Percutaneous coronary intervention vs . medical therapy in patients on dialysis with coronary artery disease in China.

BACKGROUND: The available evidence regarding the benefits of percutaneous coronary intervention (PCI) on patients receiving dialysis with coronary artery disease (CAD) is limited and inconsistent. This study aimed to evaluate the association between PCI and clinical outcomes as compared with medical therapy alone in patients undergoing dialysis with CAD in China. METHODS: This multicenter, retrospective study was conducted in 30 tertiary medical centers across 12 provinces in China from January 2015 to June 2021 to include patients on dialysis with CAD. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Secondary outcomes included all-cause death, the individual components of MACE, and Bleeding Academic Research Consortium criteria types 2, 3, or 5 bleeding. Multivariable Cox proportional hazard models were used to assess the association between PCI and outcomes. Inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) were performed to account for potential between-group differences. RESULTS: Of the 1146 patients on dialysis with significant CAD, 821 (71.6%) underwent PCI. After a median follow-up of 23.0 months, PCI was associated with a 43.0% significantly lower risk for MACE (33.9% [ n  = 278] vs . 43.7% [ n  = 142]; adjusted hazards ratio 0.57, 95% confidence interval 0.45-0.71), along with a slightly increased risk for bleeding outcomes that did not reach statistical significance (11.1% vs . 8.3%; adjusted hazards ratio 1.31, 95% confidence interval, 0.82-2.11). Furthermore, PCI was associated with a significant reduction in all-cause and cardiovascular mortalities. Subgroup analysis did not modify the association of PCI with patient outcomes. These primary findings were consistent across IPTW, PSM, and competing risk analyses. CONCLUSION: This study indicated that PCI in patients on dialysis with CAD was significantly associated with lower MACE and mortality when comparing with those with medical therapy alone, albeit with a slightly increased risk for bleeding events that did not reach statistical significance.

Efficacy and safety of omega-3-acid ethyl acetate 90 capsules in severe hypertriglyceridemia: A randomized, controlled, multicenter study.

Omega-3-acid ethyl acetate 90 capsules (containing 465 mg of eicosapentaenoic acid and 375 mg docosahexaenoic acid) is composed of highly purified omega-3 polyunsaturated fatty acid (PUFA) ethyl esters, whose lipid-lowering effect for severe hypertriglyceridemia (HTG) treatment is unclear. This study aimed to evaluate the efficacy and safety of omega-3-acid ethyl acetate 90 capsules in patients with severe HTG. In this randomized, double-blind, placebo-controlled, multicenter study, 239 patients with severe HTG were enrolled and randomized (1:1) into omega-3 group (N = 122) and placebo group (N = 117) to receive 12-week corresponding treatments. Lipid-related indexes were obtained at treatment initiation (W0), 4 weeks (W4), W8, and W12 after treatment. Adverse events and adverse drug reactions were recorded. Triacylglycerols (TAG), total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C), very-low-density lipoprotein cholesterol (VLDL-C), and apolipoprotein C-III (Apo C-III) at W4, W8, and W12 were decreased in the omega-3 group versus the placebo group (all p < 0.05). Moreover, the percentage changes of TAG, TC, non-HDL-C, and VLDL-C from W0 to W4, W8, and W12, and the percentage change of Apo C-III from W0 to W4 and W8, were more obvious in the omega-3 group compared with the placebo group (all p < 0.05). However, no difference was observed in the percentage changes of HDL-C, low-density lipoprotein cholesterol (LDL-C), and LDL-C/HDL-C ratio during follow-up between groups (all p > 0.05). Additionally, there was no discrepancy in adverse events and adverse drug reactions between groups (all p > 0.05). Omega-3-acid ethyl acetate 90 capsules exhibit satisfied lipid-lowering effect with tolerable safety profile in patients with severe HTG.

Efficacy and Safety of Ongericimab in Chinese Patients With Primary Hypercholesterolemia and Mixed Dyslipidemia.

