UMLS:C0018801 - FACTA Search

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Query: UMLS:C0018801 (heart failure)
72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heart failure is associated with increased myocardial expression of TNF-alpha. However, the role of TNF-alpha in the development of heart failure is not fully understood. In the present study, we investigated the contribution of TNF-alpha to myocardial mitochondrial dysfunction, oxidative stress, and apoptosis in a unique dog model of heart failure characterized by an activation of all of these pathological processes. Male mongrel dogs were randomly assigned (n = 10 each) to 1) normal controls; 2) chronic pacing (250 beats/min for 4 wk) with concomitant administration of etanercept, a soluble p75 TNF receptor fusion protein, 0.5 mg/kg subcutaneously twice weekly; 3) chronic pacing with administration of saline vehicle. Mitochondrial function was assessed by left ventricular (LV) tissue mitochondrial respiratory enzyme activities. Oxidative stress was assessed with aldehyde levels, and apoptosis was quantified by photometric enzyme immunoassay for cytoplasmic histone-associated DNA fragments and terminal deoxynucleotide transferase-mediated nick-end labeling (TUNEL) assays. LV activity levels of mitochondrial respiratory chain enzyme complex III and V were reduced in the saline-treated dogs and restored either partially (complex III) or completely (complex V) in the etanercept-treated dogs. Aldehyde levels, DNA fragments, and TUNEL-positive cells were increased in the saline-treated dogs and normalized in etanercept-treated dogs. These changes were accompanied by an attenuation of LV dilatation and partial restoration of ejection fraction. Our data demonstrate that TNF-alpha contributes to progressive LV dysfunction in pacing-induced heart failure, mediated in part by a local impairment in mitochondrial function and increase in oxidative stress and myocyte apoptosis.
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PMID:In vivo TNF-alpha inhibition ameliorates cardiac mitochondrial dysfunction, oxidative stress, and apoptosis in experimental heart failure. 1520 65

A marked increase in plasma TNF-alpha has been described in patients with chronic heart failure (CHF). Nevertheless, little is known about the direct role of this cytokine early after myocardial infarction (MI) and its possible effects on the subsequent development of CHF. Wistar rats were subjected to permanent in vivo coronary artery ligation. At 5, 7, and 9 days after MI, cardiac function, passive compliance of the left ventricle (LV), and cardiac geometry were evaluated. The same model was used to perform pharmacological studies 7 days and 10 wk after MI in rats treated with monomeric recombinant human soluble TNF-alpha receptor type II (sTNF-RII, 40 microg/kg iv) or a placebo on day 3. Maximal alterations of cardiac function and geometry occurred 7 days after MI, which correlated chronologically with a peak of cardiac and serum TNF-alpha, as shown by immunohistochemistry and ELISA, respectively. sTNF-RII improved LV end-diastolic pressure under basal conditions and after volume overload 7 days and 10 wk after MI. Moreover, a significant leftward shift of the pressure-volume curve in the sTNF-RII-treated group 7 days after MI indicated a preservation of LV volume. Infarct expansion index was also significantly improved by sTNF-RII 7 days after MI (P < 0.01). Nevertheless, 10 wk after MI, geometric indexes and passive pressure-volume curves were not significantly improved by the treatment. In conclusion, TNF-alpha plays a major role in cardiac alterations 7 days after MI in rats and contributes to hemodynamic derangement, but not to cardiac remodeling, in subsequent CHF.
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PMID:New insights into the pathological role of TNF-alpha in early cardiac dysfunction and subsequent heart failure after infarction in rats. 1521 Apr 53

