Impact of smoking on health-related quality of Life after percutaneous coronary intervention treated with drug-eluting stents: a longitudinal observational study.

BACKGROUND: Smoking has been shown to reduce health-related quality of life (HRQOL) in patients with coronary artery disease (CAD) undergoing percutanous coronary intervention (PCI) either by means of balloon angioplasty or with the use of bare-metal stents (BMS). Drug-eluting stents (DES) have now been widely used and are related to substantial reduction of restenosis and significantly improved HRQOL compared with BMS. This study aimed to evaluate the effects of smoking on HRQOL in patients after PCI in DES era. METHODS: A cohort of 649 patients admitted for CAD and treated with drug-eluting stents were included in this prospective, observational study. Patients were classified as non-smokers (n = 351, 54.1%), quitters (n = 126, 19,4%), or persistent smokers (n = 172, 26.5%) according to their smoking status at the time they first admitted to hospital and during the first year of follow-up. Each patient was prospectively interviewed at baseline, 6 months and 1 year following PCI. HRQOL was assessed with the use of Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). RESULTS: For the overall population, HRQOL scores at 1-year follow-up were significantly higher than baseline for all 8 domains. At 1-year follow-up, the HRQOL scores in persistent smokers were still lower than that in non-smokers in 6 domains except for bodily pain and mental health, and than that in quitters in 5 domains except for bodily pain, role emotional and mental health. There were no significant differences with regard to the scores between non-smokers and quitters except role emotional for which non-smokers had higher scores. After adjustment, persistent smokers demonstrated significantly less improvements in HRQOL than non-smokers in 6 domains except for bodily pain and social functioning and significantly less improvement than quitters for general health. Improvements of quitters were comparable to that of non-smokers in all domains. Multivariate linear regression analyses showed persistent smoking was an independent risk factor for PCS and MCS improvements. CONCLUSIONS: Persistent smoking substantially diminishes the potential quality-of-life benefits of DES. Efforts should be made to promote smoking cessation after DES implantation which could greatly improve the health quality outcomes.

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.

Establishment of the mouse model of acute exacerbation of idiopathic pulmonary fibrosis.

PURPOSE: To explore and establish an animal model of AE-IPF. METHODS: An animal model of idiopathic pulmonary fibrosis (IPF) was established using bleomycin (BLM). Then, BLM was administered a second time on day 21 to induce AE-IPF (which mimics human AE-IPF). Evaluation of the success of animal model was based on the survival of mice, as well as assessment of pathological changes in lung tissue. Preliminary investigation into the immunological mechanism of AE-IPF was also explored via the detection and identification of the inflammatory cells in mouse bronchoalveolar lavage fluid (BALF) and the concentrations of six cytokines (IL-4, IL-6, IL-10, IL-17A, MIG, and TGF-ß1) in BALF supernatants, which were closely associated with IPF and AE-IPF. The intervention role of IL-17A antibody to AE was explored. RESULTS: By week 4 after the second BLM administration, the mortality in the AE-IPF group was significantly greater (45%, 9/20) than that in stable-IPF group (0/18) (P = .0017). The average body weight in AE-IPF group was significantly lower than that in stable group (P < .0001). In AE-IPF group, inflammation and fibrosis were severer by histopathology analysis. In BALF, IL-17A, MIG (CXCL-9), IL-6, and TGF-ß1 levels in AE group were significantly higher. The percentages of neutrophils and Th17 cells in BALF were significantly higher in AE group (P < .01; P = .0281). IL-17A antibody could attenuated the lung inflammation induced by twice BLM challenges. CONCLUSION: A mouse model of AE-IPF can be established using two administrations of BLM; Th17 cells may play a key role during the pathological process of AE-IPF.

N-acetylcysteine attenuates cigaret smoke-induced pulmonary exacerbation in a mouse model of emphysema.

