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Brain-derived neurotropic factor (BDNF) is a myokine that plays a key role in regulating survival, growth, and maintenance of neurons. We investigated whether the serum BDNF level at discharge could predict the prognosis in patients with heart failure (HF). Furthermore, we aimed to examine the relationship between this myokine and exercise tolerance. We prospectively enrolled 94 patients who were hospitalized for worsening HF and had cardiac rehabilitation. At discharge, the serum BDNF level of all patients was measured using a commercial ELISA kit and they underwent a cardiopulmonary exercise test to measure peak oxygen uptake (peak VO2). Correlation was not observed between BDNF and peak VO2. Kaplan-Meier analysis demonstrated that cardiac death or rehospitalization owing to worsening HF was significantly higher in the low BDNF group (p = 0.023). The combination of peak VO2 and BDNF levels led to the identification of subgroups with significantly different probabilities of events (p = 0.005). In particular, in the low BDNF and low peak VO2 group, the frequency of rehospitalization within half a year after discharge was much higher than that in other groups. Multivariate analysis found BDNF as an independent factor of adverse events (hazard ratio 0.956; 95% confidence interval 0.911-0.999; p = 0.046). The serum BDNF level at discharge may be a useful biomarker of the prognosis in patients with HF. Furthermore, combining BDNF and peak VO2 may be useful for predicting early cardiac events. [ABSTRACT FROM AUTHOR]

We describe four cases of the patients with ST-elevation myocardial infarction (STEMI) that were treated with interleukin-11 (IL-11), a cardioprotective cytokine. Recombinant human IL-11 (rhIL-11), was intravenously administered to two cases at low dose (6 µg/kg) and to two at high dose (25 µg/kg). The cytokine administration started just after the coronary occlusion was confirmed by coronary angiography (CAG), taking 3 h. Following CAG, percutaneous coronary intervention (PCI) was performed as a standard therapy. No serious adverse drug reactions were observed. All the cases left the hospital without the symptom of heart failure. We discuss the possibility of the clinical use of rhIL-11 as an adjunct therapy to PCI for the STEMI patients. [ABSTRACT FROM AUTHOR]

Although obesity and chest-wall thickness influence the Sokolow-Lyon electrocardiographic (ECG) voltage criteria and strain pattern, these factors have not been taken into account in previous studies that evaluate the relationship between the ECG criteria and anatomic left ventricular hypertrophy (LVH). The introduction of multislice computed tomography (MSCT) has enabled assessment of not only coronary artery stenoses but also left ventricular volume and mass, left atrial volume, and chest-wall thickness. We hypothesized that evaluating the relation between the ECG voltage criteria or strain pattern and the aforementioned factors using MSCT would be highly valuable. The study population consisted of 93 patients who required MSCT angiography. The Sokolow-Lyon voltage and strain patterns were determined to detect anatomic LVH, which was defined as increased left ventricular mass. The Sokolow-Lyon voltage criteria, as an indicator of anatomic LVH, had a sensitivity of 57 %, specificity of 67 %, positive predictive value of 36 %, and negative predictive value of 82 %. By contrast, the strain pattern had a sensitivity of 65 %, specificity of 87 %, positive predictive value of 63 %, and negative predictive value of 88 %. Multivariate analysis revealed that the strain pattern was associated with the presence of anatomic LVH, whereas the Sokolow-Lyon voltage was not. This MSCT study demonstrated that even after removing the effects of various factors, the strain pattern remained associated with the presence of anatomic LVH, in contrast to the Sokolow-Lyon voltage. [ABSTRACT FROM AUTHOR]

Heat shock cognate protein 70 (Hsc70) acts as a molecular chaperone for the maintenance of intracellular proteins, which allows cancer cells to survive under proteotoxic stress. We attempted to use Hsc70 to identify key molecules in cancer cell survival. Here, we performed mass-spectrometry-based proteomics analysis utilizing affinity purification with anti-Hsc70 antibodies; as a result, 83 differentially expressed proteins were identified under stress conditions. This result implies that there was a change in the proteins with which Hsc70 interacted in response to stress. Among the proteins identified under both serum-depleted and 5-fluorouracil-treated conditions, Rab1A was identified as an essential molecule for cancer cell survival. Hsc70 interacted with Rab1A in a chaperone-dependent manner. In addition, Hsc70 knockdown decreased the level of Rab1A and increased the level of its ubiquitination under stress conditions, suggesting that Hsc70 prevented the degradation of Rab1A denatured by stress exposure. We also found that Rab1A knockdown induced cell death by inhibition of autophagosome formation. Rab1A may therefore contribute to overcoming proteotoxic insults, which allows cancer cells to survive under stress conditions. Analysis of Hsc70 interactors provided insight into changes of intracellular status. We expect further study of the Hsc70 interactome to provide a more comprehensive understanding of cancer cell physiology. [ABSTRACT FROM AUTHOR]