BACKGROUND: A phase 3 trial was conducted to evaluate the efficacy and safety of ongericimab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9, as an add-on treatment to optimized lipid-lowering therapy in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia. METHODS AND RESULTS: A total of 806 patients who were receiving stable and optimized lipid-lowering therapy but did not achieve their low-density lipoprotein cholesterol (LDL-C) targets were enrolled and randomly assigned in a 2:1:2:1 ratio to receive either ongericimab 150 mg or matching placebo every 2 weeks, or ongericimab 300 mg or matching placebo every 4 weeks for 52 weeks. Efficacy and safety were evaluated in 802 patients who received at least 1 dose of ongericimab or placebo. The primary end point was the percentage change in LDL-C from baseline to week 24. Our findings demonstrated that the least-squares mean difference of percentage change in LDL-C from baseline to week 24 was -67.7% (95% CI, -72.5% to -63.0%; P<0.0001) in the ongericimab 150 mg every 2 weeks group compared with the placebo every 2 weeks group, and -61.2% (95% CI, -67.1% to -55.2%; P<0.0001) in the ongericimab 300 mg every 4 weeks group compared with the placebo every 4 weeks group. These reductions were sustained up to week 52. Furthermore, treatment with ongericimab favorably altered other lipid parameters. A similar incidence of adverse events was observed in the ongericimab and placebo groups. CONCLUSIONS: Ongericimab, as an add-on treatment to optimized lipid-lowering therapy, significantly reduced LDL-C and was well-tolerated in Chinese patients with primary hyperlipidemia and mixed dyslipidemia who did not achieve their LDL-C targets. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04781114.

A nonlinear correlation between the serum uric acid to creatinine ratio and the prevalence of hypertension: a large cross-sectional population-based study.

OBJECTIVE: To explore the relationship between the serum uric acid to creatinine (UA/Cr) ratio and the prevalence of hypertension. METHODS: In this cross-sectional study, we included 8571 individuals from the China Health and Nutrition Survey. Logistic regression analysis and restricted cubic spline (RCS) were used to analyze the relationship between the UA/Cr ratio and hypertension. RESULTS: Compared with individuals without hypertension, individuals with hypertension had higher UA/Cr ratios. Multivariate logistic regression analysis showed that a higher UA/Cr ratio was closely related to a higher risk of hypertension (as a continuous variable, OR: 1.054, 95% CI: 1.014-1.095, p = 0.007; as a categorical variable, Q3 vs. Q1, OR: 1.183, 95% CI: 1.011-1.384, p = 0.035; Q4 vs. Q1, OR: 1.347, 95% CI: 1.146-1.582, p < 0.001). Subgroup analysis revealed that the correlation between the UA/Cr ratio and hypertension risk was stable in all subgroups except for the subgroup with diabetes and the subgroup with a BMI ≥ 28 kg/m2 (p < 0.05). Sensitivity analysis confirmed the robustness of the relationship between a higher UA/Cr ratio and a higher risk of hypertension (p < 0.05). The RCS showed that the UA/Cr ratio was nonlinearly related to hypertension risk. Further threshold effect showed that only a UA/Cr ratio less than 5.0 was related to hypertension risk (OR: 1.178, 95% CI: 1.086-1.278, p < 0.001), and the 2-piecewise linear regression model was superior to the 1-line linear regression model (p < 0.05). CONCLUSION: The UA/Cr ratio was associated with the prevalence of hypertension.

Efficacy and safety of single-pill amlodipine/losartan versus losartan in patients with inadequately controlled hypertension after losartan treatment: a multicenter, double-blind, randomized phase III clinical trial.

Objective: Single-pill amlodipine besylate (AML) plus losartan (LOS) has been used to treat inadequately controlled hypertension after antihypertensive monotherapy; however, relevant data in China are limited. This study aimed to compare the efficacy and safety of single-pill AML/LOS and LOS alone in Chinese patients with inadequately controlled hypertension after LOS treatment. Methods: In this multicenter, double-blind, randomized, controlled phase III clinical trial, patients with inadequately controlled hypertension after 4 weeks of LOS treatment were randomized to receive daily single-pill AML/LOS (5/100 mg, AML/LOS group, N = 154) or LOS (100 mg, LOS group, N = 153) tablets for 8 weeks. At weeks 4 and 8 of treatment, sitting diastolic and systolic blood pressure (sitDBP and sitSBP, respectively) and the BP target achievement rate were assessed. Results: At week 8, the sitDBP change from baseline was greater in the AML/LOS group than in the LOS group (-8.84 ± 6.86 vs. -2.65 ± 7.62 mmHg, P < 0.001). In addition, the AML/LOS group also showed greater sitDBP change from baseline to week 4 (-8.77 ± 6.60 vs. -2.99 ± 7.05 mmHg) and sitSBP change from baseline to week 4 (-12.54 ± 11.65 vs. -2.36 ± 10.33 mmHg) and 8 (-13.93 ± 10.90 vs. -2.38 ± 12.71 mmHg) (all P < 0.001). Moreover, the BP target achievement rates at weeks 4 (57.1% vs. 25.3%, P < 0.001) and 8 (58.4% vs. 28.1%, P < 0.001) were higher in the AML/LOS group than those in the LOS group. Both treatments were safe and tolerable. Conclusion: Single-pill AML/LOS is superior to LOS monotherapy for controlling BP and is safe and well tolerated in Chinese patients with inadequately controlled hypertension after LOS treatment.

