Extracellular vesicles from hypoxia-preconditioned mesenchymal stem cells alleviates myocardial injury by targeting thioredoxin-interacting protein-mediated hypoxia-inducible factor-1α pathway.

BACKGROUND: Extracellular vesicles (EVs) derived from hypoxia-preconditioned (HP) mesenchymal stem cells (MSCs) have better cardioprotective effects against myocardial infarction (MI) in the early stage than EVs isolated from normoxic (NC)-MSCs. However, the cardioprotective mechanisms of HP-EVs are not fully understood. AIM: To explore the cardioprotective mechanism of EVs derived from HP MSCs. METHODS: We evaluated the cardioprotective effects of HP-EVs or NC-EVs from mouse adipose-derived MSCs (ADSCs) following hypoxia in vitro or MI in vivo, in order to improve the survival of cardiomyocytes (CMs) and restore cardiac function. The degree of CM apoptosis in each group was assessed by the terminal deoxynucleotidyl transferase dUTP nick end-labeling and Annexin V/PI assays. MicroRNA (miRNA) sequencing was used to investigate the functional RNA diversity between HP-EVs and NC-EVs from mouse ADSCs. The molecular mechanism of EVs in mediating thioredoxin-interacting protein (TXNIP) was verified by the dual-luciferase reporter assay. Co-immunoprecipitation, western blotting, and immunofluorescence were performed to determine if TXNIP is involved in hypoxia-inducible factor-1 alpha (HIF-1α) ubiquitination and degradation via the chromosomal region maintenance-1 (CRM-1)-dependent nuclear transport pathway. RESULTS: HP-EVs derived from MSCs reduced both infarct size (necrosis area) and apoptotic degree to a greater extent than NC-EVs from CMs subjected to hypoxia in vitro and mice with MI in vivo. Sequencing of EV-associated miRNAs showed the upregulation of 10 miRNAs predicted to bind TXNIP, an oxidative stress-associated protein. We showed miRNA224-5p, the most upregulated miRNA in HP-EVs, directly combined the 3' untranslated region of TXNIP and demonstrated its critical protective role against hypoxia-mediated CM injury. Our results demonstrated that MI triggered TXNIP-mediated HIF-1α ubiquitination and degradation in the CRM-1-mediated nuclear transport pathway in CMs, which led to aggravated injury and hypoxia tolerance in CMs in the early stage of MI. CONCLUSION: The anti-apoptotic effects of HP-EVs in alleviating MI and the hypoxic conditions of CMs until reperfusion therapy may partly result from EV miR-224-5p targeting TXNIP.

Incident Heart Failure in Patients With Coronary Artery Disease Undergoing Percutaneous Coronary Intervention.

Background: The contemporary incidence of heart failure (HF) in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) remains unclear. This prospective cohort study was designed to study the incidence and predictors of new-onset HF in CAD patients after PCI (ChiCTR1900023033). Methods: From January 2014 to December 2018, 3,910 CAD patients without HF history undergoing PCI were prospectively enrolled. Demographics, medical history, cardiovascular risk factors, cardiac parameters, and medication data were collected at baseline. Multivariable adjusted competing-risk regression analysis was performed to examine the predictors of incident HF. Results: After a median follow-up of 63 months, 497 patients (12.7%) reached the primary endpoint of new-onset HF, of which 179, 110, and 208 patients (36.0, 22.1, and 41.9%) were diagnosed as having HF with reduced ejection fraction (EF) (HFrEF), HF with mid-range EF (HFmrEF), and HF with preserved EF (HFpEF), respectively. Higher B-type natriuretic peptide (BNP) or E/e' level, lower estimated glomerular filtration rate (eGFR) level, and atrial fibrillation were the independent risk factors of new-onset HF. Gender (male) and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (ACEI/ARB) prescription were the negative predictors of new-onset HF. Moreover, it was indicated that long-term ACEI/ARB therapy, instead of beta-blocker use, was linked to lower risks of development of all three HF subtypes (HFrEF, HFmrEF and HFpEF). Conclusions: This prospective longitudinal cohort study shows that the predominant subtype of HF after PCI is HFpEF and ACEI/ARB therapy is accompanied with reduced risks of incident HF across three subtypes.

