Low shear stress-induced blockage of autophagic flux impairs endothelial barrier and facilitates atherosclerosis in mice.

Atherosclerosis preferentially occurs in areas with low shear stress (LSS) and oscillatory flow. LSS has been demonstrated to correlate with the development of atherosclerosis. The sphingosine 1-phosphate receptor 1 (S1PR1), involving intravascular blood flow sensing, regulates vascular development and vascular barrier function. However, whether LSS affects atherosclerosis via regulating S1PR1 remains incompletely clear. In this study, immunostaining results of F-actin, ß-catenin, and VE-cadherin indicated that LSS impaired endothelial barrier function in human umbilical vein endothelial cells (HUVECs). Western blot analysis showed that LSS resulted in blockage of autophagic flux in HUVECs. In addition, autophagy agonist Rapamycin (Rapa) antagonized LSS-induced endothelial barrier dysfunction, whereas autophagic flux inhibitor Bafilomycin A1 (BafA1) exacerbated it, indicating that LSS promoted endothelial barrier dysfunction by triggering autophagic flux blockage. Notably, gene expression analysis revealed that LSS downregulated S1PR1 expression, which was antagonized by Rapa. Selective S1PR1 antagonist W146 impaired endothelial barrier function of HUVECs under high shear stress (HSS) conditions. Moreover, our data showed that expression of GAPARAPL2, a member of autophagy-related gene 8 (Atg8) proteins, was decreased in HUVECs under LSS conditions. Autophagic flux blockage induced by GAPARAPL2 knockdown inhibited S1PR1, aggravated endothelial barrier dysfunction of HUVECs in vitro, and promoted aortic atherosclerosis in ApoE-/- mice in vivo. Our study demonstrates that autophagic flux blockage induced by LSS downregulates S1PR1 expression and impairs endothelial barrier function. GABARAPL2 inhibition is involved in LSS-induced autophagic flux blockage, which impairs endothelial barrier function via downregulation of S1PR1.

Fibroblast growth factor 21 improves diabetic cardiomyopathy by inhibiting ferroptosis via ferritin pathway.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 2 diabetes mellitus, and its mechanisms are complex and poorly understood. Despite growing evidence suggesting that ferroptosis plays a significant role in cardiovascular disease, it has been less extensively studied in DCM. Fibroblast growth factor 21 (FGF21), whose mechanism of action is closely related to ferroptosis, is widely utilized in studies focused on the prevention and treatment of glucolipid metabolism-related diseases and cardiovascular diseases. OBJECTIVE: To confirm the significant role of ferroptosis in DCM and to investigate whether FGF21 improves DCM by inhibiting ferroptosis and elucidating its specific molecular mechanisms. METHODS: The animal DCM models were established through high-fat feeding combined with streptozotocin injection in C57BL/6J mice or by db/db mice, and the diabetic cardiomyocyte injury model was created using high glucose and high fat (HG/HF) culture of primary cardiomyocytes. Intervention modeling of FGF21 were performed by injecting adeno-associated virus 9-FGF21 in mice and transfecting FGF21 siRNA or overexpression plasmid in primary cardiomyocytes. RESULTS: The findings indicated that ferroptosis was exacerbated and played a significant role in DCM. The overexpression of FGF21 inhibited ferroptosis and improved cardiac injury and function, whereas the knockdown of FGF21 aggravated ferroptosis and cardiac injury and function in DCM. Furthermore, we discovered that FGF21 inhibited ferroptosis in DCM by directly acting on ferritin and prolonging its half-life. Specifically, FGF21 binded to the heavy and light chains of ferritin, thereby reducing its excessive degradation in the proteasome and lysosomal-autophagy pathways in DCM. Additionally, activating transcription factor 4 (ATF4) served as the upstream regulator of FGF21 in DCM. CONCLUSIONS: The ATF4-FGF21-ferritin axis mediates the protective effects in DCM through the ferroptosis pathway and represents a potential therapeutic target for DCM.

Association between serum 25-hydroxyvitamin D and vitamin D dietary supplementation and risk of all-cause and cardiovascular mortality among adults with hypertension.

