Zhaofang Yin

Adipose tissue-derived stem cells embedded with eNOS restore cardiac function in acute myocardial infarction model

This study assessed the potential therapeutic efficacy of endothelial NO syntheses (eNOS)-expressing adipose tissue-derived stem cells (ADSCs) on infarcted hearts. We isolated CD29+, CD44+, CD45- cells from adipose tissue. Multipotent property of ADSCs was characterized by induction to differentiate into myogenic, neurogenic, and endothelic lineages. We hypothesized that combination of eNOS over-expression and transplantation of ADSCs could restore NO bioavailability and improve cardiac function in infarcted hearts. Here with several lines of experimental evidences, we demonstrated that ADSCs with eNOS overexpression induced eNOS expression in host endothelial cells and vascular smooth muscle cells, both in vitro and in vivo. This effect was possibly mediated by calcium signal. Transplantation of ADSCs with eNOS embedded showed great therapeutic efficacy in reduction of infarcted size, compared with normal ADSC. Results of this study suggest that ADSCs could be an attractive vehicle for the exogenous eNOS expression into heart after infarction, which is beneficial to restoration of cardiac function. Paracrine effect by mobilizing the host endothelial cells and smooth muscle cells may be the mechanism underlying the therapeutic effect.

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/m2 for men and >110 g/m2 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.

Overexpression of CXCR1/CXCR2 on mesenchymal stromal cells may be an effective treatment for acute myocardial infarction

Bone marrow (BM)-derived mesenchymal stromal cells (MSC) participate in myocardial repair following myocardial infarction (MI). However, their reparative capability is limited, partly because of poor homing abilities. MI is associated with an inflammatory reaction. Interleukin-8 (IL-8) appears to have a fundamental role in regulating neutrophil localization in ischemic tissues through binding CXCR1/CXCR2 receptors, which show major expression on neutrophils. We hypothesize that the application of IL-8 will enhance the recruitment of overexpressing CXCR1/CXCR2 MSC to sites of degenerated tissue of myocardium, decreasing the ischemic region and improving cardiac function.

Artemisinin inhibits monocyte adhesion to HUVECs through the NF-κB and MAPK pathways in vitro

The adhesion of monocytes to human umbilical vein endothelial cells (HUVECs) plays a crucial role in the initiation of atherosclerosis. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are two important molecules involved in the adhesion of monocytes to HUVECs. Previous studies have suggested that artemisinin, apart from an anti-malarial agent, also has other effects. In the present study, we found that artemisinin significantly decreased the adhesion of monocytes to tumor necrosis factor-α (TNF-α)-stimulated HUVECs in a dose-dependent manner and suppressed the mRNA and protein level of ICAM-1 and VCAM-1 in the TNF-α-stimulated HUVECs. In addition, the nuclear factor-κB (NF-κB) inhibitor, Bay 11-7082, and mitogen-activated protein kinase (MAPK) inhibitors (SB203580 and U0126) respectively reduced the adhesion of monocytes to TNF-α-stimulated HUVECs, and suppressed ICAM-1 and VCAM-1 expression in TNF-α stimulated HUVECs. Moreover, artemisinin impeded the activation of the NF-κB and MAPK signaling pathways. Furthermore, Bay 11-7082 significantly decreased the phosphorylation of levels extracellular signal-regulated protein kinase (ERK)1/2, p38 and c-Jun N-terminal kinase (JNK). Taken together, the findings of our study indicated that artemisinin blocked monocyte adhesion to TNF-α-stimulated to HUVECs by downregulating ICAM-1 and VCAM-1 expression in the TNF-α-stimulated HUVECs. Artemisinin may thus have potential for use in the protection against the early development of atherosclerotic lesions.

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 >7‑dpf. 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.

