Purinergic signaling may be involved in embryonic development of the heart. In the present study, the effects of purinergic receptor stimulation on cardiomyogenesis of mouse embryonic stem (ES) cells ...were investigated. ADP or ATP increased the number of cardiac clusters and cardiac cells, as well as beating frequency. Cardiac-specific genes showed enhanced expression of α-MHC, MLC2v, α-actinin, connexin 45 (Cx45), and HCN4, on both gene and protein levels upon ADP/ATP treatment, indicating increased cardiomyogenesis and pacemaker cell differentiation. Real-time RT-PCR analysis of purinergic receptor expression demonstrated presence of P2X1, P2X4, P2X6, P2X7, P2Y1, P2Y2, P2Y4, and P2Y6 on differentiating ES cells. ATP and ADP as well as the P2X agonists β,γ-methylenadenosine 5′-triphosphate (β,γ-MetATP) and 8-bromoadenosine 5′-triphosphate (8-Br-ATP) but not UTP or UDP transiently increased the intracellular calcium concentration (Ca
2+
i
) as evaluated by the calcium indicator Fluo-4, whereas no changes in membrane potential were observed. Ca
2+
i
transients induced by ADP/ATP were abolished by the phospholipase C-β (PLC-β) inhibitor U-73122, suggesting involvement of metabotropic P2Y receptors. Furthermore, partial inhibition of Ca
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transients was achieved in presence of MRS2179, a selective P2Y1 receptor antagonist, whereas PPADS, a non-selective P2 receptor inhibitor, completely abolished the Ca
2+
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response. Consequently, cardiomyocyte differentiation was decreased upon long term co-incubation of cells with ADP and P2 receptor antagonists. In summary, activation of purinoceptors and the subsequent Ca
2+
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transients enhance the differentiation of ES cells toward cardiomyocytes. Purinergic receptor stimulation may be a promising strategy to drive the fate of pluripotent ES cells into a particular population of cardiomyocytes.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Electromagnetic fields (EMFs) are used to treat bone diseases. Herein, the effects of static EMFs on chondroosteogenesis and vasculogenesis of embryonic stem (ES) cells and bone mineralization of ...mouse fetuses were investigated. Treatment of differentiating ES cells with static EMFs (0.4-2 mT) stimulated vasculogenesis and chondro-osteogenesis and increased reactive oxygen species (ROS), which was abolished by the free radical scavengers trolox, 1,10-phenanthroline (phen), and the NAD(P)H oxidase inhibitor diphenylen iodonium (DPI). In contrast, EMFs of 10 mT field strength exerted inhibitory effects on vasculogenesis and chondro-osteogenesis despite robust ROS generation. EMFs of 1 mT and 10 mT increased and decreased vascular endothelial growth factor (VEGF) expression, respectively, which was abolished by DPI and radical scavengers. EMFs activated extracellular-regulated kinase 1/2 (ERK1/2), p38, and c-jun N-terminal kinase (JNK), which was sensitive to DPI treatment. The increase in VEGF by EMFs was inhibited by the ERK1/2 inhibitor U0126 but not by SB203580 and SP600125, which are p38 and JNK inhibitors, respectively, suggesting VEGF regulation by ERK1/2. Chondroosteogenesis and vasculogenesis of ES cells was blunted by trolox, DPI, and the VEGF receptor-2 (flk-1) antagonist SU5614. In mouse fetuses 1 mT EMFs increased and 10 mT EMFs decreased bone mineralization, which was abolished in the presence of trolox. Hence, EMFs induced chondro-osteogenesis and vasculogenesis in ES cells and bone mineralization of mouse fetuses by a ROS-dependent up-regulation of VEGF expression.
The mortality of patients with MI has significantly decreased in recent decades, mainly due to early reperfusion therapy with a probability of surviving of more than 90% if the patient reaches the ...hospital ...
Abstract Background Dilated cardiomyopathy (DCM) is associated with heart failure and increased mortality and there is no reliable biomarker to estimate patients' prognosis. During cardiac ...remodeling, an extensive reorganization of the extracellular matrix occurs. The study was aimed to investigate matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinase 1 (TIMP-1) and fetal tenascin-C (B+ Tn-C) and fibronectin (ED-A+ Fn) variants known to be involved in that process. Methods and results In 187 patients with DCM, levels of MMP-9, TIMP-1 and B+ Tn-C in serum as well as B+ Tn-C and ED-A+ Fn in tissue were quantified and subjected to univariate analysis. For all serum markers, concentrations above a calculated threshold were associated with decreased survival (MMP-9: p = 0.008, TIMP-1: p = 0.001, B+ Tn-C: p < 0.001) and a significantly higher risk to die or undergo transplantation. In tissue, a reexpression of B+ Tn-C and ED-A+ Fn could be shown. Protein deposition levels of ≥ 4.5% for B+ Tn-C and ≥ 2.1% for ED-A+ Fn were associated with a significantly decreased survival (p = 0.001 for B+ Tn-C, p = 0.031 for ED-A+ Fn) and an increased risk to die or undergo transplantation. In a multivariate analysis, TIMP-1 is the superior parameter to predict transplantation free survival (p = 0.027). Conclusions Serum levels of MMP-9, TIMP-1 and B+ Tn-C and tissue levels of B+ Tn-C and ED-A+ Fn are promising markers for risk assessment. The reoccurrence of ED-A+ Fn and the availability of a human antibody usable as a vehicle for targeted drug delivery might be the basis for novel therapeutic strategies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Increased markers of systemic inflammation had been found in patients with acute heart failure. These and other findings led to the hypothesis of an increased rate of bacterial translocation in ...severe or acute heart failure, leading to systemic inflammation. The present study examined if bacterial translocation occurs under physiological conditions in rats and if its rate and spectrum changes in chronic compensated ischemic heart failure.