BACKGROUND: The relationship between vitamin D status and mortality among adults with hypertension remains unclear. METHODS: This prospective cohort study involved a sample of 19,500 adults with hypertension who participated in the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2018. We utilized a weighted COX proportional hazard model to assess the association between vitamin D status and mortality. This statistical model calculates hazard ratios (HR) and their corresponding 95% confidence intervals (95% CI). RESULTS: The study indicated that lower serum 25(OH)D concentration was associated with an increased risk of all-cause mortality among individuals with hypertension. Specially. Those with concentrations between 25.0 and 49.9 nmol/L (HR = 1.71, 95%CI = 1.22-2.40) and less than 25.0 nmol/L (HR = 1.97, 95%CI = 1.15-3.39) had higher hazard ratios for all-cause mortality. Individuals with hypertension who took vitamin D supplements had a lower risk of all-cause mortality, but not the risk of CVD mortality (HR 0.75, 95%CI 0.54-1.03), compared to those who did not supplement (HR = 0.76, 95%CI = 0.61-0.94). Subgroup analysis further revealed that vitamin D supplementation was associated with a reduced risk of all-cause mortality among individuals without diabetes (HR = 0.65, 95%CI = 0.52-0.81) and individuals without CVD (HR = 0.75, 95%CI = 0.58-0.97), and a decreased risk of CVD mortality among individuals without diabetes (HR = 0.63, 95%CI = 0.45-0.88) and without CVD (HR = 0.61, 95%CI = 0.40-0.92). Furthermore, higher-dose vitamin D supplementation was also associated with a greater reduction in all-cause mortality among hypertensive individuals, and there was the potential synergistic effect of combining normal-dose calcium and vitamin D supplementation, showing a superior effect on mortality compared to low-dose supplementation in adults with hypertension. CONCLUSIONS: This prospective cohort study demonstrated a significant association between lower serum 25 (OH)D concentration and increased all-cause mortality among adults with hypertension. Furthermore, the study found that vitamin D supplementation had a strong and significantly positive correlation with reduced all-cause and CVD mortality among hypertensive individuals without diabetes or CVD. This positive correlation suggests that vitamin D supplementation could potentially be an effective strategy to reduce the risk of mortality in this specific group of people.