VSTM1 regulates monocyte/macrophage function via the NF-κB signaling pathway.

OBJECTIVE: V-set and transmembrane domain-containing protein 1 (VSTM1) is negatively correlated with inflammation. However, its effect on atherosclerosis (AS) remains largely unexplored. In this study, we aimed to assess the effect of VSTM1 on the biological function of human peripheral blood mononuclear cells /macrophages stimulated by oxidized low-density lipoprotein (ox-LDL). METHODS: U937 cells were divided into three groups as follows: control group, pLenti-VSTM1 shRNA group (VSTM1 depletion), and pLenti-VSTM1 group (VSTM1 overexpression). Cellular migration, chemotaxis, apoptosis, and secretion of inflammatory factors of monocytes/macrophages stimulated by ox-LDL were studied. RESULTS: Overexpression of VSTM1 decreased the proliferation of U937 cells and induced cellular apoptosis. Depletion of VSTM1 enhanced the invasiveness and chemotaxis, increased the inflammatory response, and reduced the incidence of cell necrosis and apoptosis. Nuclear factor κ of B cells (NF-κB) was activated in VSTM1-depleted U937 cells. CONCLUSION: VSTM1 might play an important role in the activation of monocytes/macrophages and participate in the pathogenesis of AS via regulating NF-κB activity.

Predictive and prognostic value of v-set and transmembrane domain-containing 1 expression in monocytes for coronary artery disease.

The aim of this study was to investigate the correlation between v-set and transmembrane domain-containing 1 (VSTM1) expression and incidence of major adverse cardiac events (MACE) in patients with coronary heart disease (CHD). A total of 310 patients were divided into a non-acute coronary syndrome (non-ACS) group (containing the stable angina group, and the asymptomatic coronary artery diseaseand other patients group) and an ACS group (containing unstable angina and acute myocardial infarction patients). Monocytic VSTM1 expression levels (assessed via average fluorescence intensity derived from antibody binding to VSTM1) in each group were detected and analyzed. The cut-off value of monocytic VSTM1 expression to predict the onset of ACS and MACE was confirmed. VSTM1 expression in monocytes from the ACS group was lower than that of the non-ACS group. The incidence of MACEs in the high VSTM1-expression group was much less than that of those in the low VSTM1 expression group at the 1 year follow-up stage. VSTM1 expression had an independent-inversed association with increased incidence of MACE and ACS. VSTM1 expression in monocytes may help to predict the occurrence of ACS in patients with CHD, and moreover it may provide the means to evaluate MACE prognosis during CHD patient follow-up.

Preparation and Characterization of Phosphoric Acid-Modified Biochar Nanomaterials with Highly Efficient Adsorption and Photodegradation Ability.

Phosphoric acid-modified biochar (PMBC) was prepared using biochar (BC) as the carbon source and phosphoric acid as the activating agent. The PMBC exhibited an ordered vessel structure after deashing treatment, but the sidewalls became much rougher, the polarity (O/C atomic ratio of BC = 0.2320 and O/C atomic ratio of PMBC = 0.1604) decreased, and the isoelectric points (PI of BC = 5.22 and PI of PMBC = 5.51) and specific surface area (SSA of BC = 55.322 m2/g and SSA of PMBC = 62.285 m2/g) increased. The adsorption characterization of the removal of sulfadiazine (SDZ) from PMBC was studied. The adsorption of SDZ by PMBC was in accordance with the Langmuir isotherm model and the pseudo-second-order kinetics model, and the adsorption thermodynamics were shown as Gibbs free energy < 0, an enthalpy change of 19.157 kJ/mol, and an entropy change of 0.0718 kJ/(K·mol). The adsorption of SDZ by PMBC was a complicated monolayer adsorption that was spontaneous, irreversible, and endothermic, and physical adsorption and chemical adsorption occurred simultaneously. The adsorption process was controlled by microporous capture, electrostatic interactions, hydrogen-bond interactions, and π-π interactions. PMBC@TiO2 photocatalysts with different mass ratios between TiO2 and PMBC were prepared via the in situ sol-gel method. PMBC@TiO2 exhibited both an ordered vessel structure (PMBC) and irregular particles (TiO2), and it was linked via Ti-O-C bonds. The optimal mass ratio between TiO2 and PMBC was 3:1. The removal of SDZ via PMBC@TiO2 was dependent on the coupling of adsorption and photocatalysis. The PMBC-enhanced photocatalytic performance of PMBC@TiO2 resulted in a higher absorption of UV and visible light, greater generation of reactive oxygen species, high levels of adsorption of SDZ on PMBC, and the conjugated structure and oxygen-containing functional groups that promoted the separation efficiency of the hole-electron pairs.