Dietary copper (Cu) restriction leads to cardiac hypertrophy and failure in mice, and Cu repletion (CuR) reverses the hypertrophy and prevents the transition to heart failure. The present study was undertaken to determine changes in myocardial gene expression involved in Cu deficient (CuD) cardiomyopathy and its reversal by CuR. Analysis was performed on three groups of mice: 4-week-old CuD mice that exhibited signs of cardiac failure, their age-matched copper-adequate (CuA) controls, and the CuD mice that were re-fed adequate Cu for 2 weeks. Total RNA was isolated from hearts and subjected to cDNA micro-array and real-time reverse transcription-polymerase chain reaction analysis. Dietary CuD caused a decrease in cardiac mRNA of beta-MHC, L-type Ca(2+) channel, K-dependent NCX, MMP-2, -8, and -13, NF-kappaB, and VEGF. The mRNA levels of ET-1, TGF-beta, TNF-alpha, and procollagen-I-alpha1 and III-alpha1 were increased in the CuD cardiac tissue. Copper repletion resulted in cardiac mRNA levels of most of the genes examined returning to control levels, although the K-dependent NCX and MMP-2 values did not reach those of the CuA control. In addition, CuR caused an increase in beta-MHC, L-type Ca(2+)channel, MMP-13 to levels surpassing those of CuA control, and a decrease in ET-1, and TNF-alpha mRNA levels. In summary, changes in gene expression of elements involved in contractility, Ca(2+) cycling, and inflammation and fibrosis may account for the altered cardiac function found in CuD mice. The return to normal cardiac function by CuR may be a result of the favorable regression in gene expression of these critical components in myocardial tissue.
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PMID:Dietary copper restriction-induced changes in myocardial gene expression and the effect of copper repletion. 1522 55

Heart failure (HF) is a complex clinical syndrome due to ischaemic heart disease, idiopathic cardiomyopathy, hypertension, valve heart disease and others. It is not clear if the etiology of HF influences decreased in this syndrome exercise tolerance. Controversial is also dependence of cytokine levels on etiology of HF. The aim of the study was to compare exercise capacity and cytokines levels in pts with ischaemic and dilated cardiomyopathy. We analyzed circulating levels of TNF-alpha and its soluble receptors sTNF-RI and sTNF-RII, and interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) in 41 pts with CHF, functional class NYHA I-IV, mean EF--25.2 +/- 7.1%. For determination of cytokines level (using R & D System tests) venous blood was withdrawn after 30 minutes of supine rest. All underwent echocardiography and cardiopulmonary exercise stress testing. Dilated cardiomyopathy (DCM) was diagnosed in 21 pts, ischaemic (ICM) in 20 pts. Pts with DCM were younger then with ICM (48 +/- 6.6 vs 56 +/- 6.6 yrs; p = 0.001). There were no significant differences between groups concerning BMI and EF. There were no significant differences in the level of TNF-alpha and sTNF-RI between groups. There was a trend of increased sTNF-RII in pts with ICM (3179.7 +/- 832.7 vs 2699 +/- 680.1 pg/ml; p = 0,07), IL-1beta (2.55 +/- 2.41 vs 1.49 +/- 1.68 pg/ml; p = 0.087) and IL-6 (6.25 +/- 2.21 vs 4.98 +/- 3.64 pg/ml; p = 0.065), and significant increased ESR (11.2 +/- 9.5 vs 5.5 +/- 4.7 mm/h; p = 0.04). Peak VO2 was reduced in pts with ICM group as compared to those with DCM (14.1 +/- 3.7 vs 18.1 +/- 4.8 ml/kg/min; p = 0.0069). In chronic heart failure circulating levels of cytokines tended to be higher in pts with ischaemic origin of the syndrome. The exercise capacity is lower in ischaemic cardiomyopathy.
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PMID:[Cardiopulmonary exercise testing and cytokines in chronic heart failure. Comparison of patients with ischaemic and with dilated cardiomyopathy]. 1550 92

This clinical study compared the expression of circulating proinflammatory (tumor necrosis factor-alpha [TNF-alpha] and interleukin-6) and anti-inflammatory (interleukin-10) cytokines and soluble apoptosis mediators (Fas/Fas ligand) between patients with stable chronic heart failure and depressive symptoms (as estimated by the Zung Self-Rating Depression Scale) (n = 15) and those without these symptoms (n = 20). Patients with depressive symptoms exhibited significantly higher levels of TNF-alpha and soluble Fas ligand, as well as significantly lower levels of interleukin-10, than patients without emotional distress. A disregulated cytokine network and activated apoptosis signaling molecules may be actively implicated in the pathophysiology of chronic emotional distress and depressive symptoms in patients with heart failure.
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PMID:Comparison of circulating proinflammatory cytokines and soluble apoptosis mediators in patients with chronic heart failure with versus without symptoms of depression. 1554 Dec 60