Effect of sacubitril/valsartan and ACEI/ARB on glycaemia and the development of diabetes: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Sacubitril/valsartan and angiotensin-converting enzyme inhibitor (ACEI)/angiotensin-receptor blocker (ARB) therapies were reported to affect glycaemic control and the development of diabetes mellitus (DM), but the findings are inconsistent. We examined the evidence for the effects of sacubitril/valsartan and ACEI/ARB in DM by conducting a meta-analysis. METHODS: The Cochrane Central Register of Controlled Trials (The Cochrane Library), Embase, PubMed, and ClinicalTrials.gov were searched for data from randomised clinical trials (RCTs) that evaluated the efficacy of sacubitril/valsartan and ACEI/ARB in patients, as of May 25, 2022. Patients were grouped by their disease background at baseline. The main outcomes were the number of new-onset DM and hypoglycaemia, elevated glycaemia, inadequate DM control, diabetes treatment, and diabetic complications, from baseline to the end of the trials. The risk of bias was assessed using the revised Cochrane risk-of-bias tool for randomized trials (ROB 2). The quality of the evidence was evaluated according to the Recommendations for Assessment, Development, and Evaluation guidelines. The meta-analysis of the incidence of various outcomes was conducted using fixed or random effects models. The results are expressed as binary risk, 95% confidence interval (CI), and relative risk (RR). The Mantel-Haenszel method and Z test were used to determine the overall results and determine the significance of the RR. RESULTS: This study included 31 RCTs and 86,809 subjects. Compared with placebo, sacubitril/valsartan treatment significantly reduced the risk of new-onset DM among all patients (RR = 0.78, 95% CI: 0.64-0.95), patients with heart failure (HF) (RR = 0.24, 95% CI: 0.12-0.48), HF with reduced ejection fraction (HFrEF) (RR = 0.24, 95% CI: 0.12-0.50), and HF with preserved ejection fraction (HFpEF) (RR = 0.54, 95% CI 0.34-0.85). In contrast, sacubitril/valsartan treatment significantly increased the risk of hypoglycaemia among all patients (RR = 1.91, 95% CI: 1.05-3.47), patients with not all-DM (defined as part of the study population having DM at baseline) (RR = 5.71, 95% CI: 2.02-16.21), and patients with HFpEF (RR = 7.06, 95% CI: 2.10-23.76). Compared with ACEI/ARB, sacubitril/valsartan treatment significantly increased the risk of hypoglycaemia among patients with HF (RR 1.85, 95% CI 1.12-3.06, p = 0.02) and HFpEF (RR 3.59, 95% CI 1.51-8.55, p = 0.004). Compared with placebo, ACEI/ARB treatment did significantly reduce the risk of new-onset DM among all patients (RR 0.85, 95% CI 0.77-0.93, p = 0.0007) and patients with not all-HF (defined as part of the study population having HF at baseline) (RR 0.87, 95% CI 0.82-0.93, p<0.0001) and HFpEF (RR 0.60, 95% CI 0.44-0.83, p = 0.002), diabetes complications among patients with non-HF (/not all-DM) (RR 0.87, 95% CI 0.76-0.99, p = 0.04), and subsequent diabetes treatment among patients with new-onset DM (RR 0.70, 95% CI 0.58-0.84, p = 0.0002) and significantly increased the risk of hypoglycaemia among patients with not all-DM (RR 2.06, 95% CI 1.172-3.61, p = 0.01). CONCLUSIONS: The results of our study, especially in reducing glycaemia and new-onset DM, revealed that sacubitril/valsartan had a positive effect on the control of glycaemia and the development of DM. ACEI/ARB also had a beneficial effect but the effect was weaker than that of sacubitril/valsartan. The above effects varied across diseases but the evidence was strongest in patients with HF. TRIAL REGISTRATION: CRD42022336311.

Application Value of Systemic Inflammatory Indexes in the Clinical Evaluation of Patients with Heart Failure with Preserved Ejection Fraction (HFpEF).

Background: In areas where medical resources are scarce, an economical and convenient way to assess patients' condition so that treatment plans can be adjusted in a timely manner makes sense. The clinical value of systemic inflammatory indexes (SII) such as neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), albumin-to-gamma-glutamyl-transferase ratio (AGR), white-blood-cell-count-to-mean-platelet-volume ratio (WMR), high-density-lipoprotein-cholesterol-to-C-reactive-protein ratio (HCR), etc. were explored in heart failure (HF) with preserved ejection fraction (HFpEF) because of their easy availability and clinical value in the diagnosis, therapy and prognosis of cardiovascular diseases. Methods: 189 inpatients (including 48 patients with New York Heart Association (NYHA) I in the control group, and 141 patients with NYHA II-IV in the study group) from The First Affiliated Hospital of Jinan University, during the period July 2018 to March 2022, were included by retrieving electronic medical records. Logistic regression analysis, Spearman's correlation coefficient, operating characteristic curve, etc. were used to analyze the data. Results: In patients with HFpEF, LMR (OR = 0.463, 95% CI 0.348−0.617, p = 0.000), NLR and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were independent predictors for the presence of HF, and LMR (OR = 2.630, 95% CI 2.016−3.435, p = 0.000), NLR, FAG, MHR, AGR and NT-proBNP were independent predictors for increased NYHA functional classification. There were good correlations (r > 0.4) between LMR (r = −0.667, p = 0.000), NLR, WMR, HCR, NT-proBNP (r = −0.681, p = 0.000) and NYHA functional classification, and LMR (AUC = 0.803, 95% CI 0.729−0.849, p = 0.0001), NLR and NT-proBNP (AUC = 0.805, 95% CI 0.738−0.861, p = 0.0001) had good diagnostic values (AUC > 0.7) for HF in patients with HFpEF. In addition, there were certain correlations between LMR, NT-proBNP and echocardiography indicators of cardiac structural. Conclusions: SII have a potential application value in the clinical evaluation of patients with HFpEF in the follow-up, especially in areas with limited medical resources, as they are more convenient and cost effective. Among different SII, LMR is probably the most promising metric. However, large-scale clinical trials are needed in the future to confirm these findings.