Non-Invasive Assessment of Early Atherosclerosis Based on New Arterial Stiffness Indices Measured with an Upper-Arm Oscillometric Device

The clinical significance of detecting early atherosclerosis is now widely recognized. Measurement methods available at present are usually not suitable for use in primary care where rapid screening for a large population is needed. The Arterial Velocity-pulse Index (AVI) and Arterial Pressure-volume Index (API) are new noninvasive arterial stiffness indices that can be rapidly measured using an oscillometric device. The purpose of this study was to determine whether high AVI and API values are predictive of early atherosclerosis prior to the onset of obstructive coronary artery disease (CAD). A total of 183 patients were enrolled and allocated to the CAD group (n = 109), early atherosclerosis (AS) group (n = 34) or an apparently healthy (non-AS) group (n = 40) based on the results of angiographic examinations. Measurements for arterial blood pressure, AVI, API and brachial-ankle pulse wave velocity (baPWV) were collected. Statistical analyses revealed that AVIs were significantly lower in the non-AS group than in the AS group and the CAD group. The inter-group differences in API were not statistically significant among the 3 patient groups. As a reference, baPWV was found to be statistically higher in the CAD group than in the non-AS group, whereas there was no significant difference between the CAD group and the AS group, or between the AS group and the non-AS group. The AVI and API were both significantly correlated with baPWV. This study demonstrated that AVI was more sensitive than baPWV and API in indicating early atherosclerosis, although elevated AVI and baPWV were both predictive of CAD.

Low serum paraoxonase1 activity levels predict coronary artery disease severity.

Paraoxonase1 (PON1) activity is closely related to coronary artery disease (CAD). However, whether PON1 activity can predict the degree of coronary stenosis remains unknown. In the present study, the serum PON1 activity and related factors that influence PON1 activity were analyzed in 186 patients with diagnostic coronary angiography. The serum PON1 activity was determined using a spectrophotometry-based assay in 186 patients with diagnostic coronary angiography, in which coronary stenosis severity was graded and clinically defined as single- or multi-vessel stenosis >50%. Target lesion stenosis was quantified via quantitative coronary angiography (QCA). The serum PON1 activity was significantly decreased in the CAD group, the multiple coronary stenosis subgroup, and the diabetes mellitus subgroup compared with each control group. The PON1 activity was positively correlated with the High density lipoprotein cholesterol (HDL-C) and Apolipoprotein A1 (ApoA1). Males, smoking, diabetes, and heart failure were identified as factors that influenced PON1 activity. Furthermore, a Receiver Operating Characteristic Curve (ROC) analysis indicated that a PON1 activity cut-off point of 330 U/L could predict CAD with a sensitivity of 52% and a specificity of 65%. In conclusion, low PON1 activity predicted the degree of coronary lesion, particularly in multiple vessel lesions, smokers, and diabetes, which may represent a biochemical marker for the severity of CAD.

Transient Hemodynamic Changes upon Changing a BCPA into a TCPC in Staged Fontan Operation: A Computational Model Study

The clinical benefits of the Fontan operation in treating single-ventricle defects have been well documented. However, perioperative mortality or morbidity remains a critical problem. The purpose of the present study was to identify the cardiovascular factors that dominate the transient hemodynamic changes upon the change of a bidirectional cavopulmonary (Glenn) anastomosis (BCPA) into a total cavopulmonary connection (TCPC). For this purpose, two computational models were constructed to represent, respectively, a single-ventricle circulation with a BCPA and that with a TCPC. A series of model-based simulations were carried out to quantify the perioperative hemodynamic changes under various cardiovascular conditions. Obtained results indicated that the presence of a low pulmonary vascular resistance and/or a low lower-body vascular resistance is beneficial to the increase in transpulmonary flow upon the BCPA to TCPC change. Moreover, it was found that ventricular diastolic dysfunction and mitral valve regurgitation, despite being well-known risk factors for poor postoperative outcomes, do not cause a considerable perioperative reduction in transpulmonary flow. The findings may help physicians to assess the perioperative risk of the TCPC surgery based on preoperative measurement of cardiovascular function.