Balloon Deflation Strategy during Primary Percutaneous Coronary Intervention in Acute ST-Segment Elevation Myocardial Infarction: A Randomized Controlled Clinical Trial and Numerical Simulation-Based Analysis.

BACKGROUND: Primary percutaneous coronary intervention (PCI) is the best available reperfusion strategy in patients with acute ST-segment elevation myocardial infarction (STEMI). However, PCI is associated with a serious problem known as no-reflow phenomenon, resulting in poor clinical and functional outcomes. This study aimed to compare the influences of different balloon deflation velocity on coronary flow and cardiovascular events during primary PCI in STEM as well as transient hemodynamic changes in in vitro experiments. Method and Results. 211 STEMI patients were randomly assigned to either a rapid or a slow balloon deflation group during stent deployment. The primary end point was coronary flow at the end of PCI procedure, and secondary end points included myocardial infarct size. Transient hemodynamic changes were evaluated through an in vitro experimental apparatus and a computer model. In clinical practice, the level of corrected TIMI frame count (cTFC) in slow balloon deflation after primary PCI was significantly lower than that of rapid balloon deflation, which was associated with smaller infarct size. Numerical simulations revealed that the rapid deflation led to a sharp acceleration of flow in the balloon-vessel gap and a concomitant abnormal rise in wall shear stress (WSS). CONCLUSION: This randomized study demonstrated that the slow balloon deflation during stent implantation improved coronary flow and reduced infarct size in reperfused STEMI. The change of flow in the balloon-vessel gap and WSS resulted from different balloon deflation velocity might be partly accounted for this results.

[The role of CaSR expression in diabetic cirrhosis injury and fibrosis in rats].

OBJECTIVE: To observe the role of calcium sensitive receptor (CaSR) in the pathogenesis of diabetic liver injury. METHODS: Forty Wistar rats were randomly divided into normal control group (control, n=10) and diabetes group (T1D, STZ 60 mg/kg intraperitoneal injection, n=30), and the samples were collected at the 2nd, 4th and 8th week. Rats hepatic stellate cells (HSC) were randomly divided into normal control group (Control, 10% FBS-DMEM culture, n=5), high glucose group (HG, 10% FBS-DMEM+40 mmol/L glucose, treated for 48 h, n=5) and CaSR inhibitor group (HG+Calhex 231, 10% FBS-DMEM+40 mmol/L glucose+2.5 µmol/L Calhex231 for 48h, n=5). The body weight, blood glucose, serum glutamic oxaloacetic transaminase (AST) and alanine aminotransferase (ALT) activities were measured dynamically. The changes of liver morphology and ultrastructure were observed by HE staining and Masson staining by transmission electron microscopy. The changes of CaSR and liver fibrosis related indexes were detected by Western blot. RESULTS: Compared with the control group, diabetic rats lost weight, while blood glucose, AST and ALT increased significantly, and the expression of CaSR, collagen 1(CO 1), collagen 3 (CO 3), matrix metalloproteinase(MMP)-1, -2 and -9 increased significantly. The results of the cell model were basically the same as those in vivo. Compared with the control group, the expression of α-smooth muscle actin (α-SMA) was increased, indicating that HSC differentiated into myofibroblasts in HG group. The expression of the main components of ECM (CO 1 and CO 3), and the key enzyme of ECM degradation (MMP9) were also increased, while CaSR inhibitor, Calhex231, could reduce the above changes. CONCLUSION: The up-regulation of CaSR expression is involved in the occurrence of diabetic liver injury and fibrosis.

Characteristics and outcomes of transitions among heart failure categories: a prospective observational cohort study.