The relationship between the use of GLP-1 receptor agonists and the incidence of respiratory illness: a meta-analysis of randomized controlled trials.

AIM: We aimed to assess the association between the use of Glucagon-like peptide-1 receptor agonists and the risk of 12 respiratory diseases in patients with type 2 diabetes, obesity, or overweight. METHOD: The PubMed (MEDLINE), EMBASE, Cochrane Library, and ClinicalTrials.gov databases were searched from the establishment of the database to December 24, 2022. Dichotomous outcomes were analyzed using RR and 95% CI calculated from fixed-effects models. RESULTS: Twenty-eight RCTs were ultimately included for analysis, involving a total of 77,485 participants. Compared to controls, patients with GLP-1RAs have a 14% lower risk of respiratory disease (RR 0.86, 95% CI 0.81-0.93 p < 0.0001), with Semaglutid (RR 0.82, 95% CI 0.68-0.97, p = 0.02), Liraglutide (RR 0.86. 95% CI 0.75-0.98, p = 0.03), Dulaglutide (RR 0.82, 95% CI 0.70-0.96, p = 0.02), Albiglutide (RR 0.93,95% CI 0.79-1.10, p = 0.40), Exenatide (RR 0.93, 95% CI 0.74-1.18, p = 0.55), Lixisenatide (RR 0.83, 95% CI 0.62-1.12, p = 0.22), and Efpeglenatide (RR 0.76, 95% CI 0.46-1.24, p = 0.27). Semaglutide, Liraglutide and Dulaglutide reduce the risk of respiratory diseases by 18%, 14% and 18%, respectively.Trial duration, control type, and indication were not associated with the impact of GLP-1 receptor agonists on overall respiratory disease. Among secondary outcomes, the risk of Pulmonary edema (RR 0.66, 95% CI 0.44-0.98, p = 0.04), and Bronchitis (RR 0.86, 95% CI 0.74-1.00, p = 0.04) was reduced. CONCLUSION: In conclusion, GLP-1RAs were linked to a lower risk of overall respiratory diseases, especially Pulmonary edema and Bronchitis. In the future, physicians should pay attention to the relationship between GLP-1 RA and the risk of respiratory diseases and evaluate the efficacy of GLP-1RAs in the primary and secondary prevention of respiratory diseases. Trial registration CRD42023396138.

Bioinformatics Analysis Identifies Potential Ferroptosis Key Gene in Type 2 Diabetic Islet Dysfunction.

Background: Islet ß cells dysfunction (IBCD) is a cortical component in pathogenesis of type 2 diabetic mellitus (T2DM). However, the relationship of ferroptosis and IBCD remains unknown. This study was aimed to screen potential ferroptosis key genes to reveal latent physiological and pathological process of IBCD in T2DM. Methods: Firstly, T2DM key genes were screened by combining with differentially expressed genes (DEGs) analysis and WGCNA. Then, ferroptosis-related genes (FRGs) in IBCD of T2DM were identified by taking the intersection between T2DM key genes and FRGs. Finally, T2DM-FRGs were validated in another T2DM dataset as well as islet single-cell RNA sequencing dataset and the miRNA regulated T2DM-FRG was predicted by using four miRNA databases. Results: 89 T2DM key genes were identified between DEGs and WGCNA. Then, 3 T2DM-FRGs were screened by taking the intersection of T2DM key genes and FRGs, namely ITGA6, MGST1 and ENO2. At last, MGST1 were validated as the T2DM-FRG in another T2DM islet issues dataset and islet single-cell RNA sequencing dataset. Conclusion: MGST1 may be the potential ferroptosis key gene of IBCD in T2DM.

Effects of different types of radiation therapy on cardiac-specific death in patients with thyroid malignancy.

