnancy. RESULTS: A total of 21 RCTs with 2183 patients comparing 7 regimens (oral nifedipine 50,60,90 mg; hydralazine 15,25 mg; and labetalol 220,300 mg) were identified. Compared with IV labetalol 300 mg, nifedipine 50,60, and 90 mg significantly improved the successful treatment rate of severe hypertension during pregnancy, nifedipine 50 and 90 mg and IV hydralazine 25 mg required significantly fewer doses to achieve target blood pressure (BP), and nifedipine 50 mg took significantly shorter time to achieve target BP. Subgroup analysis showed that only nifedipine 50 mg tablets, not capsules, required a significantly shorter time and fewer doses to achieve target BP than IV labetalol 300 mg. Moreover, nifedipine 60,90 mg showed superior effectiveness than IV hydralazine 15,25 mg in the successful treatment rate of severe hypertension during pregnancy. SUCRA analysis suggested that nifedipine 50,60,90 mg as the better regimens with the lower rates of overall ADR and neonatal complications. CONCLUSION: These findings demonstrated the superiority of oral nifedipine 50,60,90 mg, especially oral nifedipine 50 mg tablets, in the treatment of severe hypertension during pregnancy than IV labetalol 300 mg, while oral nifedipine 60,90 mg also showed superiority in the successful treatment rate of severe hypertension during pregnancy than IV hydralazine 15,25 mg. However, the limitations of the underlying data indicate that future large-scale and rigorous RCTs are needed to confirm such findings.

Safety and feasibility of low-dose ticagrelor in patients with ST-segment elevation myocardial infarction.

BACKGROUND: Previous studies have confirmed the safety and feasibility of half-dose ticagrelor in Chinese patients with acute coronary syndrome, but currently there is no plan for the use of ticagrelor for Chinese ST-segment elevation myocardial infarction (STEMI) patients. HYPOTHESIS: It is safe and feasible of low-dose ticagrelor in patients with STEMI. METHODS: The STEMI patients who were undergoing emergency intervention and taking ticagrelor were enrolled. Patients whose level of platelet aggregation rate (PAR) less than 30% after 7-day treatment with standard-dose ticagrelor were randomly divided into low-dose group (LD group, 45 mg twice daily) and standard-dose group (SD group, 90 mg twice daily). The changes of levels of platelet parameters were compared between the two groups. The incidence of major adverse cardiac events (MACE), bleeding events were compared between the two groups within 6 months of follow-up. RESULTS: The levels of PAR in the SD group decreased compared with baseline, and was lower than those of LD group at the same time point. The levels of platelet distribution width in both groups decreased from the baseline values (all p < .05) at 1, 3, and 6 months after grouping treatment, but there was no significant difference between the two groups. The incidence of MACE was similar between the two groups of patients. There were decreasing trends in the incidences of minimal bleeding event, minor bleeding event, dyspnea, and gout in the LD group. CONCLUSION: It is safe and feasible of low-dose ticagrelor for patients with STEMI based on the monitoring of PAR.

Influence of dl-3-N-butylphthalide on infarction size in rats with acute myocardial infarction.

OBJECTIVE: To study the influence of dl-3-N-butylphthalide (NBP) on infarction size in rats with acute myocardial infarction (AMI). METHODS: AMI model was established by ligation of the left anterior descending artery. A total of 36 healthy male Sprague-Dawley rats (weight, 180 t, 180 ght, 180 ligation of left anterior descending artery. A total of 36 healthy males were assigned to model group, sham-operation (SO) group, and the NBP group (n=12 each). The rats in the NBP group were treated with intraperitoneal injection administration of 60 mg/kg/body weight NBP once a day. The rats in the other groups were given distilled water of the same volume. The MI area in each group was detected by TTC staining. The concentrations of CK-MB and LDH were detected. The concentrations of TNF-α, IL-6, MDA, and SOD were measured by ELISA. RESULTS: Compared with the SO group, the myocardial infarct sizes in the model group and the NBP group were significantly increased (P<0.001), and the infarct size in the NBP group was lower than that in the model group (280.6±5.82% vs. 37.74±10.18%, P<0.05). The levels of TNF-α in the NBP group and model group were significantly increased compared with that in the SO group (P<0.001), while the level of TNF-α in the NBP group was significantly lower than that in the model group (29.01±0.81 pg/mg prot vs. 37.727 pg/mg prot, P<0.05). The level of IL-6 in the model group and NBP group was significantly higher than that in the SO group, and it was lower than that in the model group (24.13 group wamg prot vs. 27.53 pg/mg prot, P<0.05). The levels of MDA in the model group and the NBP group were significantly higher (<0.001), and the level of NBP group was lower than that of the model group (4.10 group wnmol/mg prot vs. 4.774.774. nmol/mg prot, P<0.05). The levels of SOD in the model group and NBP group were lower (P<0.001), and the SOD level in the NBP group was higher than that of the model group (53.490.001), and prot vs. 38.068.06he SOD prot (P<0.05). CONCLUSION: NBP can reduce the infarct size in SD rats with AMI.