Although atrial natriuretic peptide (ANP) is widely used in patients with congestive heart failure (CHF), little is known about its effect on epicardial coronary arteries. Magnetic resonance imaging (MRI) enables precise measurement of coronary vasodilation and flow velocity. In this study, we examined the changes in epicardial coronary artery size and flow velocity in response to intravenous infusion of ANP or nitroglycerin (NTG) by using 3 T MRI in patients with CHF. The study cohort contained a total of 14 subjects: 8 patients with CHF and 6 healthy volunteers as controls, randomly divided into two groups: the ANP group (0.03 μg/kg/min) and the NTG group (0.3 μg/kg/min). Cross-sectional MR angiography and phase-contrast flow velocity of the right coronary artery in the same in-plane slice were obtained at the baseline, during drug infusion, and at two subsequent time points after stopping drug infusion. A significant increase was observed in the coronary cross-sectional area at 15 min after drug infusion in both groups compared with that at baseline; however, a late peak was observed at 15 min after stopping infusion in the ANP group. No significant differences were detected in the flow velocity in both groups. Furthermore, although NTG increased the heart rate, this change was not found in the ANP group. Coronary vasodilation and flow velocity can be measured simultaneously using 3 T MRI. Using this method, we showed that the effects of ANP on the coronary artery vasodilation and flow velocity were not inferior to those of NTG, with no significant alteration in heart rate. [ABSTRACT FROM AUTHOR]

The HMG-CoA reductase inhibitors (statins) have been shown to exert several protective effects on the vasculature that are unrelated to changes in the cholesterol profile, and to induce angiogenesis. The proangiogenic effect exerted by statins has been attributed to the activation of the PI3K/Akt pathway in endothelial cells; however, it is unclear how statins activate this pathway. Pravastatin-mediated activation of Akt and MAPK occurs rapidly (within 10 min.) and at low doses (10 nM). Here, we hypothesized that FGF-2 contributes to the proangiogenic effect of statins. We found that pravastatin, a hydrophilic statin, induced phosphorylation of the FGF receptor (FGFR) in human umbilical vein endothelial cells. SU5402, an inhibitor of FGFR, abolished pravastatin-induced PI3K/Akt and MAPK activity. Likewise, anti-FGF-2 function-blocking antibodies inhibited Akt and MAPK activity. Moreover, depletion of extracellular FGF-2 by heparin prevented pravastatin-induced phosphorylation of Akt and MAPK. Treatment with FGF-2 antibody inhibited pravastatin-enhanced endothelial cell proliferation, migration and tube formation. These observations indicate that pravastatin exerts proangiogenic effects in endothelial cells depending upon the extracellular FGF-2. [ABSTRACT FROM AUTHOR]

Aims Interleukin (IL)-17-producing helper T (Th17) cells have been proposed to participate in the pathogenesis of chronic inflammation, such as autoimmune myocarditis. IL-6 gene ablation confers the resistance to experimental autoimmune myocarditis (EAM). In this study, we have addressed the pathological roles of IL-6 in the regulation of Th17 cells in EAM. Methods and results To induce EAM, mice were immunized twice with α-myosin heavy chain peptide. Three weeks after the first injection, the cardiac expression of the Th17-specific transcription factor, retinoic acid receptor-related orphan nuclear receptor (ROR γt), was up-regulated. Consistently, Th17 cells were recruited into EAM hearts, as analysed by flow cytometry. Using the mice with enhanced green fluorescence protein (eGFP) gene knocked-in at RORγt locus (RORγt-eGFP mice), we observed Th17 cell infiltration into inflamed lesions. Pre-treatment with IL-6 receptor (IL-6R)-blocking antibody (anti-IL-6R Ab) inhibited EAM induction in terms of disease severity score (3.5 ± 0.8; IgG vs. 0.5 ± 0.8; anti-IL-6R Ab, n = 6, P< 0.01) and suppressed the myocardial expression of IL-17 and RORγt. In contrast, the administration of anti-IL-6R Ab 7 days after the first immunization failed to show the inhibitory effects, suggesting that IL-6 plays important roles in EAM initiation. Finally, by generating RORγt-eGFP homozygous mice, we revealed that RORγt gene ablation conferred the resistance to EAM induction. Conclusion IL-6-mediated induction of Th17 cells is critical for the onset of EAM, but not for its progression. IL-6/Th17 signalling could be a promising therapeutic target for the prevention of myocardial inflammation. [ABSTRACT FROM AUTHOR]