Radiation therapy (RT) is one of the common and widely used treatment method for thyroid tumors. Considering that the thyroid is located close to the heart, the radiation generated during the treatment of thyroid tumors may have an adverse greater impact on the heart. This study is to explore the influencing factors, especially additional effects of RT, on cardiac-specific death among patients with malignant thyroid tumors. Collecting information from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database using SEER*Stat. Patients with malignant thyroid tumors were searched, whether receiving RT or not. Ultimately, 201, 346 eligible patients were included. Propensity Score Matching (PSM) was used to minimize bias of baseline characteristics by adjusting for confounding factors. COX (proportional hazards) and fine-gray (competing risk) model regression analysis were used to explore the effects of various influencing factors on cardiac-specific death. The present analysis showed that, compared with non-RT, RT based upon radioactive implants and beam radiation were associated with lower risk of cardiac-specific death in patients with thyroid malignancy, beam radiation therapy may had a similar effect. Besides, the remaining RT methods did not significantly increase the risk of cardiac-specific death. In addition, Asian or Pacific Islander ethnicity, female sex, marital status, combined summary stage (localized, regional, and distant), high-income, and later year of diagnosis were associated with lower risk of cardiac-specific death. While older age of diagnosis, African ethnicity, non-Hispanic ancestry, and derived AJCC stage (IV) were risk factors for cardiac-specific death. These results help to identify the factors influencing cardiac-specific death among patients with thyroid malignancies. Furthermore, it may helps to improve the clinical application of RT without too much concern about adverse cardiac effects.

Effects of GLP-1 receptor agonists on arrhythmias and its subtypes in patients with type 2 diabetes: A systematic review and meta-analysis.

Purpose: An update of a systematic review and meta-analysis of the risk of arrhythmias and their subtypes in type 2 diabetic patients receiving glucagon-like peptide 1 receptor agonist (GLP-1RA) medication according to data from the Cardiovascular Outcome Trial(CVOT). Methods: Randomized controlled trials (RCT) on GLP-1RA therapy and cardiovascular outcomes in type 2 diabetes mellitus patients published in full-text journal databases such as MEDLINE (via PubMed), Embase, Clinical Trials.gov, and the Cochrane Library from establishment to March 1, 2022 were searched. We assessed the quality of individual studies by the Cochrane risk-of-bias algorithm. RevMan 5.4.1 software was use for calculating meta-analysis. Results: A total of 60,081 randomized participants were included in the data of these 8 GLP-1RA cardiovascular outcomes trials. Pooled analysis reported no significant effect on total arrhythmia [RR=0.96, 95% CI (0.96, 1.05), p =0.36], and its subtypes such as atrial fibrillation [RR=0.96, 95% CI (0.86, 1.07), p =0.43], atrial flutter [RR= 0.82, 95% CI (0.57, 1.19), p =0.30], atrial tachycardia [RR=0.64, 95% CI (0.20, 2.01), p =0.44)], sinoatrial node dysfunction [RR=0.74, 95% CI (0.44, 1.25), p =0.26], ventricular preterm systole [RR=1.42, 95% CI (0.62, 3.26), p =0.41], second degree AV block [RR=0.96, 95% CI (0.53, 1.72), p =0.88], complete AV block [RR=0.75, 95% CI (0.49, 1.17), p =0.21], ventricular fibrillation [RR=1.00, 95% CI (0.50, 2.02), p =1.00], ventricular tachycardia [RR=1.37, 95% CI (0.91, 2.08), p =0.13] from treatment with GLP-1RA versus placebo. However, the risk of hypoglycemia was reduced by about 30% [RR=0.70, 95% CI (0.57, 0.87), p=0.001] and the risk of pneumonia by about 25% [RR=0.85, 95% CI (0.75, 0.97), p=0.01], both statistically significant differences. Conclusion: In type 2 diabetic patients, treatment with GLP-1RA has no significant effect on the risk of major arrhythmias but significantly reduces the risk of hypoglycemia and pneumonia.

HADH may be the target molecule of early vascular endothelial impairment in T2DM.