Efficacy and safety of intracoronary prourokinase during percutaneous coronary intervention in treating ST-segment elevation myocardial infarction patients: a randomized, controlled study.

BACKGROUND: Prourokinase is a single-chain plasminogen activator presenting with fewer hemorrhagic complications and reduced reocclusion rate compared with the conventional fibrinolytic agents in patients with coronary artery disease. However, prourokinase intracoronary injection during PCI for treating patients with ST-segment elevation myocardial infarction (STEMI) is rarely investigated. Therefore, this study aimed to evaluate the efficacy and safety of intracoronary prourokinase during the percutaneous coronary intervention (PCI) in treating STEMI patients. METHODS: Fifty STEMI patients who underwent primary PCI were consecutively enrolled and randomly assigned to intracoronary prourokinase group (N = 25) or control group (N = 25). During the primary PCI procedure, patients in the intracoronary prourokinase group received 10 ml prourokinase injection, while patients in control group received 10 ml saline injection as control. The primary endpoints were coronary physiological indexes, the secondary endpoints were angiographic assessments, myocardial infarct size/reperfusion assessment, cardiac function evaluations, major adverse coronary events (MACEs) and hemorrhagic complications. All patients were followed up for 3 months. RESULTS: Post PCI, the index of microcirculatory resistance (IMR) was decreased in intracoronary prourokinase group than that in control group (34.56 ± 7.48 vs. 49.00 ± 8.98, P < 0.001), while no difference of coronary flow reserve (CFR) (2.01 ± 0.32 vs. 1.88 ± 0.23, P = 0.267) or fractional flow reserve (FFR) (0.89 ± 0.05 vs. 0.87 ± 0.04, P = 0.121) was found between the two groups. The thrombolysis in myocardial infarction myocardial perfusion grade (TMPG) (P = 0.024), peak values of creatine kinase (CK) (P = 0.028), CK isoenzyme-MB (CK-MB) (P = 0.016), cardiac troponin I (cTnI) (P = 0.032) and complete ST-segment resolution (STR) (P = 0.005) were better in intracoronary prourokinase group compared with control group. At 3-months post PCI, left ventricular ejection fraction (LVEF) and wall motion score index (WMSI) were higher, while left ventricular end-diastolic diameter (LVEDd) was lower in intracoronary prourokinase group compared with control group (all P < 0.05). There was no difference in hemorrhagic complication or total MACE between the two groups. CONCLUSION: Intracoronary prourokinase during PCI is more efficient and equally tolerant compared with PCI alone in treating STEMI patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1800016207 . Prospectively registered.

Effects of Levosimendan on Right Ventricular Function in Patients with Acute Decompensated Heart Failure.

BACKGROUND: To investigate the effects of levosimendan on right ventricular (RV) function in patients with acute decompensated heart failure (ADHF). METHODS: Patients with ADHF admitted from January 2017 to October 2017 were enrolled in this study. The patients were randomized to receive 24-h intravenous levosimendan or placebo. Echocardiographic examinations were performed and the parameters were compared. Epidemiological data were recorded and compared before and after treatment. Major adverse cardiac events during hospitalization and during 1-month follow-up were compared. RESULTS: The baseline characteristics were comparable. After 24-h infusion of levosimendan and placebo, the left ventricular ejection fraction and S' were significantly increased in the levosimendan group compared with the control group (both p < 0.05). The E value in the levosimendan group significantly decreased (75.38 ± 8.32 vs. 88.21 ± 10.36, p < 0.0001), and E/e' significantly increased in the control group (19.61 ± 6.52 vs. 27.58 ± 8.22, p < 0.0001). The levels of right ventricular fractional area change (24 ± 3 vs. 20 ± 2, p < 0.0001) and tricuspid annular plane systolic excursion (1.56 ± 0.36 vs. 1.38 ± 0.21, p < 0.0001) were significantly higher in the levosimendan group than in the control group. After treatment, the values of systolic pulmonary artery pressure (SPAP) decreased in both groups (both p < 0.05), and the value of SPAP in the levosimendan group was lower than that in the control group (47.22 ± 5.6 vs. 55.85 ± 7.41, p < 0.0001). After 1-month follow-up, there was no significance in readmissions due to recurrent heart failure. CONCLUSIONS: Levosimendan seems to provide more beneficial effects among patients with ADHF to improve RV function, along with a decrease in pulmonary pressure.