Objective: Angiotensin-converting enzyme (ACE) inhibitor and angiotensin II type I receptor blockers (ARB) prevent cardiac remodeling after myocardial infarction (MI). However, it is controversial whether combination therapy of ACE inhibitor and ARB is more effective on cardiac remodeling than each agent alone. In this study, we compared the effects of an ACE inhibitor (temocapril), an ARB (CS-866), and their combination on cardiac remodeling after MI. Methods: Temocapril at 3 or 30 mg/kg/day, CS-866 at 1 or 10 mg/kg/day, or combined temocapril and CS-866 at 1.5 and 0.5 mg/kg/day or at 15 and 5 mg/kg/day, respectively, were administered to rats after MI. At 4 weeks after MI, we assessed hemodynamics, cardiac function by Doppler echocardiography and non-infarcted myocardial mRNA expression. Results: Animals treated with a combination of the two drugs had hemodynamics, heart weights and dimensions similar to the other treated animals. However, the combination of the two drugs suppressed ANP, BNP and other gene expressions related to contractile proteins of fetal type and collagens more effectively than ACE inhibitor or ARB alone. Conclusion: These data suggest that combination of the two drugs, independent of the hemodynamic effect, may improve left ventricular phenotypic change, collagen accumulation and diastolic function. [Copyright &y& Elsevier]

In non-infarcted myocardium after myocardial infarction, the change of cardiac phenotypic modulation of contractile protein, extracellular matrix and intracellular Ca2+ transport protein, such as sarcoplasmic reticulum Ca2+(SR-Ca2+)-ATPase, Na+-Ca2+ exchanger, have a important role during cardiac remodeling. However, the time course in this gene expression in the adjacent and remote left ventricular, or right ventricular myocardium after myocardial infarction has not been well examined. The purpose of this study was to examine the left ventricular function and regional cardiac gene expression after myocardial infarction. Myocardial infarction was produced in Wistar rats by the ligation of the left anterior descending coronary artery. After 3 weeks, 2 months and 4 months from myocardial infarction, we performed Doppler echocardiography and measured the systolic and diastolic function. Then, we analyzed the contractile protein, extracellular matrix and intracellular Ca 2+ transport protein mRNAs of cardiac tissues in the adjacent and the remote noninfarcted myocardium, and right ventricular myocardium by Northern blot hybridization. Fractional shortening of infarcted heart progressively decreased. Peak early diastolic filling wave (E wave) velocity increased, and the deceleration rate of the E wave velocity was more rapid in myocardial infarction areas. Atrial filling wave (A wave) velocity decreased, resulting in a marked increase in the ration of E wave to A wave velocity. Expression of myocardial α-skeletal actin, β-MHC and ANP mRNA, or collagen I and III mRNA were higher at 3 weeks after myocardial infarction. SR Ca2+-ATPase mRNA in the adjacent non-infarcted myocardium was decreased at 2 months, and that in remote myocardium was decreased at 4 months after infarction. Na+-Ca2+ exchanger mRNA levels were increased at 3 weeks, but was decreased at 2 months in the adjacent non-infarcted myocardium and at 4 months in the remote myocardium. These findings suggest that the compensation for myocardial infarction by myocardial gene expression in non-infarcted myocardium may occur at an early phase after myocardial infarction, and myocardial dysfunction may begin from adjacent to remote non-infarcted myocardium during progressive cardiac remodeling. [ABSTRACT FROM AUTHOR]