Jianping Bin

Effects of Beta-Blockers on Heart Failure with Preserved Ejection Fraction: A Meta-Analysis

Background Effects of beta-blockers on the prognosis of the heart failure patients with preserved ejection fraction (HFpEF) remain controversial. The aim of this meta-analysis was to determine the impact of beta-blockers on mortality and hospitalization in the patients with HFpEF. Methods A search of MEDLINE, EMBASE, and the Cochrane Library databases from 2005 to June 2013 was conducted. Clinical studies reporting outcomes of mortality and/or hospitalization for patients with HFpEF (EF ≥ 40%), being assigned to beta-blockers treatment and non-beta-blockers control group were included. Results A total of 12 clinical studies (2 randomized controlled trials and 10 observational studies) involving 21,206 HFpEF patients were included for this meta-analysis. The pooled analysis demonstrated that beta-blocker exposure was associated with a 9% reduction in relative risk for all-cause mortality in patients with HFpEF (95% CI: 0.87 – 0.95; P < 0.001). Whereas, the all-cause hospitalization, HF hospitalization and composite outcomes (mortality and hospitalization) were not affected by this treatment (P = 0.26, P = 0.97, and P = 0.88 respectively). Conclusions The beta-blockers treatment for the patients with HFpEF was associated with a lower risk of all-cause mortality, but not with a lower risk of hospitalization. These finding were mainly obtained from observational studies, and further investigations are needed to make an assertion.

Histamine H2 receptor activation exacerbates myocardial ischemia/reperfusion injury by disturbing mitochondrial and endothelial function

There is evidence that H2R blockade improves ischemia/reperfusion (I/R) injury, but the underlying cellular mechanisms remain unclear. Histamine is known to increase vascular permeability and induce apoptosis, and these effects are closely associated with endothelial and mitochondrial dysfunction, respectively. Here, we investigated whether activation of the histamine H2 receptor (H2R) exacerbates myocardial I/R injury by increasing mitochondrial and endothelial permeability. Serum histamine levels were measured in patients with coronary heart disease, while the influence of H2R activation was assessed on mitochondrial and endothelial function in cultured cardiomyocytes or vascular endothelial cells, and myocardial I/R injury in mice. The serum histamine level was more than twofold higher in patients with acute myocardial infarction than in patients with angina or healthy controls. In neonatal rat cardiomyocytes, histamine dose-dependently reduced viability and induced apoptosis. Mitochondrial permeability and the levels of p-ERK1/2, Bax, p-DAPK2, and caspase 3 were increased by H2R agonists. In cultured human umbilical vein endothelial cells (HUVECs), H2R activation increased p-ERK1/2 and p-moesin levels and also enhanced permeability of HUVEC monolayer. All of these effects were abolished by the H2R blocker famotidine or the ERK inhibitor U0126. After I/R injury or permanent ischemia, the infarct size was reduced by famotidine and increased by an H2R agonist in wild-type mice. In H2R KO mice, the infarct size was smaller; myocardial p-ERK1/2, p-DAPK2, and mitochondrial Bax were downregulated. These findings indicate that H2R activation exaggerates myocardial I/R injury by promoting myocardial mitochondrial dysfunction and by increasing cardiac vascular endothelial permeability.

Detrimental effect of fractalkine on myocardial ischaemia and heart failure

AIMS Fractalkine (FKN) is a newly identified membrane-bound chemokine; its role in myocardial ischaemia and heart failure is largely unknown. We attempted to investigate the role of FKN in myocardial ischaemia and ischaemia or pressure overload-induced ventricular remodelling and heart failure. METHODS AND RESULTS FKN-induced changes of heart failure-related genes in cultured rat cardiac cells and the effect of FKN on cultured cardiomyocyte injury during anoxia/reoxygenation (A/R) were examined. The direct influence of FKN neutralization on heart failure and the potential mechanism was also investigated. In mice with failing hearts, myocardial FKN expression was correlated with the lung weight/body weight ratio, left ventricular fractional shortening, and brain natriuretic peptide expression. In cultured rat cells, exposure to FKN increased natriuretic peptide A expression in cardiomyocytes, matrix metalloproteinase-9 expression in fibroblasts, and intercellular adhesion molecule-1 expression in microvascular endothelial cells. FKN also promoted cardiomyocyte damage during A/R and neutralizing FKN antibody treatment improved heart failure induced by myocardial infarction or pressure overload. Neutralizing FKN or its receptor inhibited the activation of mitogen-activated protein kinases (MAPKs) in hypoxic cardiomyocytes or ischaemic myocardium. CONCLUSION FKN promotes myocardial injury and accelerates the progress of heart failure, which is associated with the activation of MAPKs.