Comparative Effectiveness of Taxane-Containing Regimens for Treatment of HER2-Negative Metastatic Breast Cancer: A Network Meta-analysis.

STUDY OBJECTIVES: To compare the effectiveness of different taxane-containing regimens and to identify the best strategy for the treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). DESIGN: Network meta-analysis of 20 randomized controlled trials (RCTs). PATIENTS: A total of 6577 patients with HER2-negative MBC who received treatment (20 different regimens) with taxanes (paclitaxel [4267 patients] or docetaxel [2310 patients]). MEASUREMENTS AND MAIN RESULTS: The PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched (through March 2019) for RCTs that evaluated any taxane-containing regimens for the treatment of HER2-negative MBC. A network meta-analysis in a Bayesian framework was performed using the random-effects model. We compared the surface under the cumulative ranking (SUCRA) curve for each regimen. Overall, paclitaxel-based combinations were superior to paclitaxel alone in objective response rate (ORR) (odds ratio 1.60, 95% credible interval [CrI] 1.15-2.16) and overall survival (OS) (hazard ratio 1.08, 95% CrI 1.01-1.15). Docetaxel-based combinations were also superior to paclitaxel alone in ORR. Among the paclitaxel-based regimens, based on the results of SUCRA, paclitaxel + bevacizumab + capecitabine was likely to be the most efficacious in improving ORR, OS, and progression-free survival (PFS), whereas paclitaxel + gemcitabine was likely to be the most efficacious in 1-year OS rate. Among the docetaxel-based regimens, based on the results of SUCRA, docetaxel + gemcitabine was likely to be the most efficacious in improving PFS and OS. CONCLUSION: These findings demonstrated that paclitaxel-based combinations can provide significant improvement in ORR and OS compared with paclitaxel alone. The regimens of paclitaxel + bevacizumab + capecitabine, docetaxel + gemcitabine, and paclitaxel + gemcitabine may be superior to other regimens for the treatment of HER2-negative MBC.

Comparison of myocardial microcirculatory perfusion after catheter-administered intracoronary thrombolysis with anisodamine versus standard thrombus aspiration in patients with ST-elevation myocardial infarction.

OBJECTIVE: To evaluate efficacy, safety and feasibility of targeted intracoronary injection using pro-urokinase combined with anisodamine (TCA) versus thrombus aspiration (TA) in ST-elevation myocardial infarction (STEMI) patients with high thrombus loads. BACKGROUND: The best method of avoiding thrombus detachment and stroke in PCI patients with high thrombus loads has not yet been established. METHODS: STEMI patients receiving coronary artery angiography or percutaneous coronary intervention (CAG/PCI) with thrombus grade ≥ 3 from January 1, 2017 to June 30, 2018 were randomly assigned to targeted intracoronary thrombolysis (pro-urokinase and anisodamine via catheter (TCA) group), or the TA group which followed the standard thrombus aspiration procedure. Parameters compared included thrombus grade, index of microcirculatory resistance (IMR), postoperative myocardial SPECT, thrombosis in myocardial infarction (TIMI) scores including flow grade, corrected TIMI frame counts (CTFCs), and TIMI myocardial perfusion grade (TMPG). Adverse events were followed up within 3 months. RESULTS: Thirty-nine patients were finally enrolled. In primary CAG/PCI, the TCA group had higher percentages of TIMI 3 flow and lower IMR values compared with the TA group. The ratio of TMPG 3 grade in the TCA group was higher in repeat CAG, and the perfusion descending area (PDA) presented by SPECT was lower than in the TA group. No significant difference was seen in major adverse coronary events (MACEs) or bleeding events at follow-up. CONCLUSIONS: TCA appears to be effective, safe, and feasible for repatency and reduction of high thrombus burden in primary PCI and may protect myocardial microcirculation with improved outcomes.

Arctigenin Attenuates Ischemia/Reperfusion Induced Ventricular Arrhythmias by Decreasing Oxidative Stress in Rats.