AIMS: Patients with heart failure (HF) are typically designated as having reduced, mid-range, or preserved ejection fraction (EF) (HFrEF, HFmrEF, or HFpEF, respectively) because of the importance of left ventricular EF (LVEF) on therapeutic decisions and prognosis. However, such designations are not necessarily static, as there are many transitions among the three HF phenotypes during follow-up. This prospective longitudinal cohort study sought to examine the HF transitions over time and their clinical characteristics, prognosis, and response to medical therapy. METHODS AND RESULTS: We identified 1920 patients from a prospective cohort with a primary diagnosis of HF between 1 January 2007 and 31 December 2012. The enrolled HF patients were re-classified into three groups on the basis of baseline and 1 year follow-up echocardiography: HF with improved EF (HFiEF), HF with deteriorated EF (HFdEF), and HF with unchanged EF (HFuEF). The primary outcome was 5 year all-cause mortality. According to 1 year follow-up echocardiography, 490 (25.5%) were diagnosed as HFiEF, 179 (9.3%) as HFdEF, and 1251 (65.2%) as HFuEF. Ischaemic heart disease was an independent predictor of HFdEF, and beta-blocker prescription was an independent predictor of HFiEF. During the 5 year follow-up, patients with HFdEF had higher mortality, whereas patients with HFiEF had lower mortality. After adjustment, HFiEF, compared with HFuEF, was associated with a 62.1% decreased risk for mortality. Finally, the use of beta-blockers was associated with improved prognosis of patients with HFiEF and HFuEF. CONCLUSIONS: In this cohort of patients with HF, LVEF is a dynamic factor related to coexisting conditions and drug therapy. HFiEF and HFdEF are distinct HF phenotypes with different clinical outcomes than other phenotypes.

[Exogenous spermine alleviates myocardial injury induced by hyperglycemia by inhibiting golgi stress].

OBJECTIVE: To investigate whether Golgi stress (GAS) is involved in diabetic cardiomyopathy (DCM) and whether myocardial protection of exogenous spermine is associated with regulation of GAS. METHODS: Sixty Wistar rats were randomly divided into normal control group (Control), diabetic group (T1D, STZ 60 mg/kg intraperitoneal injection) and spermine group (T1D+Sp, spermine 5 mg/(kg·d) intraperitoneal injection) for 12 weeks. H9C2 rat cardiomyocytes were randomly divided into control group (Control, 10% FBS-DMEM culture), high glucose group (HG, 10% FBS-DMEM+40 mmol/L glucose) and spermine group (HG+Sp, 10% FBS-DMEM+40 mmol/L glucose+5 µmol/L spermine). Rat serum creatine kinase isoenzyme (CK-MB) and cardiac troponin T (cTnT) were detected by ELISA; Golgi protein GOLPH3, GM130 and Cleaved Caspase3 protein expressions were analyzed using Western blot; immunofluorescence was used to detect GOLPH3 cell localization. RESULTS: In the animal model, compared with the normal group, myocardial ultrastructural damage was obvious,the blood glucose, the serum myocardial enzymes CK-MB and cTnT, the expressions of GOLPH3 and cleaved caspase3 were increased or up-regulated significantly,meanwhile, the body weight,the ejection fraction (EF) and the expression of GM130 were decreased or down-regulated markedly in the diabetic group. In the cell model, similar results were obtained. Immunofluorescence showed stress fragmentation of Golgi apparatus. Exogenous spermine treatment could significantly alleviate the above mentioned damages. CONCLUSION: Golgi stress occurs in diabetic cardiomyopathy (DCM), and myocardial protection of exogenous spermine is associated with a reduction in Golgi stress (GAS).

Prognostic impact of HbA1c variability on long-term outcomes in patients with heart failure and type 2 diabetes mellitus.