Tumor necrosis factor a (TNF-alpha) is a proinflammatory cytokine that is produced by activated macrophages. It has been shown to stimulate the release of endothelial cytokines and NO, increase vascular permeability, decrease contractility, and induce a prothrombotic state. The most studied TNF-a gene mutation in heart disease is a gamma to alpha substitution, which occurs when 308 nucleotides move upstream from the transcription initiation site in the TNF promoter and has been associated with elevated levels of TNF-alpha. The TNF1 allele (wild type) contains gamma at this site, while the TNF2 allele has an alpha substitution at the site. The TNF2 allele is a more powerful transcriptional activator, therefore leading to higher TNF-alpha levels. Most of the studies to date have failed to conclusively show any link between the polymorphism and heart disease, both coronary artery disease and cardiomyopathy/heart failure.
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PMID:Tumor necrosis factor alpha polymorphism in heart failure/cardiomyopathy. 1559 43

The process of heart failure appears to be a common and coordinated response to cardiac injury and dysfunction. The contemporary mechanistic viewpoint that predictable, shared, highly regulated events underlie the complex heart failure process implies that an improved understanding of these mechanisms is fundamental to the advancement of cardiovascular biology and the subsequent development of targeted, effective treatment strategies for patients with congestive heart failure (CHF). Cardiac remodeling (CR) is the restructuring and reshaping of the heart that underlies heart failure progression. CR is a major determinant of the clinical course of CHF, irrespective of its etiology. The traditional concepts of cellular remodeling in the failing heart are based on well-established data indicating characteristic alterations in cell size, shape, and the ability to perform contractile work. The role of programmed cell death and the exciting possibility of cardiomyocyte regeneration are areas of intense investigation. Notably, the accumulating data in both animal and human hearts suggesting cardiomyocyte regeneration and renewal indicate that cellular remodeling is a complex and dynamic process that is not completely understood. For the development of new treatments to regenerate and restore failing myocardium, the possibilities offered by controlling cell death and enhancing cell renewal as a therapeutic target are unprecedented. Based on a critical review of the available literature, the traditional concepts and mechanisms describing the regulation of remodeling are largely inadequate. The neurohormonal (RAAS and adrenergic systems) and innovative cytokine hypothesis (TNF-alpha and others) of remodeling and failure do not account for all the cellular and molecular changes that result in the progression of CHF. Given that these contemporary concepts serve as the basis for the majority of our current heart failure treatments, it is not surprising that CHF is an emerging epidemic in our society. To define new therapeutic targets and to control the process of remodeling, novel biomolecules and mechanisms for the coordinated control of CR must be further defined.
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PMID:Cardiac remodeling and failure: from molecules to man (Part I). 1571 Feb 85

Dilated Cardiomyopathy (DCM) is a disease of the myocardium and one of the leading causes of death in patients with heart diseases. We explored the role of increased Nitric oxide and TNF-alpha on the pathogenesis and progression of DCM. 25 patients with DCM, and 20 apparently healthy age and sex matched controls, were studied. Patients were divided into 2 groups according to the presence or absence of pulmonary hypertension. All patients and controls were subjected to full cardiological assessment including plain chest x-ray, 12 lead ECG, and thorough 2D and Doppler echocardiography study. Laboratory investigations included measurement of plasma nitrite, nitrate and TNF-alpha levels. Plasma nitrite, nitrate and TNF-alpha concentrations were significantly elevated in DCM patients as compared to controls, and the elevation correlated with the decreasing functional status of the patients. It is concluded that plasma nitrite, nitrate, and TNF-alpha levels in DCM are not only linked to the severity of heart failure at presentation and during follow up, but also to the worsening of left ventricular function as evidenced by the decrease in ejection fraction and increase in end systolic and diastolic ventricular diameters during the echocardiography evaluation.
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PMID:The role of oxidative products of nitrous oxide and the tumor necrosis factor alpha in dilated cardiomyopathy. 1572 85