BACKGROUND/AIMS: Arctigenin (ATG) has been shown to possess anti-inflammatory, immunemodulatory, anti-viral, anti-microbial, anti-carcinogenic, vasodilatory and anti-platelet aggregation properties. However, the protective role of ATG in prevention of arrhythmias induced by myocardial ischemia/reperfusion is unknown. The aim of this study was to investigate the anti-arrhythmia effect of ATG in an ischemia/reperfusion injured rat heart model and explore the related mechanisms. METHODS: Rats were randomly exposed to sham operation, myocardial ischemia/ reperfusion (MI/R) alone, ATG+ MI/R, pretreated with ATG in low (12.5 mg/kg/day), medium (50 mg/kg/day) and high dose (200 mg/kg/day), respectively. Ventricular arrhythmias were assessed. The activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and the level of malondialdehyde (MDA) in myocardial tissue were determined by chemical analysis. RESULTS: Compared to MI/R, rats pretreated with ATG in doses of 50 mg/kg/day and 200 mg/kg/day showed significantly reduced incidence and duration of ventricular fibrillation, ventricular tachycardia and ventricular ectopic beat (VEB), and decreased the arrhythmia score during the 30-min ischemia. Incidence and duration of ventricular tachycardia, infarction size and arrhythmia scores in these groups were significantly decreased during the 120-min reperfusion. No ventricular fibrillation occurred during the period of reperfusion. Rats pretreated with ATG in doses of 50 mg/kg/day and 200 mg/kg/ day markedly enhanced the activities of antioxidant enzymes SOD and GSH-Px, reduced the level of MDA. No differences were observed between the group pretreated with a low dose of ATG and the sham group. Administration of ATG significantly increased the expression of antioxidant stress protein Nrf2, Trx1 and Nox1. CONCLUSION: Our data suggested that ATG plays anti-arrhythmia role in ischemia/reperfusion injury, which is probably associated with attenuating oxidative stress by Nrf2 signaling pathway.

Effects of intensive pitavastatin therapy on glucose control in patients with non-ST elevation acute coronary syndrome.

Objective: This study aimed to investigate the effects of intensive pitavastatin therapy on glucose control in patients with non-ST elevation acute coronary syndrome (ACS). Methods: Patients who had ACS with significant stenosis on initial coronary angiography and received successful percutaneous coronary intervention (PCI) in the Second Hospital of Hebei Medical University, Shijiazhuang, China from August 2015 to January 2016 were enrolled in this study. The patients were randomized to receive pitavastatin (4 mg daily) or atorvastatin (20 mg daily). PCI was performed within 72 hours after admission according to the current clinical practice at the physician's discretion. The examinations of blood lipid levels and blood markers of glucose metabolism were performed at baseline and after 6-month follow-up using standard techniques. The inflammatory markers, including white blood cell, high-sensitivity C-reactive protein (hs-CRP) and fibrinogen, were also assessed before PCI and 24 hours after PCI. An independent adverse event assessment committee evaluated major adverse cardiovascular events (MACE) and any other adverse events. Results: A total of 132 patients were enrolled and randomly divided into the pitavastatin group (n = 65) or the atorvastatin group (n = 67), which had similar baseline characteristics and PCI procedural characteristics. For the inflammatory biomarkers at 24 hours after PCI, the fibrinogen level was significantly increased in the atorvastatin group; the hs-CRP levels were significantly increased in both groups, however, the hs-CRP level in the pitavastatin group was lower than that in the atorvastatin group. In addition, the blood lipid parameters (e.g., TC, LDL-C, TG, non-HDL-C and Apo B) were significantly decreased in both groups after 6-month follow-up (P < 0.01), but these parameters between the two groups had no significant difference. After 6-month follow-up, the FPG, IRI, HOMA-IR and HbA1c levels were significantly decreased in the pitavastatin group (P < 0.05) but slightly increased in the atorvastatin group, indicating that the glucose homeostasis was improved in patients in the pitavastatin group but not in the atorvastatin group. Furthermore, the incidence of MACE was not significantly different between the two groups (P > 0.05). After 6-month antiplatelet treatment, the PAR value was significantly decreased in both groups (P < 0.01), but the PAR value in the pitavastatin group was lower than that in the atorvastatin group. Conclusion: Pitavastatin therapy may improve the glucose homeostasis for patients with ACS undergoing PCI and has more favorable outcomes than atorvastatin therapy.

Comparison of ticagrelor and high-dose clopidogrel on the platelet functions in patients with inadequate response to clopidogrel.