BACKGROUND: The prognostic impact of long-term glycemic variability on clinical outcomes in patients with heart failure (HF) and type 2 diabetes mellitus (T2DM) remains unclear. We determined and compared hemoglobin A1c (HbA1c) variability and clinical outcomes for patients with HF with preserved ejection fraction (HFpEF), HF with mid-range ejection fraction (HFmrEF) and HF with reduced ejection fraction (HFrEF) in a prospective longitudinal study. METHODS: Patients with HF and T2DM, undergone 3 or more HbA1c determinations during the first 18 months, were then followed for 42 months. The primary outcome was death from any cause. Secondary outcome was composite endpoints with death and HF hospitalization. Cox proportional hazards models were used to compare outcomes for patients with HFpEF, HFmrEF and HFrEF. RESULTS: Of 902 patients enrolled, 32.2% had HFpEF, 14.5% HFmrEF, and 53.3% HFrEF. During 42 months of follow-up, 270 (29.9%) patients died and 545 (60.4%) patients experienced composite endpoints of death and HF readmission. The risk of all-cause death or composite endpoints was lower for HFpEF than HFrEF. Moreover, higher HbA1c variability was associated with higher all-cause mortality or composite endpoints and HbA1c variability was an independent predictor of all-cause mortality or composite endpoints, regardless of EF. CONCLUSIONS: This prospective longitudinal study showed that the all-cause death and composite events was lower for HFpEF than HFrEF. HbA1c variability was independently and similarly predictive of death or combined endpoints in the three HF phenotypes.

Serum uric acid is associated with incidence of heart failure with preserved ejection fraction and cardiovascular events in patients with arterial hypertension.

The objective of the present study was to evaluate clinical implications of serum uric acid (UA) on the progression of heart failure with preserved ejection fraction (HFpEF) in hypertensive patients. A total of 1009 adult patients with left ventricular hypertrophy and suspected left ventricular diastolic dysfunction were enrolled at our hospital from January 2008 to December 2011. With a median follow-up of 7.2 years, 136 (13.2%) patients developed new-onset HFpEF and 151 (15.0%) had major adverse cardiovascular events (MACEs). Compared with the lowest UA tertile of UA (<302 µmol L-1 ), subjects in the highest tertile (>367 µmol L-1 ) had a higher risk of developing new-onset HFpEF (HR: 1.761, 95% CI: 1.119-2.772, P = .015) as well as MACEs (HR: 1.664, 95% CI: 1.086-2.547, P = .019). Our findings indicate that hyperuricemia is associated with detrimental effects in terms of the incidence of new-onset HFpEF as well as MACEs in hypertensive patient.

Resveratrol suppresses doxorubicin-induced cardiotoxicity by disrupting E2F1 mediated autophagy inhibition and apoptosis promotion.

The clinical use of doxorubicin (DOX) is limited by cardiotoxicity, involving the dysregulation of autophagy and apoptosis in the myocardium, which were partly reversed by resveratrol (RSV) supplement. However, a definitive mechanisms accounting for DOX's cardiotoxicity and the protective role of RSV remain poorly defined. The aim of the present study was to clarify the specific role of E2F transcription factor 1 (E2F1) in regulating autophagy and apoptosis in DOX-induced cardiotoxicity as well as the protective effects of RSV. Autophagy and apoptosis were successfully induced by the serum deprivation strategy in H9c2 cardiomyocytes. DOX inhibited autophagy through activating E2F1/mammalian target of rapamycin complex 1 (mTORC1) pathway and further induced apoptosis by activating E2F1/AMP-activated protein kinase α2 (AMPKα2) pathway in starved H9C2 cells. And RSV supplement showed increased autophagy and decreased apoptosis, accompanied with inhibitory effect on E2F1/mTORC1 as well as E2F1/AMPKα2 pathway. Moreover, the favorable effect of RSV on autophagy and apoptosis was dependent on E2F1. The same result was observed in the mouse model of DOX-induced cardiotoxicity in both non-myocardial ischemia and myocardial ischemia condition. Injection with DOX and RSV in combination, resulted in a reduced apoptotic ratio and activated autophagy process compared with the DOX treatment alone. In conclusions, RSV, which has been suggested to attenuate DOX-induced cytotoxicity, significantly blocks induction of E2F1/mTORC1 and E2F1/AMPKα2 pathway by DOX, leading to acceleratory autophagy and inhibitory apoptosis. And E2F1 plays a key role for the protective effect of RSV.

Association of hemoglobin A1c variability and the incidence of heart failure with preserved ejection fraction in patients with type 2 diabetes mellitus and arterial hypertension.