Optimal treatment for post-MI heart failure in rats: dapagliflozin first, adding sacubitril-valsartan 2 weeks later.

Background: Based on previous research, both dapagliflozin (DAPA) and sacubitril-valsartan (S/V) improve the prognosis of patients with heart failure (HF). Our study aims to investigate whether the early initiation of DAPA or the combination of DAPA with S/V in different orders would exert a greater protective effect on heart function than that of S/V alone in post-myocardial infarction HF (post-MI HF). Methods: Rats were randomized into six groups: (A) Sham; (B) MI; (C) MI + S/V (1st d); (D) MI + DAPA (1st d); (E) MI + S/V (1st d) + DAPA (14th d); (F) MI + DAPA (1st d) + S/V (14th d). The MI model was established in rats via surgical ligation of the left anterior descending coronary artery. Histology, Western blotting, RNA-seq, and other approaches were used to explore the optimal treatment to preserve the heart function in post-MI HF. A daily dose of 1 mg/kg DAPA and 68 mg/kg S/V was administered. Results: The results of our study revealed that DAPA or S/V substantially improved the cardiac structure and function. DAPA and S/V monotherapy resulted in comparable reduction in infarct size, fibrosis, myocardium hypertrophy, and apoptosis. The administration of DAPA followed by S/V results in a superior improvement in heart function in rats with post-MI HF than those in other treatment groups. The administration of DAPA following S/V did not result in any additional improvement in heart function as compared to S/V monotherapy in rats with post-MI HF. Our findings further suggest that the combination of DAPA and S/V should not be administered within 3 days after acute myocardial infarction (AMI), as it resulted in a considerable increase in mortality. Our RNA-Seq data revealed that DAPA treatment after AMI altered the expression of genes related to myocardial mitochondrial biogenesis and oxidative phosphorylation. Conclusions: Our study revealed no notable difference in the cardioprotective effects of singular DAPA or S/V in rats with post-MI HF. Based on our preclinical investigation, the most effective treatment strategy for post-MI HF is the administration of DAPA during the 2 weeks, followed by the addition of S/V to DAPA later. Conversely, adopting a therapeutic scheme whereby S/V was administered first, followed by later addition of DAPA, failed to further improve the cardiac function compared to S/V monotherapy.

A five-parameter score for predicting saphenous vein graft degenerative and/or occlusive disease in recurring ischemic symptoms after one year post coronary artery bypass grafting.

BACKGROUND: The recurrence rate of ischemic symptoms after coronary artery bypass grafting (CABG) is increasing in recent years. How to prevent and treat saphenous vein graft disease (SVGD [symptomatic ⩾50% stenosis in at least one Saphenous vein graft]) has been a clinical challenge to date. Different pathogenesis may exist in SVGD of different periods. There are currently few available scores for estimating the risk of SVGD after one year post CABG. OBJECTIVE: We sought to develop and validate a simple predictive clinical risk score for SVGD with recurring ischemia after one year post CABG. METHODS AND RESULTS: This was a cross-sectional study and the results were validated using bootstrap resampling on a separate cohort. A nomogram and risk scoring system were developed based on retrospective data from a training cohort of 606 consecutive patients with recurring ischemia >1 year after CABG. Logistic regression model was used to find the predictive factors and to build a nomogram. To assess the generalization, models were validated using bootstrap resampling and an external cross-sectional study of 187 consecutive patients in four other hospitals. In multivariable analysis of the primary cohort, native lesion vessel number, SVG age, recurring ischemia type, very low-density lipoprotein level, and left ventricular end-diastolic diameter were independent predictors. A summary risk score was derived from nomogram, with a cut-off value of 15. In internal and external validation, the C-index was 0.86 and 0.82, indicating good discrimination. The calibration curve for probability of SVGD showed optimal agreement between actual observations and risk score prediction. CONCLUSION: A simple-to-use risk scoring system based on five easily variables was developed and validated to predict the risk of SVGD among patients who recurring ischemia after one year post CABG. This score may be useful for providing patients with individualized estimates of SVGD risk.

Rutin alleviates cardiomyocyte injury induced by high glucose through inhibiting apoptosis and endoplasmic reticulum stress.