OBJECTIVE: To evaluate the effects of ticagrelor and high-dose clopidogrel on the platelet functions in patients with inadequate response to clopidogrel. METHODS: In this prospective, randomized and controlled study, patients who had been diagnosed as acute coronary syndrome (ACS) with inadequate response to clopidogrel in the Second Hospital of Hebei Medical University from July 2015 to June 2016 were enrolled. Inadequate response to clopidogrel was defined as absolute reduction of platelet aggregation rate (PAR) <30% or PAR >70%. Eligible patients were randomly assigned to two groups, the high-dose group and the ticagrelor group. Clinical information and intervention protocols were compared. The PAR of the two groups were measured at the time of baseline, the 24th hour, 72nd hour, and the 7th day after treatments, the other platelet-related parameters were measured including platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW) at the same time points. Besides, the markers of platelet activation human P-selectin (CD62P) and thromboxane A2 (TXA2) were also recorded to compare. The incidence of major adverse cardiac events (MACE) and the side effects between two groups were followed up for three months. RESULTS: A total of 74 patients were finally enrolled, 38 of whom were assigned to the ticagrelor group and the rest of them to the high-dose clopidogrel group. The baseline clinical and procedural characterists were similar. There were no significant differences in baseline levels of PAR between the two groups [(79.38±11.20)% vs. (73.97±12.74)%, P>0.05]. For both groups, the levels of PAR significantly decreased at each time point (P<0.001). Besides, the levels of PAR in ticagrelor group were lower than those in high-dose clopidogrel group at the 24th hour, 72nd hour and 7th day after treatments: [(25.92±10.31)% vs. (37.95±11.63)%, P<0.001], [(28.02±14.61)% vs. (30.64±10.73)%, P<0.001], [(37.17±11.11)% vs. (36.80±7.26)%, P<0.001]. The baseline levels of platelet related parameters were similar between the two groups (P>0.05), and there were no significant differences in the levels of PLT, PDW, and MPV at the 24th hour, 72nd hour and 7th day. It was lower in ticagrelor group than that in clopidogrel group at the 24th hour [(5.47±1.03) ng/ml vs. (8.02±1.45) ng/ml, P<0.001] while the CD62P concentrations in the two groups significantly decreased comparing to the baseline levels (P<0.001). During 3-month follow-up, the incidences of MACE and side effects were not significantly different between the two group. CONCLUSIONS: ticagrelor could further decrease levels of platelet aggression rate and CD62p compared with high-dose clopidogrel, without serious side effects.

Efficacy and Safety of Pulmonary Arterial Hypertension-specific Therapy in Pulmonary Arterial Hypertension: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Previous meta-analyses of pulmonary arterial hypertension (PAH)-specific therapy for PAH pooled PAH-specific combination therapy and monotherapy. This flaw may threaten the authenticity of their findings. METHODS: PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials that evaluated any PAH-specific medications in the treatment of PAH. We calculated ORs with 95% CIs for dichotomous data and standardized mean differences for continuous data. RESULTS: In total, 35 randomized controlled trials involving 6,702 patients were included. In monotherapy vs placebo/conventional therapy, significance was obtained in mortality reduction (OR, 0.50 [95% CI, 0.33 to 0.76]; P = .001), 6-min walk test (mean difference, 31.10 m [95% CI, 25.40 to 36.80]; P < .00001), New York Heart Association/World Health Organization functional class (OR, 2.48 [95% CI, 1.51 to 4.07]; P = .0003), and hemodynamic status based on mean pulmonary artery pressure, pulmonary vascular resistance, cardiac index, and incidence of withdrawal due to adverse effects. In combination therapy vs monotherapy, significance was reached for the 6-min walk test (mean difference, 19.96 m [95% CI, 15.35 to 24.57]; P < .00001), functional class (OR, 1.65 [95% CI, 1.20 to 2.28]; P = .002), hemodynamic status, and incidence of withdrawal due to adverse effects (OR, 2.01 [95% CI, 1.54 to 2.61]; P < .00001) but not for mortality reduction (OR, 0.98 [95% CI, 0.57 to 1.68]; P = .94). CONCLUSIONS: Our meta-analysis revealed that PAH-specific monotherapy could improve mortality, exercise capacity, functional class, and hemodynamic status compared with placebo or conventional therapy. However, combination therapy could further improve exercise capacity, functional class, and hemodynamic status compared with monotherapy, but it had no proven effect on mortality. Combination therapy had a much higher incidence of withdrawal due to adverse effects than monotherapy.

Effect of rhBNP on renal function in STEMI-HF patients with mild renal insufficiency undergoing primary PCI.

This study aims to investigate the effect of recombinant human brain natriuretic peptide (rhBNP) on renal function and contrast-induced nephropathy (CIN) incidence in ST-segment elevation myocardial infarction and heart failure (STEMI-HF) patients with mild renal insufficiency undergoing primary percutaneous coronary intervention (PCI). A total of 116 participants were randomized into rhBNP (rhBNP, n = 57) and nitroglycerin group (NIT, n = 59), receiving intravenous rhBNP or nitroglycerin from admission to 72 h after PCI. Renal function was assessed by serum creatinine (SCr), estimated glomerular filtration rate (eGFR), Cystatin-C (Cys-C) and ß2-microglobulin before and after primary PCI, and calculated the incidence of CIN within 72 h after PCI. There were no significant differences in SCr, eGFR and ß2-microglobulin between the two groups (P > 0.05, respectively). Compared with the NIT group, the total urinary volume within 72 h was higher while the level of Cys-C at 24 and 72 h after PCI was lower in the rhBNP group. rhBNP was associated with a decline in the incidence of CIN (12.28 vs. 28.81 %, P < 0.05). No differences were detected in mortality and re-hospitalization in 3 months between the two groups. The incidence of renal injury was not different between rhBNP and nitroglycerin in STEMI-HF patients with mild renal insufficiency. However, infusion of rhBNP was associated with a decline in incidence of CIN.