Resveratrol improves myocardial ischemia and ischemic heart failure in mice by antagonizing the detrimental effects of fractalkine

Objectives:To test the hypothesis that resveratrol would improve cardiac remodeling by inhibiting the detrimental effects of fractalkine. We previously reported that fractalkine exacerbates heart failure. Furthermore, this study sought to determine whether resveratrol targets fractalkine to improve myocardial ischemia and cardiac remodeling. Design:Randomized and controlled laboratory investigation. Setting:Research laboratory. Subjects:Neonatal rat cardiac cells and C57BL/6 mice. Interventions:Cardiac cells were treated with recombinant mouse soluble fractalkine for 24 hrs or pretreated with 25 µM resveratrol. Cardiomyocytes were exposed to anoxia/reoxygenation, H2O2, or pretreatment with resveratrol. Ex vivo murine hearts were perfusioned with soluble fractalkine or pretreated with resveratrol after global ischemia. Mice were subjected to the left coronary artery ligation to induce myocardial infarction and randomized to treatment with resveratrol or vehicle alone for 42 days. Measurements and Main Results:In a murine myocardial infarction model, we found that resveratrol increased survival and delayed the progression of cardiac remodeling evaluated by serial echocardiography. At 6 wks, the heart weight/body weight ratio, lung weight/body weight ratio, and old infarct size were significantly smaller in resveratrol-treated mice than in untreated myocardial infarction mice. In cultures of neonatal rat cells, exposure to soluble fractalkine increased the atrial natriuretic peptide expression by cardiomyocytes, matrix metalloproteinase-9 and procollagen expression by fibroblasts, and intercellular adhesion molecule-1 expression by microvascular endothelial cells, while it decreased autophagy in cardiomyocytes. All these effects were blocked by coculture with resveratrol. The methyl thiazolyl tetrazolium assay showed that soluble fractalkine reduced the viability of cultured cardiomyocytes during exposure to anoxia/reoxygenation or H2O2, while pretreatment with resveratrol blocked this effect. Perfusion of ex vivo murine hearts with soluble fractalkine after global ischemia led to an increase of infarct size, which was prevented by pretreatment with resveratrol. Conclusion:Resveratrol alleviates the deleterious effects of fractalkine on myocardial ischemia and thus reduces subsequent cardiac remodeling.

Efficacy of Contrast-enhanced US and Magnetic Microbubbles Targeted to Vascular Cell Adhesion Molecule–1 for Molecular Imaging of Atherosclerosis

PURPOSE To evaluate whether microbubbles targeted to vascular cell adhesion molecule-1 (VCAM-1) (CD106) coupled with a magnetic guidance system could improve the efficacy of contrast-enhanced molecular ultrasonography (US) of atherosclerosis in the aorta. MATERIALS AND METHODS The animal research committee at Southern Medical University approved all experiments. Adherence of magnetic VCAM-1-targeted microbubbles, control inactive magnetic microbubbles, and nonmagnetic VCAM-1-targeted microbubbles to VCAM-1-Fc was determined in vitro by using a flow chamber at variable shear stress (1-24 dyne/cm(2)) under magnetic field guidance. Attachment of microbubbles under magnetic field guidance was determined in vivo with fluorescent microscopy and contrast-enhanced US of the abdominal aorta in wild-type (C57BL/6) or apolipoprotein E (APOE)-deficient mice on a regular or hypercholesterolemic diet. General factorial analysis of variance was used to compare the targeted effect of the microbubbles among different animal groups to identify significant differences. RESULTS Attachment was noted for magnetic and nonmagnetic microbubbles but not for inactive magnetic microbubbles; firm attachment at high shear stress (16-20 dyne/cm(2)) was achieved only with magnetic microbubbles. Fluorescence intensity and video intensity were significantly higher in magnetic microbubbles with magnetic field guidance than in inactive magnetic microbubbles and nonmagnetic microbubbles (P < .05). Video intensity from retained magnetic microbubbles in APOE-deficient mice was significantly greater than that in wild-type mice (mean video intensity for APOE-deficient mice: 28.25 [interquartile range, or IQR, 26.55-29.20] with a hypercholesterolemic diet and 16.10 [IQR, 14.15-18.75] with a regular diet; mean video intensity for wild-type mice: 9.55 [IQR, 8.85-10.5] with a hypercholesterolemic diet and 2.90 [IQR, 1.25-3.85] with a regular diet; P < .001). CONCLUSION Use of a magnetic targeted microbubble system results in greater attachment to endothelial VCAM-1 in atherosclerotic aortas in conditions of high shear stress and improved detection of early inflammatory changes of atherosclerosis.