Diabetic cardiomyopathy is a common complication of diabetes, in which endoplasmic reticulum stress (ERS) serves an important role. Rutin can treat the myocardial dysfunction of diabetic rats. However, to the best of our knowledge, studies on the effects of Rutin on myocardial injury caused by diabetes from the perspective of ERS have not previously been reported. In the present study, the role of rutin in the regulation of ERS in myocardial injury was assessed. Different high glucose concentrations were used to treat H9C2 myoblast cells to establish a myocardial damage model. A cell counting kit-8 assay was used to determine cell viability. A lactate dehydrogenase kit was used to detect cytotoxicity. Apoptosis levels were determined using a TUNEL assay. Western blotting was used to determine the expression levels of apoptosis-related proteins and ERS-related proteins, including heat shock protein A family member 5, inositol-requiring enzyme-1α, X-box binding protein 1, activating transcription factor 6, C/EBP-homologous protein (CHOP), cleaved caspase-12 and caspase-12. The anti-apoptotic and anti-ERS effects of Rutin on H9C2 cardiac cells induced by high glucose were examined after the administration of the ERS activator thapsigargin (TG). The results indicated that rutin could dose-dependently inhibit the level of apoptosis and ERS induced by high glucose in H9C2 cells. After administration of the ERS activator TG, it was demonstrated that TG could reverse the anti-apoptotic and anti-ERS effects of rutin on H9C2 cells stimulated with high glucose. Collectively, the present results suggested that rutin may alleviate cardiomyocyte model cell injury induced by high glucose through the inhibition of apoptosis and ERS.

Analysis of individualized antiplatelet therapy for patients of acute coronary syndrome after percutaneous coronary intervention under the guidance of platelet function: A one-center retrospective cohort study.

ABSTRACT: There is controversy in clinical application of antiplatelet drugs by monitoring platelet function. Therefore, we explored whether early and dynamic medication could bring better clinical outcomes for patients under the guidance of platelet function tests (PFT).In this retrospective cohort study, we analyzed the prognostic events of 1550 patients with acute coronary syndrome (ACS) at Tianjin People's Hospital in China. They received dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) from January 2017 to December 2018. The primary endpoint was based on the Bleeding Academic Research Consortium (BARC) 3 or 5 major bleeding. Secondary endpoints included MACCE (all-cause death, nonfatal myocardial infarction, stroke, stent thrombosis, and unplanned target vessel reconstruction) and BARC 1 to 2 minor bleeding. The endpoint events within 1 year after PCI were recorded. Patients were divided into a guided group and a control group according to the drug adjustment by PFT results. After the propensity scores matched, the end points of 2 groups were compared, and subgroup analysis was performed on major bleeding events.After propensity score matching, there were 511 cases in the guided group and the control group, respectively. The primary endpoint events occurred in 10 patients (1.96%) in the guided group and 23 patients (4.5%) in the control group (HR: 0.45; 95% CI, 0.21-0.95; P = .037). After the guided group adjusted drug doses, the risk of major bleeding was lower than standard DAPT of the control group. Although some patients in the guided group reduced doses earlier, the incidence of MACCE events did not increase in the guided group compared with the control group (4.89% vs 6.07%; P = .41). There was no statistical difference in BARC 1 to 2 minor bleeding (P = .22). Subgroup analysis showed that PFT was more effective in patients with diabetes and multivessel disease.Early observation of dynamic PFT in ACS patients after PCI can guide individualized antiplatelet therapy to reduce the risk of major bleeding without increasing the risk of ischemia.

A study of the sequential treatment of acute heart failure with sacubitril/valsartan by recombinant human brain natriuretic peptide: A randomized controlled trial.

ABSTRACT: This study aimed to investigate the effects of the basic treatment for heart failure and sequential treatment with rh-brain natriuretic peptide (rhBNP) alone or the combination of rhBNP and sacubitril/valsartan. Cardiac structure, pulmonary artery pressure, inflammation and oxidative stress in patients with acute heart failure were evaluated.Three hundred patients with acute heart failure were included. According to the random number table method, the patients were divided into 3 groups of 100 patients per group: the standard treatment group (treated with an angiotensin-converting enzyme inhibitor, ß receptor blocker, and corticosteroid antagonist), rhBNP group (basic treatment combined with rhBNP) and sequential treatment group (basic treatment for heart failure combined with rhBNP followed by sacubitril/valsartan). The changes in NT-probrain natriuretic peptide (BNP) levels, cardiac troponin T (cTnT) levels, cardiac structure, pulmonary artery pressure, and the levels inflammatory factors and oxidative stress factors were compared among the 3 groups at 1, 4, 12, and 36 weeks after treatment.The sequential treatment group displayed superior outcomes than the standard treatment group and the rhBNP group in terms of left atrium diameter, left ventricular end diastolic volume, left ventricular ejection fraction, pulmonary artery pressure, NT-proBNP levels, and cTnT levels, which respond to damage to the heart structure and myocardium. This result may be related to the decreased levels of inflammatory factors and the correction of oxidative stress imbalance.Sacubitril/valsartan significantly reduce the serum levels of inflammatory factors in patients with acute heart failure while decreasing the levels of oxidizing factors and increasing the levels of antioxidant factors. These changes may be one of the explanations for the better cardiac structure and better pulmonary artery pressure observed in the sequential treatment group.