Effects of liposomal prostaglandin E1 on periprocedural myocardial injury in patients with unstable angina undergoing an elective percutaneous coronary intervention.

OBJECTIVES: The aim of this study was to explore whether intravenous administration of liposomal prostaglandin E1 (lipo-PGE1) can reduce the incidence of periprocedural myocardial injury (PMI) in patients with unstable angina undergoing an elective percutaneous coronary intervention (PCI). PATIENTS AND METHODS: In this randomized-controlled study, a total of 219 patients were randomly assigned to a lipo-PGE1 group (n=110) and a control group (n=109). Patients in the lipo-PGE1 group received 20 µg/day of lipo-PGE1 diluted in 10 ml of normal saline through an intravenous injection over 5 min starting at 3 days before PCI and continuing for 4 days after PCI. In the control group, 10 ml of normal saline was administered using the same method. The primary end point was the occurrence of PMI defined as an elevation of cardiac troponin I above the upper limit of normal within 24 h after the procedure. The secondary end points were (i) changes in inflammatory factors including plasma high-sensitivity C-reactive protein, tumor necrosis factor α, and interleukin 6 before and at 24 h after PCI; (ii) the incidence of major adverse cardiac events in the patients during hospitalization and 30 days of follow-up after discharge, including cardiac deaths, severe heart failure, malignant arrhythmias, and target vessel revascularization. RESULTS: Within 24 h after PCI, the incidence of PMI was significantly lower in the lipo-PGE1 group compared with that in the control group (20 vs. 36.69%, P=0.009). Although the procedure induced a significant increase in high-sensitivity C-reactive protein, tumor necrosis factor α, and interleukin 6 levels, the values were significantly lower in the lipo-PGE1 group than those in the control group at 24 h after PCI (P<0.05). The proportion of thrombolysis in myocardial infarction grade 3 in the lipo-PGE1 group was higher than that in the control group (92.72 vs. 82.56%, P=0.037). There were no significant differences between the lipo-PGE1 group and the control group in the incidence of major adverse cardiac events during hospitalization and 30 days of follow-up (2.1 vs. 4%, P=0.72). Multivariate logistic analysis showed that lipo-PGE1 was an independent protective factor against PMI (odds ratio 0.385, 95% confidence interval 0.195-0.760, P=0.006). CONCLUSION: Intravenous lipo-PGE1 can reduce the incidence of PMI following elective PCI in patients with unstable angina. The benefit of lipo-PGE1 may be associated with the effects of anti-inflammation as well as improvement in coronary microvascular perfusion.

Comparative efficacy and safety of OADs in management of GDM: network meta-analysis of randomized controlled trials.

OBJECTIVE: We conducted a network meta-analysis to evaluate the efficacy and safety of oral antidiabetic drugs (OADs) for gestational diabetes. DATA SOURCES: We searched PubMed, the Cochrane Library, ClinicalTrials.gov, and related reviews from inception to October 2014. STUDY SELECTION: We included randomized clinical trials comparing efficacy and safety between different OADs or OADs vs insulin in patients with gestational diabetes. DATA SYNTHESIS: We included 18 randomized clinical trials. Traditional and network meta-analyses were performed to compare different OADs or OADs vs insulin. Traditional meta-analyses confirmed that there was no significant difference in maternal fasting blood glucose or glycated hemoglobin levels in patients treated with insulin, metformin, and glyburide. Compared to insulin, metformin was associated with lower maternal weight gain (weighted mean difference [WMD], -1.49 kg; 95% confidence interval [CI], -2.26 to -0.31), shorter gestational age (WMD, -0.16 wk; 95% CI, -0.30 to -0.03), and increased incidence of premature birth (odds ratio [OR], 1.63; 95% CI, 1.07 to 2.48). Compared to insulin, glyburide was associated with higher neonatal birth weight (WMD, 130.68 g; 95% CI, 55.98 to 205.38), increased incidence of neonatal hypoglycemia (OR, 2.64; 95% CI, 1.59 to 4.38), and increased incidence of macrosomia (OR, 3.09; 95% CI, 1.59 to 6.04). Network meta-analysis revealed that glyburide was associated with higher maternal weight gain, higher neonatal birth weight, increased incidence of neonatal hypoglycemia, and increased incidence of macrosomia than was metformin. CONCLUSION: Both metformin and glyburide are suitable for use in the management of gestational diabetes because of good glycemic control. However, glyburide treatment is associated with increased risk of neonatal hypoglycemia, high maternal weight gain, high neonatal birth weight, and macrosomia.