BACKGROUND: This study aimed to investigate the association between variability in hemoglobin A1c (HbA1c) and left ventricular (LV) diastolic function and incidence of symptomatic heart failure with preserved ejection fraction (HFpEF) in patients with type 2 diabetes mellitus (T2DM) and arterial hypertension. METHODS: A retrospective cohort study was conducted on eligible patients with T2DM and hypertension and without clinical signs or symptoms of heart failure in our hospital medical record database. Variability in HbA1c was measured by standard deviation (SD) and coefficient of variation (CV). Risk of new onset of symptomatic HFpEF was evaluated by multivariable cox regression analysis. RESULTS: A total of 201 subjects were categorized according to the median value of HbA1c variability indicators. Over a median follow-up of 7.3 years, the percentage of subjects who had new incidence of symptomatic HFpEF was higher in those with higher HbA1c-SD level (5/105 vs. 13/96, P=0.029) and higher HbA1c-CV level (5/101 vs. 13/100, P=0.046). Multivariable cox regression analysis also showed that higher HbA1c variability [HbA1c-SD (HR 1.754, 95% CI: 1.003-3.104, P=0.049) or HbA1c-CV (HR 1.604 95% CI: 1.064-2.419, P=0.024)] was associated with the presence of new-onset symptomatic HFpEF, independent of HbA1c-mean level, in T2DM and hypertensive patients. Moreover, lower HbA1c variability generated more prominent improvement in LV diastolic function (E/E') during the follow-up. CONCLUSIONS: HbA1c variability may provide additional valuable information as a potential predictor of the progression of HFpEF in T2DM and hypertensive patients.

Low fT3 is associated with diminished health-related quality of life in patients with acute coronary syndrome treated with drug-eluting stent: a longitudinal observational study.

Acute coronary syndrome (ACS) patients with low triiodothyronine (T3) syndrome characterized by low free T3 (fT3) levels with normal thyroxine (T4) and thyroid-stimulating hormone (TSH) have a higher rate of death. The impact of fT3 on Health related quality of life (HRQOL) in patients with ACS is still unknown. 528 ACS patients treated with drug-eluting stent (DES) were included in this prospective, observational study. Patients were classified into low fT3 group (n=126) and normal fT3 group (n=402) according to serum fT3 level. Every patient was prospectively interviewed at baseline and 1 year following percutaneous coronary intervention (PCI). HRQOL was assessed with the use of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). Low fT3 patients had poorer HRQOL than normal fT3 patients both at baseline and 1-year follow-up (all p<0.05). During 1-year follow-up, HRQOL scores for all patients were significantly higher than baseline. Low fT3 patients had lesser gains in physical functioning, bodily pain, general health, vitality, social functioning and role emotional (all p<0.05). Generally, low fT3 patients demonstrated less improvement in Physical Component Score (PCS) (p=0.008) and Mental Component Score (MCS) (p=0.001). The percentage of patients reaching MCID for PCS and MCS was lower in low fT3 group than that in normal fT3 group (p<0.001). Multivariate linear regression analyses showed that low level of fT3 was an independent risk factor for PCS and MCS improvements. In conclusion, a low fT3 level is a predictor of worse HRQOL improvement in ACS patients treated with DES.

Impact of long-term glycemic variability on development of atrial fibrillation in type 2 diabetic patients.

OBJECTIVE: It is well known that patients with type 2 diabetes mellitus (T2DM) have a high risk of atrial fibrillation (AF). The current study was designed to determine the relationship between long-term glycemic variability and incidence of new-onset AF in T2DM patients. METHODS: Between January 2008 and December 2009, we conducted a retrospective cohort study in patients with T2DM referred to our hospital. In 505 consecutive patients without any medical history of AF at baseline, the relationship between hemoglobin A1c (HbA1c) variability and future AF incidence was evaluated, with adjustments for other possible confounding factors. HbA1c variability was determined by standard deviation (SD) and coefficient of variation (CV). RESULTS: Over a median of 6.9-year follow-up period, 48 patients (9.5%) developed incident AF. Multiple cox regression revealed that higher HbA1c-SD (HR: 1.726, 95% CI: 1.104-1.830, p=0.001) or HbA1c-CV (HR: 1.241, 95% CI: 1.029-1.497, p=0.024) remained the remarkable predictor of new-onset AF after adjusting for age, body mass index, left ventricular mass index, and left atrium diameter. Receiver operating curve analysis identified thresholds for HbA1c-SD (0.665%, sensitivity 71.4%, specificity 54.9%) and HbA1c-CV (8.970%, sensitivity 73.8%, specificity 47.1%) to detect new-onset AF development. CONCLUSION: In patients with T2DM, higher HbA1c variability is significantly associated with future AF development.