A randomized comparison of two paclitaxel-coated balloons for the treatment of in-stent restenosis: The LONGTY ISR China randomized trial (LONGTY DCB vs. SeQuent Please DCB).

OBJECTIVES: This study sought to compare the efficacy and clinical safety of the LONGTY drug-coated balloon (DCB) with those of SeQuent Please DCB in patients with in-stent restenosis (ISR). BACKGROUND: Although DCB technologies have evolved, little is known about the clinical efficacy of the new-generation LONGTY DCB. METHODS: This was a prospective, multicenter, randomized, noninferiority trial comparing LONGTY DCB with SeQuent Please DCB in patients with ISR. The primary endpoint was target lesion late lumen loss at 9 months' follow-up. RESULTS: A total of 211 patients with ISR from 13 Chinese sites were included (LONGTY DCB, n = 105; SeQuent Please DCB, n = 106). Device success was achieved in all patients. At the 9 month angiographic follow-up, target lesion late lumen loss was 0.35 ± 0.42 mm with LONGTY and 0.38 ± 0.45 mm with SeQuent Please (p for noninferiority <.001). The target lesion revascularization rates at 1 year were similar in both DCB groups (15.24 vs. 13.21%; p = .673). Over an extended follow-up of 2 years, the clinical endpoints, including cardiac death, myocardial infarction, and thrombus rate, were extremely low and similar in both groups. CONCLUSIONS: In this multicenter, head-to-head, randomized trial, the new-generation LONGTY DCB was noninferior to the SeQuent Please DCB for the primary endpoint of target lesion late lumen loss at 9 months.

Optimization of GRACE Risk Stratification by N-Terminal Pro-B-type Natriuretic Peptide Combined With D-Dimer in Patients With Non-ST-Elevation Myocardial Infarction.

We aimed to explore the utility of multiple biomarkers with GRACE risk stratification for non-ST-elevation myocardial infarction (NSTEMI). A total of 1,357 patients diagnosed with NSTEMI were enrolled in this study at multiple medical centers in Tianjin, China. The outcomes were 1-year all-cause death and major adverse cardiac events (MACE: all-cause death, hospital admission for unstable angina, hospital admission for heart failure, nonfatal recurrent myocardial infarction, and stroke). C-index, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were calculated to verify that the biomarkers improve the predictive accuracy of the GRACE score. A total of 57 participants died, while 211 participants experienced 231 MACEs during follow-up (mean: 339 days). For all-cause death, the combination of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and D-dimer improved the predictive accuracy of GRACE the most, with C-index, IDI, and NRI values of 0.88, 0.085, and 1.223, respectively. For MACE, trigeminal combination of NT-proBNP, fibrinogen, and D-dimer resulted in C-index, IDI, and NRI values of 0.80, 0.079, and 0.647, respectively. As a result, NT-proBNP, D-dimer, fibrinogen, and GRACE comprise a new scoring system for assessing 1-year clinical events. Kaplan-Meier analysis revealed a significant increase in 1-year mortality (score ≥3.85 vs <3.85, p < 0.0001) and 1-year MACE (score ≥1.72 vs <1.72, p < 0.0001) between different score groups. In conclusion, the combination of NT-proBNP and D-dimer added prognostic value to GRACE for all-cause death. Combining NT-proBNP, fibrinogen, and D-dimer increased the prognostic value of GRACE for MACE. This newly developed scoring system is strongly correlated with all-cause mortality and MACE, and can be easily utilized in clinical practice.

Chlorogenic acid prevents acute myocardial infarction in rats by reducing inflammatory damage and oxidative stress.

Recent studies have suggested that the prevention of myocardial infarction (MI) through diet is very important and that the intake of polyphenol-rich foods can improve cardiovascular health. In this study, adult male SD rats were randomly divided into 2 groups. The chlorogenic acid (CGA) group (n = 18) was administered 100 mg/kg/day CGA by gavage, and the control (CON) group (n = 18) was given the equivalent volume of water for 4 weeks. A model of MI was established by ligating the left anterior descending (LAD) coronary artery, which was monitored by an electrocardiogram (ECG). Blood samples were analyzed by enzyme-linked immunosorbent assays and biochemical experiments 24 h after the operation. In addition, histopathological analysis was performed to assess the size and severity of the infarct area. The administration of CGA before MI minimized weight gain and was associated with decreased postoperative mortality. CGA moderated the coronary artery ligation-induced changes observed by ECG and decreased the plasma levels of the myocardial markers. In the histopathological analysis, CGA notably reduced infarct size and decreased myocardial injury and fibrosis. Furthermore, CGA significantly reduced the levels of pro-inflammatory factors, and this reduction was accompanied by an upregulation of anti-inflammatory cytokines and an increase in antioxidant enzyme activities. This study indicated that CGA improved the survival rate after MI and demonstrated that CGA had a protective effect on MI by reducing the inflammatory response and exerting antioxidant activity.