OBJECTIVE: The purpose of this study was to investigate the effects of cigaret smoke (CS) on a mouse model of emphysema and examine the protective role of N-acetylcysteine (NAC) in the CS-induced exacerbation of pulmonary damage in the mice. METHOD: Particulate matter (PM) in sidestream cigaret smoke aerosol was analyzed by a scanning mobility particle sizer spectrometer. A mouse model of emphysema was established by an injection of porcine pancreatic elastase (PPE) into the trachea. Mice with emphysema were then exposed to filtered air, or sidestream CS with intragastric administration of NAC or normal saline. Mouse body weight, survival, pulmonary tissue histology, total antioxidant capacity (T-AOC) and malonaldehyde (MDA) contents in lung tissue, and inflammatory responses were examined. RESULTS: Particles with a size of ≤346 nm constituted 99.06% of CS PM. Mice exhibited ruptured alveolar septal, alveolar fusion, significantly increased mean lining interval, and reduced mean alveolar number (all p < 0.05), 21 d after PPE injection. Exposure of mice with emphysema to CS exacerbated the pulmonary tissue damage, caused weight loss, significantly increased mortality, decreased T-AOC, elevated MDA contents in lung tissue, and increased interleukin (IL)-1ß levels in bronchoalveolar lavage (BAL) fluids (all p < 0.05). Administration of NAC attenuated those CS-induced adverse effects in the mice and increased anti-inflammatory factor IL-10 levels in BAL fluids significantly (all p < 0.05). CONCLUSIONS: Exposure of mice with emphysema to CS exacerbated the pulmonary damage, and NAC reduced the CS-mediated pulmonary damage by preventing oxidative damage and reducing inflammatory responses.

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.

Development and assessment of the efficacy and safety of human lung-targeting liposomal methylprednisolone crosslinked with nanobody.

Glucocorticoid (GC) hormone has been commonly used to treat systemic inflammation and immune disorders. However, the side effects associated with long-term use of high-dose GC hormone limit its clinical application seriously. GC hormone that can specifically target the lung might decrease the effective dosage and thus reduce GC-associated side effects. In this study, we successfully prepared human lung-targeting liposomal methylprednisolone crosslinked with nanobody (MPS-NSSLs-SPANb). Our findings indicate that MPS-NSSLs-SPANb may reduce the effective therapeutic dosage of MPS, achieve better efficacy, and reduce GC-associated side effects. In addition, MPS-NSSLs-SPANb showed higher efficacy and lower toxicity than conventional MPS.

Association between long-term prescription of metformin and the progression of heart failure with preserved ejection fraction in patients with type 2 diabetes mellitus and hypertension.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and hypertension are 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 metformin prescription in these patients. METHODS: Using a propensity score matching of 1:2 ratio, this retrospective claims database study compared metformin prescription (n = 130) and non-metformin therapy (n = 260) in patients with T2DM and hypertension and without clinical signs or symptoms of heart failure. RESULTS: With a follow-up of 6 years, the new-onset symptomatic HFpEF occurred in 6 of 130 patients in metformin group and 31 of 260 patients in non-metformin group (P = .020). Metformin also generated more prominent improvement in left ventricular (LV) diastolic function and hypertrophy. And Cox proportional hazards regression model revealed that metformin prescription (HR 0.351, 95% CI: 0.145-0.846, P = .020) was associated with a reduced risk of new onset of symptomatic HFpEF. CONCLUSIONS: Long-term metformin exposure was associated with protective effects in terms of the incidence of new-onset symptomatic HFpEF, LV diastolic dysfunction and hypertrophy in patients with T2DM and hypertension, which might be beneficial for the delay of HFpEF progression.

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.

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.

Visit-to-visit variability in low-density lipoprotein cholesterol is associated with adverse events in non-obstructive coronary artery disease.

OBJECTIVE: A higher visit-to-visit variability in low-density lipoprotein cholesterol (LDL-C) is associated with an increased frequency of cardiovascular events. We investigated the association between the visit-to-visit LDL-C variability and all-cause mortality, myocardial infarction (MI), and coronary revascularization in a population with non-obstructive coronary artery disease (CAD). METHODS: From this retrospective cohort of individuals who underwent coronary angiography from 2006 to 2010, a total of 2.012 consecutive patients with non-obstructive CAD, who underwent three or more LDL-C determinations during the first 2 years, were identified and followed up for 5 years. The variability in the visit-to-visit LDL-C was measured by standard deviation (SD) and coefficient of variation (CV). The risk of all-cause mortality and composite endpoints, MI, and coronary revascularization were evaluated by a multivariable Cox regression analysis. RESULTS: During a 5-year follow-up, a total of 99 (4.92%) mortality cases and 154 (7.65%) cases of composite endpoints were observed. The percentage of subjects who experienced mortality or composite endpoints was higher in those with a higher LDL-C-SD or LDL-C-CV level. The association between the LDL-C variability and clinical endpoints was regardless of possible confounding factors. CONCLUSION: Among the patients with non-obstructive CAD, a higher visit-to-visit LDL-C variability is associated with increasing all-cause mortality or composite endpoints during the long-term follow-up.