Model design for screening effective Antihyperlipidemic drugs using zebrafish system.

The purpose of this paper was to explore a new method for screening lipid-lowering drugs in zebrafish models. The suitable drug concentrations of atorvastatin (ATV), fenofibrate (FEF) and ezetimibe (EZE) were first determined. Then, the serum cholesterol and triglyceride levels were detected in high-fat diet (HFD)-fed zebrafish. The HFD zebrafish models were constructed and the effects of drugs on them were observed by Oil red O staining and fluorescence labeling. Statistical analyses among groups were conducted using SPSS software. The lowest drug concentration (LDC) and the highest (HDC) of ATV, FEF and EZE were 0.3 µM/37.0µM, 1.2µM/3.5µM, and 6.3 µM/26.4µM, respectively, while, the intermediate (IDC) was, in order, 18.5µM, 1.8µM, 13.2µM. The cholesterol and triglyceride levels in HFD-fed zebrafish were increased after 7 weeks fat feeding (p<0.05). Moreover, the levels of triglyceride were significantly decreased after LDC of ATV and FEF treated (p<0.05), but not that of EZE. While, the cholesterol levels were reduced in three groups (p<0.05). Moreover, the 5 dpf high-fat zebrafish model was established successfully and maintained stably for 24h. ATV produced effects in a concentration-dependent manner, while only IDC and HDC of FEF and EZE made effects on this model. Intravascular cholesterol levels were significantly increased after HCD treatment and decreased after drug treated. The high-fat zebrafish model induced by HFD-fed was available and successful, besides, the Oil red O staining may be an available and rapid method for screening lipid-lowering drugs.

[Lipid-lowering effect of seven traditional Chinese medicine monomers in zebrafish system].

The present study aimed to study lipid-lowering effect of seven traditional Chinese medicine monomers in zebrafish system. Zebrafish were fed with high fat diet to establish a hyperlipemia model, then fasted and bathed with seven traditional Chinese medicine monomers stigmasterol, triacontanol, chrysophanol, vanillic acid, shikimic acid, polydatin and oleanolic acid respectively. The oil red O staining was used to detect the blood lipids of zebrafish. Serum total cholesterol and triglyceride levels were detected to validate the lipid-lowering effect. The result showed that a zebrafish model of hyperlipemia could be established by feeding larvae zebrafish with high fat diet. Among the seven traditional Chinese medicine monomers, chrysophanol had lipid-lowering effect. Chrysophanol significantly reduced serum total cholesterol and triglyceride levels in adult zebrafish fed with high fat diet. Chrysophanol accelerated peristalsis frequency of zebrafish intestine and the excretion of high fat food. It is concluded that chrysophanol has lipid- lowering effect in zebrafish, and the mechanism of the effect may be due to the roles of chrysophanol in reducing lipid absorption from gastrointestinal tract and accelerating the excretion of food.

Association between long-term prescription of aldosterone antagonist and the progression of heart failure with preserved ejection fraction in hypertensive patients.

BACKGROUND: Hypertension complicated with left ventricular hypertrophy (LVH) and diastolic dysfunction is independently related to increasing risk of subsequent incident heart failure with preserved ejection fraction (HFpEF). This study was designed to evaluate the influences of long-term aldosterone antagonist prescription in these patients. METHODS: Using a propensity score matching of 1:2 ratio, this retrospective claims database study compared spironolactone prescription (n=65) and non-spironolactone therapy (n=130) in hypertensive patients with LVH [left ventricular mass index (LVMI)>125g/m(2) for men and >110g/m(2) for women] and suspected diastolic dysfunction (E/E' ratio between 8 and 15) and without clinical signs or symptoms of heart failure. RESULTS: With a median follow-up of 7.4years, the new-onset symptomatic HFpEF occurred in 3 of 65 patients in the spironolactone group and 21 of 130 patients in the non-spironolactone group (P=0.021). Spironolactone also generated more prominent improvement in diastolic function and LVH. And multivariate logistic regression model revealed that spironolactone prescription (OR 0.177, 95% CI: 0.045-0.687, P=0.012) was associated with a reduced risk of new onset of symptomatic HFpEF, and the elevation of LVMI (OR 1.053, 95% CI: 1.011-1.097, P=0.012) or E/E' (OR 1.280, 95% CI: 1.015-1.615, P=0.037) was associated with a high risk of new onset of symptomatic HFpEF. CONCLUSIONS: Long-term aldosterone antagonist exposure was associated with protective effects in terms of the incidence of new-onset symptomatic HFpEF, LV diastolic dysfunction and LVH in hypertensive patients, which might be beneficial for the delay of HFpEF progression.