Background: Type 2 diabetes mellitus (T2DM) will significantly increase the risk of atherosclerosis (AS). Vascular endothelial cell dysfunction (VECD) is the foundation of AS. Early identification and intervention of VECD caused by T2DM can help us effectively delay or even suppress the occurrence of AS. Methods: We downloaded the gene expression profiles from the Gene Expression Omnibus (GEO). The differential expression genes (DEGs) were identified in R software and weighted gene co-expression network analysis (WGCNA) was performed to further screen the target genes. In addition, we used the receiver operating characteristic curve (ROC curve) to verify the diagnostic efficiency of target genes. Finally, target genes were validated by quantitative polymerase chain reaction (qPCR). Results: Four target genes (CLUH, COG4, HADH, and MPZL2) were discovered in early vascular endothelial impairment caused by T2DM through differential expression analysis and WGCNA. The ROC curve of target genes showed that HADH had the best diagnostic efficacy in VECD and AS. qPCR showed that the mRNA level expression of HADH and MPZL2 were decreased in human coronary artery endothelial cells (HCAECs) treated with high glucose and palmitic acid. Conclusion: HADH may be the target gene in early VECD caused by T2DM.

Risk of stroke and retinopathy during GLP-1 receptor agonist cardiovascular outcome trials: An eight RCTs meta-analysis.

Purpose: To explore the risk of stroke (including ischemic and hemorrhagic stroke) in type 2 diabetes mellitus treated with glucagon-like peptide 1 receptor agonist (GLP-1RA) medication according to data from the Cardiovascular Outcome Trials(CVOT). Methods: Randomized controlled trials (RCT) on GLP-1RA therapy and cardiovascular outcomes in type 2 diabetics published in full-text journal databases such as Medline (via PubMed), Embase, Clinical Trials.gov, and the Cochrane Library from establishment to May 1, 2022 were searched. We assess the quality of individual studies by using the Cochrane risk of bias algorithm. RevMan 5.4.1 software was use for calculating meta- analysis. Results: A total of 60,081 randomized participants were included in the data of these 8 GLP-1RA cardiovascular outcomes trials. Pooled analysis reported statistically significant effect on total stroke risk[RR=0.83, 95%CI(0.73, 0.95), p=0.005], and its subtypes such as ischemic Stroke [RR=0.83, 95%CI(0.73, 0.95), p=0.008] from treatment with GLP-1RA versus placebo, and have no significant effect on the risk of hemorrhagic stroke[RR=0.83, 95%CI(0.57, 1.20), p=0.31] and retinopathy [RR=1.54, 95%CI(0.74, 3.23), p=0.25]. Conclusion: GLP-1RA significantly reduces the risk of ischemic stroke in type 2 diabetics with cardiovascular risk factors.

Effect of radiotherapy on cardiac-specific death in patients with non-malignant tumors of central nervous system and related clinical features.

Importance: Cardiac-specific death from radiation caused by radiation therapy (RT) in patients with malignant tumors has received extensive attention, however, little is known regarding the potential cardiotoxic effects of RT in patients with non-malignant tumors. Objectives and methods: In this study, we used the SEER data to explore the incidence of post-radiation cardiovascular complications in patients with non-malignant tumors of central nervous system (CNS), and identify the influencing factors of cardiac-specific death. Results: Ultimately 233, 306 patients were included (97.8% of patients had brain tumors and 2.2% had spinal cord tumors). For patients with non-malignant tumors of CNS, RT {yes (odds ratio [OR] 0.851, 95% confidence interval [CI] 0.774-0.936, p = 0.001, before propensity score matching (PSM); OR 0.792, 95% CI 0.702-0.894, p < 0.001, after PSM) vs. no} was associated with lower risk of cardiac-specific death, other clinical features affecting cardiac death similar to those in patients with non-malignant tumors of CNS receiving RT. For patients with non-malignant tumors of CNS receiving RT, female, married status, Hispanic ethnicity, surgery, and tumor site (brain exclude nerve and endocrine, nervous system) were associated with lower risks of cardiac-specific death, while earlier year of diagnosis, older age of diagnosis, Black, larger tumor and bilateral tumor were risk factors for cardiac-specific death. Conclusions: Our study shows the influencing factors for cardiac-specific death in patients with non-malignant tumors of CNS, and found RT is associated with lower risk of cardiac-specific death. These results can facilitate the identification of patients with non-malignant tumors of CNS who can benefit from RT while avoiding cardiovascular events. In addition, this study helps to enhance the clinical use of RT in these populations, especially in patients who may have impaired cardiac function due to CNS tumors.