Acute and acute-on-chronic kidney injury of patients with decompensated heart failure: impact on outcomes

BackgroundAcute worsening of renal function, an independent risk factor for adverse outcomes in acute decompensated heart failure (ADHF), occurs as a consequence of new onset kidney injury (AKI) or acute deterioration of pre-existed chronic kidney disease (CKD) (acute-on-chronic kidney injury, ACKI). However, the possible difference in prognostic implication between AKI and ACKI has not been well established.MethodsWe studied all consecutive patients hospitalized with ADHF from 2003 through 2010 in Nanfang Hospital. We classified patients as with or without pre-existed CKD based on the mean estimated glomerular filtration rate (eGFR) over a six-month period before hospitalization. AKI and ACKI were defined by RIFLE criteria according to the increase of the index serum creatinine.ResultsA total of 1,005 patients were enrolled. The incidence of ACKI was higher than that of AKI. The proportion of patients with diuretic resistance was higher among patients with pre-existed CKD than among those without CKD (16.9% vs. 9.9%, P = 0.002). Compared with AKI, ACKI was associated with higher risk for in-hospital mortality, long hospital stay, and failure in renal function recovery. Pre-existed CKD and development of acute worsening of renal function during hospitalization were the independent risk factors for in-hospital death after adjustment by the other risk factors. The RIFLE classification predicted all-cause and cardiac mortality in both AKI and ACKI.ConclusionsPatients with ACKI were at greatest risk of adverse short-term outcomes in ADHF. Monitoring eGFR and identifying CKD should not be ignored in patients with cardiovascular disease.

Long non-coding RNA MALAT1 promotes gastric cancer tumorigenicity and metastasis by regulating vasculogenic mimicry and angiogenesis.

MALAT1 is an oncogenic long non-coding RNA that has been found to promote the proliferation of many malignant cell types and non-malignant human umbilical vein endothelial cells (HUVECs). However, the functions of MALAT1 in vasculogenic mimicry (VM) and angiogenesis and the potential mechanisms responsible have not yet been investigated in any malignancy. Here, in situ hybridization and CD31/periodic acid-Schiff double staining of 150 gastric cancer (GC) clinical specimens revealed that MALAT1 expression was tightly associated with densities of VM and endothelial vessels. MALAT1 knockdown markedly reduced GC cell migration, invasion, tumorigenicity, metastasis, and VM, while restricting HUVEC angiogenesis and increasing vascular permeability. Moreover, MALAT1 was found to regulate expression of VE-cadherin, β-catenin, MMPs 2 and 9, MT1-MMP, p-ERK, p-FAK, and p-paxillin, which have been established as classical markers of VM and angiogenesis and components of associated signaling pathways. Consistent with this, the p-ERK inhibitors U0126 and PD98059 both effectively blocked GC cell VM. In conclusion, MALAT1 can promote tumorigenicity and metastasis in GC by facilitating VM and angiogenesis via the VE-cadherin/β-catenin complex and ERK/MMP and FAK/paxillin signaling pathways.

Disruption of histamine H2 receptor slows heart failure progression through reducing myocardial apoptosis and fibrosis

Histamine H2 receptor (H2R) blockade has been reported to be beneficial for patients with chronic heart failure (CHF), but the mechanisms involved are not entirely clear. In the present study, we assessed the influences of H2R disruption on left ventricular (LV) dysfunction and the mechanisms involved in mitochondrial dysfunction and calcineurin-mediated myocardial fibrosis. H2R-knockout mice and their wild-type littermates were subjected to transverse aortic constriction (TAC) or sham surgery. The influences of H2R activation or inactivation on mitochondrial function, apoptosis and fibrosis were evaluated in cultured neonatal rat cardiomyocytes and fibroblasts as well as in murine hearts. After 4 weeks, H2R-knockout mice had higher echocardiographic LV fractional shortening, a larger contractility index, a significantly lower LV end-diastolic pressure, and more importantly, markedly lower pulmonary congestion compared with the wild-type mice. Similar results were obtained in wild-type TAC mice treated with H2R blocker famotidine. Histological examinations showed a lower degree of cardiac fibrosis and apoptosis in H2R-knockout mice. H2R activation increased mitochondrial permeability and induced cell apoptosis in cultured cardiomyocytes, and also enhanced the protein expression of calcineurin, nuclear factor of activated T-cell and fibronectin in fibroblasts rather than in cardiomyocytes. These findings indicate that a lack of H2R generates resistance towards heart failure and the process is associated with the inhibition of cardiac fibrosis and apoptosis, adding to the rationale for using H2R blockers to treat patients with CHF.