Effects of Smoking Cessation with Nicotine Replacement Therapy on Vascular Endothelial Function, Arterial Stiffness, and Inflammation Response in Healthy Smokers.

The effects of nicotine replacement therapy (NRT)-aided smoking cessation on vascular function are not fully clarified. We investigated 100 healthy smokers who were motivated to quit and received NRT for a 3-month period. Vascular endothelial function (measured by reactive hyperemia-peripheral arterial tonometry [RH-PAT]), arterial stiffness (measured by augmentation index [AI] and brachial-ankle pulse wave velocity [baPWV]), and systemic inflammation markers (including serum soluble intercellular adhesion molecule-1 [sICAM-1] and interleukin-1ß [IL-1ß]) were assessed at baseline and 3 and 12 months of follow-up. After 3 months of intervention, endothelial function, arterial stiffness, and inflammatory markers significantly improved (RH-PAT increased, AI and baPWV decreased, sICAM-1 and IL-1ß decreased, all P < .05) for the participants who abstained from smoking completely, but for those who did not abstained completely, RH-PAT, AI, baPWV, and IL-1ß remained unchanged. At 12 months follow-up, endothelial function (RH-PAT), arterial stiffness (AI and baPWV), and inflammatory markers (sICAM-1 and IL-1ß) were further improved in participants who abstained from smoking (P < .001), while the above parameters deteriorated in continued smokers (P < .05). In conclusion, vascular dysfunction can be reversible after NRT-aided smoking cessation in healthy smokers and vascular function could be further damaged if they continue smoking.

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.

Development of a non-infectious rat model of acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease with severe pulmonary fibrosis. The main cause of IPF-associated death is acute exacerbation of IPF (AE-IPF). This study aims to develop a rat model of AE-IPF by two intratracheal perfusions with bleomycin (BLM). METHODS: Ninety male Sprague Dawley (SD) rats were randomized into three groups: an AE-IPF model group (BLM + BLM group), an IPF model group (BLM group), and a normal control group. Rats in the BLM + BLM group underwent a second perfusion with BLM on day 28 after the first perfusion with BLM. Rats in the other two groups received saline as the second perfusion. Six rats in each group were sacrificed on day 31, day 35, and day 42 after the first perfusion, respectively. Additional 18 rats in each group were observed for survival. RESULTS: Rats in the BLM + BLM group had significantly worse pulmonary alveolar inflammation and fibrosis than rats in the BLM group. Rats in the BLM + BLM group also developed large amounts of hyaline membrane, showed high levels of albumin (ALB) and various inflammatory factors in the bronchoalveolar lavage fluid (BALF), and had markedly increased lung water content. Furthermore, rat survival was reduced in the BLM + BLM group. The pathophysiological characteristics of rats in the BLM + BLM group resemble those of patients with AE-IPF. CONCLUSIONS: A second perfusion with BLM appears to induce acute exacerbation of pulmonary fibrosis and may be used to model AE-IPF in rats.

Erratum: Identification of a nanobody specific to a human pulmonary surfactant protein A.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

Surfactant protein-A nanobody-conjugated liposomes loaded with methylprednisolone increase lung-targeting specificity and therapeutic effect for acute lung injury.