[Effects of pretreatment with recombinant human B-type natriuretic peptide on infarct size in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention].

OBJECTIVES: To investigate whether the administration of recombinant human B-type natriuretic peptide (rhBNP) before primary percutaneous coronary intervention (PCI) could further limit the infract size, improve left ventricular function, and alleviate cardiac dilation in patients with acute ST-segment elevation myocardial infarction(STEMI). METHODS: A total of 93 consecutive patients presenting chest pain within 12 hours from the onset, suspicious of first STEMI located at anterior wall undergoing primary PCI, were eligible for enrollment and randomly assigned to either rhBNP group (rhBNP administration starting at 5 min before PCI, 1.5 µg/kg bolus intravenous injection followed by 0.007 5-0.03 µg·kg(-1)·min(-1) for up to 120 hours, n=48) or nitroglycerin (NIT) group (NIT treatment starting at 5 min before PCI, 10-100 µg/min intravenous infusion for 120 hours, n=45). Primary PCI was performed in both groups using post-conditioning (PC) technique. TIMI flow grade, corrected TIMI frame count, and TIMI myocardial perfusion grade were compared between the two groups at the time of infarct related artery (IRA) re-patency. The levels of serum creatine kinase MB isoenzyme (CK-MB) and troponin I (TnI) were measured. Echocardiography was performed at baseline 7 days and 6 months later. RESULTS: Baseline characteristics were similar between the two groups. The percentage of TIMI grade 3 and TIMI myocardial perfusion grade 3 after PCI both tended to be higher in rhBNP group than those in NIT group (95.8%(46/48) vs. 86.7%(39/45), P=0.162) and (72.9%(35/48) vs. 62.2%(28/45), P=0.500). The corrected TIMI frame count was significantly decreased in rhBNP group (21.0±8.7 vs. 28.2±14.8, P=0.005). The myocardial infarct size expressed as the AUC of CK-MB ((3 249±1 101) U/L vs. (4 474±1 661)U/L, P=0.010) or AUC of TnI ((3 670±942) µg/L vs. (4 541±1 098) µg/L, P=0.021) was significantly decreased in rhBNP group compared with those in NIT group. At 7 days after primary PCI, the left ventricular ejection fraction (LVEF) tended to be higher (P>0.05), while the E/e' index and wall motion score index (WMSI) ((11.95±3.31 vs. 14.60±4.09, P=0.030) and (1.74±0.17 vs. 2.40±0.55, P<0.001)) were significantly improved in rhBNP group compared with those in NIT group. BNP level was also significantly lower in rhBNP group compared that in NIT group ((68.3±37.8) ng/L vs. (129.4±64.4) ng/L, P<0.001). During 6-month follow-up, LVEF and WMSI were significantly improved in rhBNP group compared those in NIT group(51.7%±12.7% vs. 46.9%±9.6%, P=0.024 and 1.69±0.35 vs. 1.92±0.47, P=0.020). CONCLUSION: Administration of rhBNP before PCI with post-conditioning procedure can further improve myocardial perfusion, limit myocardial infarct size, ameliorate cardiac dysfunction and postpone left ventricular early-stage and long-term remodeling in STEMI patients undergoing primary PCI.

Risk of fracture with thiazolidinediones: an updated meta-analysis of randomized clinical trials.

OBJECTIVE: The use of thiazolidinediones (TZDs) has been associated with increased fracture risk. We performed a comprehensive literature review and meta-analysis to estimate the risk of fractures with TZDs METHODS: We searched MEDLINE, Embase and the Cochrane Database, from inception to May 2014. We included all randomized trials that described the risk of fractures or changes in bone mineral density (BMD) with TZDs. We pooled data with odds ratios (ORs) for fractures and the weighted mean difference in BMD. To assess heterogeneity in results of individual studies, we used Cochran's Q statistic and the I(2) statistic. RESULTS: We included 24,544 participants with 896 fracture cases from 22 randomized controlled trials. Meta-analysis showed that the significantly increased incidence of fracture was found in women (OR=1.94; 95%CI: 1.60-2.35; P<0.001), but not in men (OR=1.02; 95%CI: 0.83-1.27; P=0.83). For women, the fracture risk was similar in rosiglitazone (OR=2.01; 95%CI: 1.61-2.51; P<0.001) and pioglitazone (OR=1.73; 95%CI: 1.18-2.55; P=0.005) treatment and appeared to be similar for participants aged <60years old (OR=1.89; 95%CI: 1.51-2.36; P<0.001) and aged ≥60years old (OR=2.07; 95%CI: 1.51-2.36; P<0.001). There was a non-significant trend towards increased risk of fractures in different cumulative durations of TZD exposure. TZD treatment was also associated with significant changes in BMD among women at the lumbar spine(weighted mean difference: -0.49%, 95%CI: -0.66% to -0.32%; P<0.001), the femoral neck (weighted mean difference: -0.34%, 95%CI: -0.51% to -0.16%; P<0.001) and the hip(weighted mean difference: -0.33%, 95%CI: -0.52% to -0.14%; P<0.001). CONCLUSIONS: Our results suggest that TZD treatment is associated with an increased risk of fractures in women, effects of rosiglitazone and pioglitazone are similar, fracture risk is independent of age and fracture risk has no clear association with duration of TZD exposure.