Effect of Sacubitril/Valsartan on Reducing the Risk of Arrhythmia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background and Objective: Relevant data of PARADIGM-HF reveals sacubitril/valsartan (SV) therapy led to a greater reduction in the risks of arrhythmia, and sudden cardiac death than angiotensin converting enzyme inhibitor (ACEI)/angiotensin receptor inhibitor (ARB) therapy in HFrEF, however, inconsistent results were reported in subsequent studies. Here, we conduct a meta-analysis of related randomized controlled trials (RCTs) to evaluate the protective effect of SV on reducing the risk of arrhythmias. Methods and Results: RCTs focused on the difference in therapeutic outcomes between SV and ACEI/ARB were searched from PUBMED, EMBASE, ClinicalTrials.gov, and Cochrane Library. The results were extracted from each individual study, expressed as binary risk, 95% confidence interval (CI) and relative risk (RR). Sixteen RCTs including 22, 563 patients met the study criteria. Compared with ACEI/ARB therapy, SV therapy did significantly reduce in the risks of severe arrhythmias among patients with heart failure with reduced ejection fraction (HFrEF) (RR 0.83, 95% CI 0.73-0.95, p = 0.006), ventricular tachycardia (VT) among patients with HFrEF (RR 0.69, 95% CI 0.51-0.92, p = 0.01), cardiac arrest among patients with heart failure (HF) (RR 0.52, 95% CI 0.37-0.73, p = 0.0002), cardiac arrest among patients with HFrEF (RR 0.49, 95% CI 0.32-0.76, p = 0.001), cardiac arrest or ventricular fibrillation (VF) among patients with HF (RR 0.63, 95% CI 0.48-0.83, p = 0.001), and cardiac arrest or VF among patients with HFrEF (RR 0.65, 95% CI 0.47-0.89, p = 0.008), but reduced the risks of arrhythmias (RR 0.87, 95% CI 0.74-1.01, p = 0.07), atrial arrhythmias (RR 0.98, 95% CI 0.83-1.16, p = 0.85), and atrial fibrillation (RR 0.98, 95% CI 0.82-1.17, p = 0.82) among all patients with no significant between-group difference. The merged result was robust after sensitivity analysis, and there was no publication bias. Conclusion: Our meta-analysis provides evidence that, compared with ACEI/ARB, SV can additionally reduce the risks of most arrhythmias, just the significant differences are revealed in reducing the risks of VT, severe arrhythmias, and cardiac arrest in patients with HFrEF. Besides, the positive effect of SV on VF according to statistical result of combining VF with cardiac arrest in patients with HFrEF is credibility.

Bivalirudin Attenuates Thrombin-Induced Endothelial Hyperpermeability via S1P/S1PR2 Category: Original Articles.