The advent of nanomedicine requires novel delivery vehicles to actively target their site of action. Here, we demonstrate the development of lung-targeting drug-loaded liposomes and their efficacy, specificity and safety. Our study focuses on glucocorticoids methylprednisolone (MPS), a commonly used drug to treat lung injuries. The steroidal molecule was loaded into functionalized nano-sterically stabilized unilamellar liposomes (NSSLs). Targeting functionality was performed through conjugation of surfactant protein A (SPANb) nanobodies to form MPS-NSSLs-SPANb. MPS-NSSLs-SPANb exhibited good size distribution, morphology, and encapsulation efficiency. Animal experiments demonstrated the high specificity of MPS-NSSLs-SPANb to the lung. Treatment with MPS-NSSLs-SPANb reduced the levels of TNF-α, IL-8, and TGF-ß1 in rat bronchoalveolar lavage fluid and the expression of NK-κB in the lung tissues, thereby alleviating lung injuries and increasing rat survival. The nanobody functionalized nanoparticles demonstrate superior performance to treat lung injury when compared to that of antibody functionalized systems.

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.

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.

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.

Optimizing methods for the study of intravascular lipid metabolism in zebrafish.

The zebrafish (Danio rerio) is a useful vertebrate model for use in cardiovascular drug discovery. The present study aimed to construct optimized methods for the study of intravascular lipid metabolism of zebrafish. The lipophilic dye, Oil Red O, was used to stain fasting zebrafish one to eight days post-fertilization (dpf) and to stain 7-dpf zebrafish incubated in a breeding system containing 0.1% egg yolk as a high-fat diet (HFD) for 48 h. Three-dpf zebrafish were kept in CholEsteryl boron-dipyrromethene (BODIPY) 542/563 C11 water for 24 h which indicated the efficiency of CholEsteryl BODIPY 542/563 C11 intravascular cholesterol staining. Subsequently, 7-dpf zebrafish were incubated in water containing the fluorescent probe CholEsteryl BODIPY 542/563 C11 and fed a high-cholesterol diet (HCD) for 10 d. Two groups of 7-dpf zebrafish were incubated in regular breeding water and fed with a regular or HCD containing CholEsteryl BODIPY 542/563 C11 for 10 d. Finally, blood lipids of adult zebrafish fed with regular or HFD for seven weeks were measured. Oil Red O was not detected in the blood vessels of 7-8-dpf zebrafish. Increased intravascular lipid levels were detected in 7-dpf zebrafish incubated in 0.1% egg yolk, indicated by Oil Red O staining. Intravascular cholesterol was efficiently stained in 3-dpf zebrafish incubated in breeding water containing CholEsteryl BODIPY 542/563 C11; however, this method was inappropriate for the calculation of intravascular fluorescence intensity in zebrafish >7­dpf. In spite of this, intra-aortic fluorescence intensity of zebrafish fed a HCD containing CholEsteryl BODIPY 542/563 C11 was significantly higher (P<0.05) than that of those fed a regular diet containing CholEsteryl BODIPY 542/563 C11. The serum total cholesterol and triglyceride levels of adult zebrafish fed a HFD were markedly increased compared to those of the control group (P<0.05). In conclusion, the use of Oil Red O staining and CholEsteryl BODIPY 542/563 C11 may have applications in zebrafish intravascular lipid metabolism research and screens for novel lipid-regulating drugs.

A novel nanobody specific for respiratory surfactant protein A has potential for lung targeting.

Lung-targeting drugs are thought to be potential therapies of refractory lung diseases by maximizing local drug concentrations in the lung to avoid systemic circulation. However, a major limitation in developing lung-targeted drugs is the acquirement of lung-specific ligands. Pulmonary surfactant protein A (SPA) is predominantly synthesized by type II alveolar epithelial cells, and may serve as a potential lung-targeting ligand. Here, we generated recombinant rat pulmonary SPA (rSPA) as an antigen and immunized an alpaca to produce two nanobodies (the smallest naturally occurring antibodies) specific for rSPA, designated Nb6 and Nb17. To assess these nanobodies' potential for lung targeting, we evaluated their specificity to lung tissue and toxicity in mice. Using immunohistochemistry, we demonstrated that these anti-rSPA nanobodies selectively bound to rat lungs with high affinity. Furthermore, we intravenously injected fluorescein isothiocyanate-Nb17 in nude mice and observed its preferential accumulation in the lung to other tissues, suggesting high affinity of the nanobody for the lung. Studying acute and chronic toxicity of Nb17 revealed its safety in rats without causing apparent histological alterations. Collectively, we have generated and characterized lung-specific nanobodies, which may be applicable for lung drug delivery.