A phase 3 double-blind randomized (CONSORT-compliant) study of azilsartan medoxomil compared to valsartan in Chinese patients with essential hypertension.

BACKGROUND: Azilsartan medoxomil (AZL-M), an angiotensin II receptor blocker, has a well-characterized efficacy and safety profile in patients with hypertension. AZL-M is approved for use in over 40 countries globally; however, it is not yet approved in China. Therefore, a phase 3 registration study to assess the efficacy (antihypertensive effect), safety, and tolerability of AZL-M compared with valsartan in Chinese patients with essential hypertension was undertaken. METHODS: This multicenter, double-blind, randomized, 8-week phase 3 study compared AZL-M with valsartan in Chinese patients aged ≥18 years with essential hypertension. Endpoints included change from baseline to week 8 in trough sitting clinic systolic blood pressure (scSBP) and ambulatory blood pressure monitoring parameters. RESULTS: Overall, 612 patients (mean age, 57.1 years; 57.5% male) were randomized to AZL-M 80 mg (n = 209), AZL-M 40 mg (n = 199), or valsartan 160 mg (n = 204). Baseline mean scSBP was similar in all groups (157.9-158.5 mm Hg). The mean reduction in trough scSBP from baseline to week 8 was significantly greater with AZL-M 80 mg than with valsartan (-24.2 vs -20.6 mm Hg; P = .010), and noninferior with AZL-M 40 mg versus valsartan (-22.5 vs -20.6 mm Hg; P = .184). Mean reduction in 24-hour mean systolic blood pressure (n = 257) was significantly greater with both AZL-M 80 mg (-17.0 mm Hg; P < .001) and AZL-M 40 mg (-14.7 mm Hg; P = .014) than with valsartan (-9.4 mm Hg). Treatment-emergent adverse events had similar incidence (52.8%-56.5%) across the treatment groups and were generally mild or moderate. Dizziness was the most frequent treatment-related treatment-emergent adverse events (AZL-M 80 mg, 1.9%; AZL-M 40 mg, 1.5%; valsartan, 1.0%). The safety and tolerability of AZL-M were comparable with valsartan. CONCLUSIONS: AZL-M was noninferior to valsartan at the 40-mg dose and superior to valsartan at the 80-mg dose in reducing trough scSBP, and showed acceptable safety-consistent with the AZL-M safety profile in other populations-in Chinese adults with hypertension. TRIAL REGISTRATION NUMBER: NCT02480764.

Evaluation of the inhibition of chlorophenols towards human cytochrome P450 3A4 and differences among various species.

Chlorophenols (CPs) are important pollutants detected frequently in the environment. This study intended to detect the inhibitory effects of fourteen CPs (2-CP, 3-CP, 4-CP, 4C2AP, 4C3MP, 2.4-DCP, 2.3.4-TCP, 2.4.5-TCP, 2.4.6-TCP, 3.4.5-TCP, 2.3.4.5-TECP, 2.3.4.6-TECP, 2.3.5.6-TECP and PCP) towards human liver cytochrome P450 3A4 (CYP3A4). Throughout the tests, testosterone was used as the probe substrate and CPs were used as inhibitors. A series of experiments (enzyme activity assays, preliminary screening tests, inhibition kinetics determination) were conducted to determine the inhibition of CPs towards human liver CYP3A4. CPs with the inhibitory effect >80% were selected for the inhibition evaluation in liver microsomes from different animal species (monkey, rat, dog, pig). The results showed that 2.3.4-TCP, 3.4.5-TCP, and 2.3.4.5-TECP inhibited the activities of CYP3A4 by 80.3%, 93.4%, 91.6%, respectively. Inhibition kinetics type were non-competitive and inhibition kinetics constant (Ki) values were 26.4 µM, 13.5 µM, and 8.8 µM for the inhibition of 2.3.4-TCP, 3.4.5-TCP, and 2.3.4.5-TECP towards human CYP3A4, respectively. Inhibition kinetics type was competitive and Ki value was 4.9 µM for the inhibition of 2.3.4-TCP towards CYP3A4 in Monkey liver microsomes (MyLMs). Inhibition kinetic types were non-competitive and Ki values were 8.1 µM and 28.7 µM for the inhibition of 3.4.5-TCP and 2.3.4.5-TECP towards CYP3A4 in MyLMs. Inhibition kinetic types were non-competitive and Ki values were 13.8 µM, 0.6 µM, and 6.1 µM for the inhibition of 2.3.4-TCP, 3.4.5-TCP, and 2.3.4.5-TECP towards CYP3A4 in Dog liver microsomes (DLMs), respectively. By comparing Ki values and inhibition kinetic types, the dog was the most suitable model to assess the inhibition of 2.3.4-TCP and 2.3.4.5-TECP towards CYP3A4, and monkey was the most suitable model to assess the inhibition of 3.4.5-TCP towards CYP3A4. In conclusion, our recent study on the inhibition of CPs towards CYP3A4 and species differences was important for further toxicological studies of CPs in human bodies.