Aims: To explore the role of the Sphingosine 1-Phosphate (S1P)/Receptor2 (S1PR2) pathway in thrombin-induced hyperpermeability (TIP) and to test whether bivalirudin can reverse TIP via the S1P-S1PRs pathway. Methods and Results: Using western blot, we demonstrated that Human umbilical vein endothelial cells (HUVECs) that were cultured with 2 U/ml thrombin showed significantly increased S1PR2 expression while S1PR1and three kept unchanged. Such increment was attenuated by JTE-013 pretreatment and by presence of bivalirudin. Exposure of 2 U/ml of thrombin brought a higher level of S1P both intracellularly and extracellularly within the HUVECs by using ELISA detecting. Thrombin induced S1P and S1PR2 increment was restored by usage of PF543 and bivalirudin. Bivalirudin alone did not influenced the level of S1P and S1PR1,2, and S1PR3 compare to control group. As a surrogate of cytoskeleton morphology, phalloidin staining and immunofluorescence imaging were used. Blurry cell edges and intercellular vacuoles or spaces were observed along thrombin-exposed HUVECs. Presence of JTE-013 and bivalirudin attenuated such thrombin-induced permeability morphological change and presence of heparin failed to show the protective effect. Transwell chamber assay and probe assay were used to measure and compare endothelial permeability in vitro. An increased TIP was observed in HUVECs cultured with thrombin, and coculture with bivalirudin, but not heparin, alleviated this increase. JTE-013 treatment yielded to similar TIP alleviating effect. In vivo, an Evans blue assay was used to test subcutaneous and organ microvascular permeability after the treatment of saline only, thrombin + saline, thrombin + bivalirudin, thrombin + heparin or thrombin + JTE-013. Increased subcutaneous and organ tissue permeability after thrombin treatment was observed in thrombin + saline and thrombin + heparin groups while treatment of bivalirudin and JTE-013 absent this effect. Conclusion: S1P/S1PR2 mediates TIP by impairing vascular endothelial barrier function. Unlike heparin, bivalirudin effectively blocked TIP by inhibiting the thrombin-induced S1P increment and S1PR2 expression, suggesting the novel endothelial protective effect of bivalirudin under pathological procoagulant circumstance.

Cardiac magnetic resonance image segmentation based on convolutional neural network.

OBJECTIVE: In cardiac medical imaging, the extraction and segmentation of the part of interest is the key to the diagnosis of heart disease. Due to irregular diastole and contraction, magnetic resonance imaging (MRI) images have poorly defined boundaries, and traditional segmentation algorithms have poor performance. In this paper, a cardiac MRI segmentation technique using convolutional neural network and image saliency is suggested. METHODS: The convolutional neural network is used for detecting target area, filter out the ribs, muscles and the other parts of the anatomy where the contrast is not clearly defined. It can also be used to extract the region of interest (ROI), and compute the contrast of the ROI in order to improve clarity of the heart tissue within the ROI. The cardiac image diagnosis is performed using the obtained saliency image and compared with the segmentation result of the region growth algorithm. Finally, the images of 85 patients were used to train and test the algorithm model. Here, 46 patients were randomly selected for training, and the remaining 39 were harnessed for further tests. RESULTS: Segmentation accuracy of our algorithm model in ventricles, septum and the apex of the heart segment reaches 93.14%, 92.58% and 96.21% respectively, which are better than the segmentation method based on the regional growth technique. CONCLUSIONS: The segmentation method using convolutional neural network and image saliency can meet the needs of automatic heart segmentation tasks based on cardiac MRI image sequences. The segmented image is able to assist the doctor to observe the patient's heart health more effectively. As such, our proposed technique has strong potential in clinical applications.

Superior hybrid hydrogels of polyacrylamide enhanced by bacterial cellulose nanofiber clusters.

Hybrid polyacrylamide/bacterial cellulose nanofiber clusters (PAM/BC) hydrogels with high strength, toughness and recoverability were synthesized by in situ polymerization of acrylamide monomer in BC nanofiber clusters suspension. The hybrid gels exhibited an extremely large elongation at break of 2200%, and a high fracture stress of 1.35MPa. Additionally, the original length of hydrogels could be recovered after releasing the tensile force. Compressive results showed that the PAM/BC hybrid gels could reach a strain of about 99% without break, and was able to completely recover its original shape immediately after releasing the compression force. The compressive stress at 99% reached as high as 30MPa. Nearly no hysteresis in cyclic compressive tests was observed with these hybrid gels. The FT-IR, XRD and TGA analysis showed that hydrogen bonds between the PAM chains and BC nanofiber clusters mainly contributed to the superior mechanical properties of hybrid hydrogels. The cell viability results suggested that PAM/BC hybrid hydrogel was benign for biomedical application. These PAM/BC hydrogels offer a great promise as biomaterials such as bone and cartilage repair materials.