Myocardial infarction (MI) was induced by proximal ligation of the left anterior descending coronary artery or a sham operation was performed. Rats were followed up for six months and mesenteric lymph nodes of the surviving animals with large MI were excised and bacterial translocation was quantified by cultivating viable bacteria.
Induction of a large MI led to a significant cardiac remodelling, elevated levels of atrial natriuretic peptide, and pulmonary oedema. There was no difference in the spectrum or in the rate of bacterial translocation compared with controls, neither comparing all cultured bacteria nor predefined subgroups (e.g., intestinal bacteria).
Bacterial translocation is a physiological process with no gradual increase in chronic compensated heart failure in rats.
Observational studies in selected patients have shown remarkably low restenosis rates after ultrasound-guided stent implantation. However, it is unknown whether this implantation strategy improves ...long-term angiographic and clinical outcome in routine clinical practice. Methods and Results-- A total of 550 patients with a symptomatic coronary lesion or silent ischemia were randomly assigned to either ultrasound-guided or angiography-guided implantation of </=2 tubular stents. The primary end points were angiographic dichotomous restenosis rate, minimal lumen diameter, and percent diameter stenosis after 6 months as determined by quantitative coronary angiography. Secondary end points were the occurrence rates of major adverse cardiac events (death, myocardial infarction, coronary bypass surgery, and repeat percutaneous intervention) after 6 and 12 months of follow-up. At 6 months, repeat angiography revealed no significant differences between the groups with ultrasound- or angiography-guided stent implantation with respect to dichotomous restenosis rate (24.5% versus 22.8%, P=0.68), minimal lumen diameter (1.95+/-0.72 mm versus 1.91+/-0.68 mm, P=0.52), and percent diameter stenosis (34.8+/-20.6% versus 36.8+/-19.6%, P=0.29), respectively. At 12 months, neither major adverse cardiac events (relative risk, 1.07; 95% CI 0.75 to 1.52; P=0.71) nor repeat percutaneous interventions (relative risk 1.04; 95% CI 0.64 to 1.67; P=0.87) were reduced in the ultrasound-guided group.
This study does not support the routine use of ultrasound guidance for coronary stenting. Angiography-guided optimization of tubular stents can be performed with comparable angiographic and clinical long-term results.
Tissue remodelling in ischemic cardiomyopathy (ICM), dilated cardiomyopathy (DCM), and hypertensive heart disease (HHD) is accompanied by the re-occurrence of fetal tenascin-C (Tn-C) variants. The ...study was aimed to comparatively analyze the serum levels of Tn-C containing the FNIIIB (B+ Tn-C) or FNIIIC (C+ Tn-C) domain in heart failure patients due to ICM, DCM, and HHD.
119 male patients with congestive heart failure (45 with ICM, 43 with DCM, 31 with HHD) were included. Measurement of serum levels of B+ and C+ Tn-C was performed using Enzyme Linked Immunosorbent Assay (ELISA). Results were correlated to clinical, laboratory, echocardiographic, and spiroergometric parameters.
Analysis of Tn-C concentrations according to heart failure etiology revealed no significant differences. There was an association of C+ Tn-C serum levels to enlargement of the left atrium in DCM (p < 0.01) and the left ventricle in HHD (p < 0.05). In patients with ICM, C+ Tn-C showed a strong negative correlation to the stress test performance (p = 0.002, R2: -0.691). Most strikingly, there was a strong correlation between BNP and B+ Tn-C (p = 0.038, R2: 0.466) as well as C+ Tn-C (p = 0.001, R2: 0.814) in DCM patients.
The present study highlights the impact of Tn-C variants as biomarkers reflecting the extent of cardiac remodeling in heart failure patients. Furthermore, B+ Tn-C can be suggested as an additional tool to estimate ICM performance in patients. Especially in combination with BNP, analysis of Tn-C might pave the way for a more precise evaluation of heart failure patients.
The original text in the manuscript published in the American Heart Journal (2012;163:938-45) reads as follows:"Because most of the patients will not be able to provide full informed consent before ...randomization, an individualized informed consent process covering 4 different scenarios has been validated and approved by the central ethical committee at the University of Leipzig, Germany, and also all local ethical committees.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
After this relocation, the valve was in its proper position, but it was upside down. ...a Medtronic CoreValve prosthesis (Medtronic Inc., Minneapolis, Minnesota) was successfully placed as a ...valve-in-valve sandwich (C, Online Video 4), and normal valve function was re-established.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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