Long-term prescription of beta-blocker delays the progression of heart failure with preserved ejection fraction in patients with hypertension: A retrospective observational cohort study.

BACKGROUND: Hypertension complicated with left ventricular hypertrophy (LVH) and diastolic dysfunction is one of the most common risks for heart failure with preserved ejection fraction (HFpEF). This study was designed to evaluate the influences of long-term beta-blocker prescription in these patients. METHODS: This retrospective analysis included eligible patients diagnosed with hypertension, LVH (left ventricular (LV) mass index >125 g/m(2) for men and >110 g/m(2) for women) and suspected diastolic dysfunction (E/E' ratio between 8 and 15) and without clinical signs or symptoms of heart failure in our hospital medical record database (January 2005-December 2009). A total of eligible 1498 patients were enrolled, of whom 803 received beta-blocker prescription and 695 accepted non-beta-blocker therapy. RESULTS: With a median follow-up of 7.2 years, the new-onset symptomatic HFpEF occurred in 48 of 803 patients in the beta-blocker group (6.0%) and 92 of 695 patients in the non-beta-blocker group (13.2%, p < 0.001). Beta-blockers also generated more prominent improvement in diastolic function and LVH. And Cox proportional hazards model revealed that beta-blocker (hazard ratio (HR) 0.327, 95% confidence interval (CI): 0.121-0.540, p = 0.009) or angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (ACEI/ARB) exposure (HR 0.422, 95% CI: 0.210-0.699, p = 0.015) was associated with a reduced risk of new onset of symptomatic HFpEF, and the elevation of LVMI (HR 1.210, 95% CI: 1.069-1.362, p = 0.040) or E/E' (HR 1.398, 95% CI: 1.306-1.541, p = 0.032) was associated with a high risk of new onset of symptomatic HFpEF. CONCLUSIONS: Long-term beta-blocker exposure was associated with protective effects in terms of the incidence of new-onset symptomatic HFpEF, LV diastolic dysfunction and LVH, which might be beneficial for the delay of HFpEF progression.

Application of chrysophanol in zebrafish to reduce dietary introduced lipid and its possible mechanism.

PURPOSE: To explore the therapeutic potential and mechanism of chrysophanol on lipid-lowering function. METHODS: Zebrafish or larvae were employed to evaluate the effect of chrysophanol on lipid-lowering. Zebrafish of 5 day post fertilization (dpf, larva) and 13-week old were fed with high-cholesterol diet or high-fat to investigate the influence of chrysophanol comparing with atorvastain and co-administration of chrysophanol and atorvastain on subsistent blood lipid using the fluorescence microscope and lipid panel screen. Thereafter, we enrolled zebrafish of 7 dpf fed with high-fat diet to explore the lipid-lowering mechanism of chrysophanol basing on the frequency of peristalsis and the residual on the digestive wall. RESULTS: Chrysophanol could significantly lower cholesterol both in zebrafish and larvae (P < 0.05), and the co-administration of chrysophanol and atorvastatin had the best performance in reducing cholesterol (P < 0.05). Chrysophanol and atorvastain could also significantly lower triglyceride. Moreover, we found that chrysophanol attached on the digestive wall for a long time and enhanced the frequency of peristalsis. CONCLUSIONS: Chrysophanol has lipid-lowering effect both in zebrafish and larvae which may be attributed to the effect on the frequency of peristalsis and fat absorption, and co-administration with atorvastain performs better lipid-lowering effect in zebrafish.