ODYSSEY EAST: Alirocumab efficacy and safety vs ezetimibe in high cardiovascular risk patients with hypercholesterolemia and on maximally tolerated statin in China, India, and Thailand.

BACKGROUND: The proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab significantly reduces low-density lipoprotein cholesterol (LDL-C). OBJECTIVE: This study (ODYSSEY EAST) assessed the efficacy and safety of alirocumab vs ezetimibe in high cardiovascular risk patients from Asia. METHODS: Patients (n = 615) from China, India, and Thailand with hypercholesterolemia at high cardiovascular risk on maximally tolerated statin were randomized (2:1) to alirocumab (75 mg every 2 weeks [Q2W]; with dose increase to 150 mg Q2W at week 12 if week 8 LDL-C was >1.81 mmol/L [>70 mg/dL]) or ezetimibe (10 mg daily) for 24 weeks. The primary efficacy endpoint was percentage change in calculated LDL-C from baseline to week 24. Safety was assessed throughout. RESULTS: Baseline data were similar in both groups. LDL-C levels were reduced from baseline to week 24 by 56.0% and 20.3% in the alirocumab and ezetimibe groups, respectively (P < .0001 vs ezetimibe). Overall, 18.8% of alirocumab-treated patients received a dose increase to 150 mg Q2W. At week 24, 85.1% of alirocumab-treated and 40.5% of ezetimibe-treated patients reached LDL-C <1.81 mmol/L (<70 mg/dL, P < .0001 vs ezetimibe). Treatment-emergent adverse events occurred in 68.5% of alirocumab-treated and 63.1% of ezetimibe-treated patients, with upper respiratory tract infection the most common (alirocumab: 13.3%; ezetimibe: 14.1%). Injection-site reactions occurred more frequently in alirocumab-treated patients (2.7%) than in ezetimibe-treated patients (1.0%). CONCLUSIONS: Alirocumab significantly reduced LDL-C vs ezetimibe in high cardiovascular risk patients from Asia and was generally well tolerated. These findings are consistent with previous ODYSSEY studies.

Comparison of the effect of recombinant human pro-urokinase and tirofiban on myocardial blood flow perfusion in ST elevation myocardial infarction patients receiving primary percutaneous coronary intervention: A one-center retrospective observational study.

Ischemia/reperfusion (I/R) injury is associated with primary percutaneous coronary intervention (PPCI). The current study was performed to compare the effect of tirofiban and recombinant human pro-urokinase (rh-proUK) on the improvement of coronary slow blood after PPCI.Sixty-five ST elevation myocardial infarction (STEMI) patients treated with rh-proUK and an equal number treated with tirofiban after PPCI were employed in the current study. The clinicopathological information regarding the biochemical parameters, thrombolysis in myocardial infarction (TIMI) grade, hemodynamics parameters, thrombus core (TS), sum-STR, left ventricular ejection fraction (LVEF), blood routine parameters, high-sensitivity C-reactive protein (CRP) level, uric acid, hepatorenal function, electrocardiogram (ECG), and echocardiography before and after the interventions were collected. The differences in those parameters between the 2 groups then compared with assess the treatment effect and side effects associated with the both therapies.The results showed that the TIMI level post-intervention (P = .03), the proportion of TIMI myocardial perfusion grade level III (P = .04), the changes in thrombus score (P < .001) in rh-proUK group were significantly higher than those in tirofiban group while the corrected TIMI Frame Count (CTFC) (P = .02), the incidence of slow flow (P = .02), the thrombus score post-intervention (P < .001), the stent length (P = .02), and the number of receiving administration of sodium nitroprusside (P = .01) were significantly lower than those in tirofiban group. Moreover, the levels of CK (P < .001), CK-MB (P = .01), and NT-proBNP 24-hour post-intervention (P < .02) were significantly lower in rh-proUK group than those in tirofiban group and the sum-STR right after the intervention (P < .03) of rh-proUK group was significantly higher than that of tirofiban group. No significant difference was detected between the 2 therapies regarding major adverse cardiac events (MACE).The findings outlined in the current study showed that the improvement effect of rh-proUK on blood flow condition was stronger right after the intervention and the therapy had a similar safety when compared with tirofiban during a 30-day follow-up.