Safety and feasibility of transulnar versus transradial artery approach for coronary catheterization in non-selective patients.

BACKGROUND: Transradial approach catheterization is now widely used in coronary angiography and angioplasty. The ulnar artery, which is one of the two terminal branches of the brachial artery, may be a potential approach for cardiac catheterization. The aim of this study was to evaluate the safety and feasibility of a transulnar approach for coronary catheterization in non-selective patients. METHODS: A total of 535 consecutive patients were randomly assigned to transulnar approach (TUA) group (n = 271) or transradial approach (TRA) group (n = 264) upon arrival at the catheterization laboratory. Allen's test and inverse Allen's test were not routinely performed. Ultrasound-Doppler assessment of the forearm artery was performed before the procedure, two days after the procedure, and 30 days after the procedure. The primary endpoints of study were the rate of successful artery cannulation and the access-site related complications. The secondary endpoints included the number of needle punctures, total time for the procedure, and major adverse cardiac events (MACE). RESULTS: Successful puncture of the objective artery was obtained in 91.5% of the patients in the TUA group, and 95.1% of the patients in the TRA group (P > 0.05). There was no significant difference in hematoma complications between the two groups (7.7% vs. 4.2%, P = 0.100). A motor abnormality of the hand was observed in one patient in the TUA group. There were no arteriovenous fistula or pseudoaneurysm observed in our study. Three (1.1%) patients in the TUA group and 8 (3.0%) patients in the TRA group had occlusion of the access artery (P = 0.137), but none of the patients had symptoms or signs of hand ischemia. There were no significant differences in MACE between the two groups during follow-up. CONCLUSION: The transulnar approach is an effective and safe technique for coronary catheterization in non-selective patients.

Thrombolysis Followed by Early Percutaneous Coronary Intervention via Transradial Artery Approach in Patients with ST-Segment Elevation Infarction.

BACKGROUND: The purpose of this study was to investigate the safety and efficacy of thrombolysis followed by early percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: A total of 161 patients were enrolled in the study. Fifty-three of them who underwent thrombolysis in non-PCI hospital and immediately transferred to receive early PCI were assigned to the early PCI group (E-PCI); the rest of the patients were assigned to the primary PCI group (P-PCI). Coronary angiography and PCI were performed via the transradial artery approach for patients in both groups. Angiographic parameters, bleeding complications and total hospital stay were compared between the two groups. All patients were followed-up for 30 days to evaluate major adverse cardiac events (MACE). RESULTS: Before PCI procedure, the thrombus score of IRA in the E-PCI group was lower, and the percentage of TIMI flow grade (TFG) 3 was higher (both p < 0.05) compared to those in the P-PCI group. The myocardial reperfusion in the E-PCI group was better than that in the P-PCI group. There was a trend towards a lower peak value of serum creatine kinase MB in the E-PCI group, and left ventricular ejection fraction (LVEF) before discharge in E-PCI was higher than that in the P-PCI group (54.38 ± 5.29% vs. 52.19 ± 7.00%, respectively, p = 0.028). No significant differences were found in the incidences of bleeding complications and hospital stay between the two groups. There was no significant difference in the 30-day MACE between the two groups (p = 0.863), and no significance of cumulative MACE-free survival rates were found between the two groups as well (p = 0.522). Variables predicting MACE upon patient follow-up according to univariable Cox regression analyses showed that a history of hyperlipidemia, smokers, TFG of infarction related artery before PCI < 2, and low levels of LVEF were associated with poor clinical outcomes (all p < 0.05). CONCLUSIONS: It is safe and efficacious for STEMI patients to receive thrombolysis followed by early PCI via the transradial artery approach. KEY WORDS: Major adverse cardiac event; Percutaneous coronary intervention; Radial artery; ST-segment elevation myocardial infarction; Thrombolysis.