Elevated Orai1 and STIM1 expressions upregulate MACC1 expression to promote tumor cell proliferation, metabolism, migration, and invasion in human gastric cancer.

ORAI calcium release-activated calcium modulator 1 (Orai1)- and stromal interacting molecule 1 (STIM1)-mediated store-operated Ca(2+) entry (SOCE) have been increasingly implicated in tumor progression; however, its role in gastric cancer (GC) is not well elucidated. We aimed to determine whether SOCE influences GC prognosis and elucidate the underlying mechanisms. Orai1 and STIM1 expressions were higher in GC tissues compared to adjacent non-tumor tissues according to RT-PCR and western blotting. Higher Orai1 and/or STIM1 expression was associated with more advanced disease, more frequent recurrence, and higher mortality rates in our study of 327 GC patients. The disease-free survival rates of Stage I-III patients and the overall survival rates of Stage IV patients were significantly worse when the tumors had high Orai1 and/or STIM1 expressions. Orai1 and/or STIM1 knockdown caused significantly reduced tumor growth and metastasis in athymic mice. Orai1 and/or STIM1 knockdown lowered the proliferation, metabolism, migration, and invasion of two GC cell lines. Also, Orai1 and/or STIM1 knockdown changed the markers of the cell cycle and epithelial-mesenchymal transition (EMT). These effects were reversed by metastasis-associated in colon cancer-1 (MACC1) overexpression. In summary, the composite molecules of SOCE suggest a poor prognosis for GC by promoting tumor cell proliferation, metabolism, migration, and invasion by targeting MACC1.

In vivo ultrasound molecular imaging of inflammatory thrombosis in arteries with cyclic Arg-Gly-Asp-modified microbubbles targeted to glycoprotein IIb/IIIa.

ObjectiveUltrasound molecular imaging has the potential to detect activated platelets, thus identifying atherosclerotic plaque instability before onset of serious clinical events. However, it has not been well defined in inflammatory arterial thrombosis. We hypothesized that microbubbles (MBs) target glycoprotein IIb/IIIa (GP IIb/IIIa) could achieve a noninvasive in vivo detection of inflammatory thrombosis in large arteries through contrast-enhanced ultrasound (CEU) imaging. Materials and MethodsLipid shell–based gas-filled MBs were modified covalently with a cyclic Arg-Gly-Asp (RGD) peptide (MB-cRGD) targeted to activated GP IIb/IIIa or a negative control peptide (MB-CON) via thiol-maleimide coupling. Adherence of MB-cRGD and MB-CON to GP IIb/IIIa was determined in vitro by using a parallel plate flow chamber at variable shear stress (0.5–8 dynes/cm2). Inflammatory platelet thrombosis was induced by periadvential application of arachidonic acid (AA) to one of the bilateral carotids of C57BL/6 mice (n = 20) and confirmed through intravital fluorescence microscopy. Attachment of MBs was determined in vivo with CEU imaging of bilateral carotids in the AA application mice with (n = 10) or without (n = 10) pretreatment of GP IIb/IIIa antagonist. The expression of integrin GP IIb/IIIa was assessed through immunohistochemistry. ResultsMicrobubble-cRGD but not MB-CON had excellent affinity to GP IIb/IIIa under all shear stress conditions. Successful inflammatory platelet activation and thrombosis in AA application carotids were noted through intravital fluorescence microscopy. Contrast video intensity from adhered MB-cRGD in the thrombi was significantly higher than that from MB-CON (P < 0.05). Video intensity of MB-cRGD in the thrombi was suppressed significantly by preblocking with GP IIb/IIIa antagonist (P < 0.05) but not for MB-CON. Immunohistochemical finding demonstrates that expression of integrin GP IIb/IIIa in the thrombi was abundant; it was inhibited significantly through pretreatment with GP IIb/IIIa antagonist (P < 0.05). ConclusionsCyclic RGD–modified MBs targeted to GP IIb/IIIa with CEU are capable of detecting inflammation-activated platelets and thrombosis in large arteries, thus providing a potential tool for identification of vulnerable atherosclerotic plaques.