Atractylodesin III maintains mitochondrial function and inhibits caspase-3 activity to reverse apoptosis of cardiomyocytes in AMI rats.

The aim of the present study was to analyze the effects of Atractylodesin III (codonopsis pilosula) extract that maintains mitochondrial function, up-regulates Bcl-2, inhibits Caspase-3 activity, and ultimately leads to cardiomyocyte apoptosis in a rat model of acute myocardial infarction (AMI). 30 male Sprague-Dawley rats aged 6 months, weighed 150-200 g were randomly divided into sham operation group (SOG), model group (MG) and intervention group (IG). The IG was intragastrically administered with atractylodesin III (30 mg/kg/d) for 7 days. The model group was treated with (30 mg/kg/d) of sterile saline. After 4.5 h, the heart samples from each group were taken, the myocardial infarct size was detected by 2, 3, 5-triphenyltetrazolium chloride (TTC) staining.After ematoxylin & Eosin (HE) staining apoptosis indices were determined by Terminal deoxynucleotidyl transferase TdT-mediated dUTP Nick-End Labeling (TUNEL) method. Apoptosis-related genes and protein including Bcl-2, Bax, and Caspase-3 expression were determined by quantitative real time polymerase chain reaction (qRT-PCR) and western blot respectively. The infarct size and apoptotic index of the MG were significantly higher than SOG. However, infarct size and apoptotic index were reduced in IGcompared to MG (P < 0.05). The levels of Bax and Caspase-3 in the MG were significantly higher, while Bcl-2 and Bcl-2/Bax were lower than those in the SOG. The IG has lower levels of Bax and Caspase-3, higher levels of Bcl-2 and Bcl-2/Bax (P < 0.05) compared to MG. Atractylodesin III decreased apoptosis of myocardial cells in AMI, up-regulated Bcl-2 expression, and inhibited Bax and Caspase-3 activity.

The Clinical Pharmacokinetics and Pharmacodynamics of Warfarin When Combined with Compound Danshen: A Case Study for Combined Treatment of Coronary Heart Diseases with Atrial Fibrillation.

Warfarin is used as anticoagulant and Compound Danshen prescription (CDP) is able to promote blood circulation. The combination might produce a synergic effect for patients of coronary heart diseases (CHDs) with atrial fibrillation (AF). Whether the combination increases the bleeding risk of warfarin is unclear, so the effects of Compound Danshen dripping pill (CDDP) on the pharmacokinetics (PK) and pharmacodynamics (PD) profiles of warfarin was investigated in patients. The dose and blood concentrations of warfarin, the four indicators of blood coagulation, prothrombin time, activated partial thromboplatin time, thrombin time, fibrinogen, and international normalized ratio value were compared when with and without CDDP treatment. The population PK (PPK) and PPK-PD models were established to assess patient demographics, genetic polymorphisms and CDDP as covariates. And the Seattle Angina Questionnaire was used to evaluate clinical efficacy, and the bleeding risk of combination was analyzed. The results indicated that CDDP had little influence on PK and PD profiles of warfarin in most patients and the combination of CCDP and warfarin would be a promising alternative regime for CHD with AF patients. The study was registered on China Clinical Trial Registry with number ChiCTR-ONRC-13003523.

IRF-5 accelerates leukocyte adhesion to endothelial cells in ischemia-reperfusion injury through regulating the transcription of VCAM-1.

Ischemia-reperfusion injury (IRI) has been implicated in many pathological conditions, including cardiovascular diseases. Adhesion of leukocytes to the surface of endothelial cells has been considered as one of the principle steps in the pathological cascade of inflammatory tissue damage during IRI. The role of the transcriptional factor interferon regulatory factor-5 (IRF-5) in endothelial physiology remains unknown. Here, we report that IRF-5 is expressed in human umbilical vein endothelial cells (HUVECs) and is rapidly upregulated in response to IRI, mediated by the JAK2/STAT3 pathway. Importantly, IRF-5 is involved in IRI-induced attachment of THP-1 leukocytes to HUVECs. Mechanistically, it was found that IRF-5 targeted the expression of vascular cell adhesion molecule 1 (VCAM-1) at the transcriptional level by binding to its promoter. In conclusion, we identify IRF-5 as a new regulator and thus a therapeutic target in IRI-driven cardiovascular pathologies.