During chemotherapy with anthracyclines, attenuated neuregulin signaling by the erbB2 receptor inactivating antibody Trastuzumab enhances the heart failure risk. We compared the effects of attenuated neuregulin/erbB signaling and of daunorubicin on splicing of the Bcl-x gene and on mitochondrial activation of apoptosis in cardiomyocytes. Attenuating erbB signals in cultured neonatal rat cardiomyocytes by the erbB2 antagonist tyrphostin AG825, by the erbB1/4 antagonist AG1478 or by antisense-induced lowering of erbB2 receptors resulted in an augmented Bcl-xS/Bcl-xL ratio, mitochondrial release of cytochrome c, activation of caspase 9 and caspase 3, and nucleosome-sized DNA fragmentation. A similar DNA fragmentation and caspase 3 activation was induced by TNF-alpha, but without Bcl-xS/Bcl-xL increase, cytochrome c release or caspase 9 activation. A BH4-domain containing HIV TAT fusion protein added to cardiomyocytes under attenuated erbB signaling lowered the enhanced Bcl-xS/Bcl-xL ratio, the cytochrome c release, the caspase 3 activation and the DNA fragmentation, while apoptosis was not modified by the fusion protein in TNF-alpha treated cardiomyocytes. Enhancement of Bcl-xS/Bcl-xL by reducing Bcl-xL via siRNA transfection mimicked the mitochondrial apoptotic activation due to erbB signal attenuation. Daunorubicin also caused Bcl-xS/Bcl-xL enhancement and mitochondrial apoptotic activation in cultured cardiomyocytes; this was attenuated by BH4-fusion protein or by neuregulin-1 and augmented by siRNA-mediated Bcl-xL lowering. We conclude that activation of mitochondrial apoptosis due to altered Bcl-x splicing contributes as a common mechanism of anthracyclines and erbB signal attenuation to the enhanced heart failure risk under this combination.
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PMID:Apoptosis-modulating interaction of the neuregulin/erbB pathway with anthracyclines in regulating Bcl-xS and Bcl-xL in cardiomyocytes. 1573 8

Sex hormones are important modifiers of the acute inflammatory response to injury, an important aspect of myocardial depression and apoptosis following ischemia or endotoxemia. Hemorrhage, trauma, ischemia/reperfusion, burn and sepsis each lead to cardiac dysfunction. Gender has been shown to influence the inflammatory response as well as outcomes following acute injury. The mechanisms by which sex affects the inflammatory response and the outcome to acute injury are being actively investigated. It is now recognized that myocardial inflammation plays a crucial role in I/R-induced myocardial dysfunction. Inflammatory mediators, such as TNF-alpha are produced by cardiomyocytes and contribute to myocardial functional depression and apoptosis. Gender differences in the inflammatory response following burn injury have been demonstrated. However, gender differences in the setting of acute I/R-induced inflammation are unclear. In addition, a critical component of the signal transduction pathway leading to myocardial inflammation is the activation of p38 mitogen-activated protein kinase (MAPK). In other systems, it appears that gender differences exist in the p38 MAPK signaling pathway. The inflammatory response, including the p38 MAPK signaling cascade and expression of proinflammatory cytokines such as TNF-alpha and IL-1beta, may precipitate cardiomyocyte apoptosis following I/R injury. Apoptosis may be an essential component in the pathogenesis of heart failure, and there is evidence that myocyte apoptosis in the failing human heart is markedly lower in women than in men. The prevention of cell death attenuates I/R-induced injury on myocardial anatomy and performance. This review will: 1) examine evidence for gender differences in the outcome to acute injury; 2) explain the myocardial inflammatory response to acute injury; and 3) elucidate the various mechanisms by which gender and sex hormones affect the myocardial response to acute injury.
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PMID:Intracellular signaling mechanisms of sex hormones in acute myocardial inflammation and injury. 1576 71

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