A multi-scale model of the coronary circulation applied to investigate transmural myocardial flow

Distribution of blood flow in myocardium is a key determinant of the localization and severity of myocardial ischemia under impaired coronary perfusion conditions. Previous studies have extensively demonstrated the transmural difference of ischemic vulnerability. However, it remains incompletely understood how transmural myocardial flow is regulated under in vivo conditions. In the present study, a computational model of the coronary circulation was developed to quantitatively evaluate the sensitivity of transmural flow distribution to various cardiovascular and hemodynamic factors. The model was further incorporated with the flow autoregulatory mechanism to simulate the regulation of myocardial flow in the presence of coronary artery stenosis. Numerical tests demonstrated that heart rate (HR), intramyocardial tissue pressure (Pim ), and coronary perfusion pressure (Pper ) were the major determinant factors for transmural flow distribution (evaluated by the subendocardial-to-subepicardial (endo/epi) flow ratio) and that the flow autoregulatory mechanism played an important compensatory role in preserving subendocardial perfusion against reduced Pper . Further analysis for HR variation-induced hemodynamic changes revealed that the rise in endo/epi flow ratio accompanying HR decrease was attributable not only to the prolongation of cardiac diastole relative to systole, but more predominantly to the fall in Pim . Moreover, it was found that Pim and Pper interfered with each other with respect to their influence on transmural flow distribution. These results demonstrate the interactive effects of various cardiovascular and hemodynamic factors on transmural myocardial flow, highlighting the importance of taking into account patient-specific conditions in the explanation of clinical observations.

Low systolic blood pressure for predicting all-cause mortality in patients hospitalised with heart failure: a systematic review and meta-analysis

Heart failure (HF) is still a major global health concern, contributing to high mortality and morbidity. Despite the advances in medical treatment, the prognosis of acute HF patients remains poor. Therefore, early risk stratification is of greater importance in the management of patients hospitalised with HF. Higher systolic blood pressure (SBP) may confer a better prognosis in these patients. A well-designed meta-analysis has summarised that each 10mmHg increase in SBP was associated with a 13% reduction in death risk among chronic HF patients. Increasing attention has focused on the prognostic role of SBP on acute HF. However, no previous meta-analysis has summarised the prognostic value of SBP in acute HF settings. This meta-analysis aimed to investigate quantitatively the association between low SBP on admission or discharge and all-cause mortality risk in hospitalised HF patients. Two reviewers independently searched the PubMed and Embase databases to identify relevant studies published from their inception to March 2018. The search terms used were: systolic blood pressure AND heart failure AND mortality OR death AND admission OR hospitalisation OR hospitalised OR discharge. The inclusion criteria were: (a) observational studies including post hoc analyses of randomised clinical trials; (b) enrollment of hospitalised HF patients; (c) low SBP on admission or discharge as exposure; (d) all-cause mortality as outcome measures; and (e) providing multivariable adjusted risk estimate for the lowest versus the reference higher SBP category and per unit SBP decrease. Studies with stable HF, aortic/ mitral valve disease population were excluded. Moreover, studies with unclear timing measurement of SBP or inhospital death as an outcome measure were also excluded. The Newcastle–Ottawa scale was applied to examine the methodological quality of the included studies. Data analyses were performed using STATA 12.0. For the categorical analysis, we pooled risk estimates for the lowest versus the reference higher SBP category. For analysing SBP as continuous data, we recalculated the risk estimate by per 10mmHg decrease of SBP using the following formula: HR101⁄4 exp (ln (HR1) 10). Fifteen studies involving 133,549 HF patients were ultimately included in this meta-analysis (Table 1). Meta-analysis from six studies showed that the lowest SBP on admission increased the risk of all-cause mortality (hazard ratio (HR) 2.22; 95% confidence interval (CI) 1.72–2.86) when compared with the reference higher SBP category. There was no evidence of publication bias according to the Begg’s test (P1⁄4 0.210) or Egger’s test (P1⁄4 0.119). However, the lowest SBP on discharge was not associated with an increased all-cause mortality (HR 1.35; 95% CI 0.66–2.73) in pooling three studies. Meta-analysis from seven studies indicated that the pooled HR of all-cause mortality was 1.10 (95% CI 1.06–1.15) per 10mmHg admission SBP decrease in a random effect model. Egger’s test (P1⁄4 0.061) but not Begg’s test (P1⁄4 0.266) revealed the presence of publication bias. Subgroup analyses indicated that both categorical and continuous low admission SBP were consistently associated with a higher risk of all-cause mortality in the study design, follow-up period, study quality or whether with reduced left ventricular ejection fraction subgroups. This meta-analysis shows that low SBP on admission is independently associated with an increased risk of death among patients hospitalised with HF. Patients with the lowest admission SBP increases 2.22-fold risk