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

Tumor necrosis factor-alpha (TNF alpha) is a proinflammatory cytokine with negative inotropic effects. Recently, elevated levels of TNF alpha have been identified in patients with advanced heart failure. Although the clinical significance of this finding is unclear at present, there is increasing evidence that this cytokine may play a primary pathophysiologic role in the development and pathogenesis of heart failure in humans. Indeed, many of the clinical hallmarks of heart failure, including left ventricular dysfunction, cardiomyopathy, and pulmonary edema can be explained by the known biological effects of TNF alpha in humans. The present review will summarize recent evidence with regard to the biological role for TNF alpha in the adult mammalian heart, as well as summarize the increasing body of clinical information that implicates this cytokine in the pathophysiology of heart failure.
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PMID:Tumor necrosis factor-alpha and the failing human heart. 748 17

Cardiopulmonary bypass-induced organ dysfunction remains a clinical problem in certain groups of patients. Although the pathogenesis is multifactorial, it is likely that a panendothelial injury consequent upon widespread humoral and cellular activation is a major contributor to this process. The biologically active products of complement activation are certainly capable of inducing many of the features of the post-perfusion syndrome. The complex interactions between complement and many of the other proposed mediators of this response also supports this contention. However, it is equally certain that many of the other proposed mediators have some role to play. Inhibition of one cell type or inflammatory cascade is therefore unlikely to abolish all the adverse effects of CPB but will, at least in experimental systems, permit a more precise determination of the pathogenesis of this problem. The temptation to simply measure elevated circulating levels of newly identified mediators must be resisted and more effort applied to examining the pathophysiological effects of specific inhibitors. This type of investigation should initially be effected in experimental models where reproducible conditions can be ensured. In conjunction with this, far more precise end-points are required in order to assess the effect of any potential therapeutic intervention in a clinical setting. In particular, new techniques of evaluating endothelial injury need to be developed. In clinical studies careful consideration must be given to the patient population studied. Whilst patients undergoing routine coronary artery surgery form a relatively homogeneous group, the magnitude of endothelial injury sustained is probably small and, especially in terms of lung function, the signal will be diluted by other non-bypass-related events. The study of high risk groups would seem more appropriate despite their heterogeneity. An important unanswered question is why certain sub-populations of patients are at increased risk of clinically relevant bypass-induced injury. The endothelium of these patients may be different: the neonatal pulmonary microcirculation is not the same as that of an adult (with increased fluid filtration pressure and a higher microvascular surface area per unit lung mass [5,6]), children with pulmonary hypertension have histological evidence of an altered/damaged endothelium (S.G. Haworth, Personal Communication) whilst pre-existing sepsis could clearly induce a degree of endothelial dysfunction. A further possibility is that the inflammatory response in these patients is already "primed". Some patients with heart failure have been shown to have elevated circulating TNF.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Organ dysfunction and cardiopulmonary bypass: the role of complement and complement regulatory proteins. 829 8

Clinical and experimental data have shown that after acute myocardial infarction there is a significant release of tumour necrosis factor alpha. Therefore, an attempt was made to correlate changes in serum tumour necrosis factor alpha concentrations with indices of infarct extent in patients with acute myocardial infarction. In 50 patients with acute myocardial infarction, blood samples for evaluation of tumour necrosis factor alpha and alpha-hydroxybutyrate-dehydrogenase were collected every 6 h until 120 h after admission. Infarct extent was estimated by clinical parameters such as the occurrence of heart failure and rhythm disturbances, by enzymatic methods such as cumulative release of alpha-hydroxybutyrate-dehydrogenase and imaging techniques, by late resting single photon emission tomography--201 thallium scintigraphy--using an extent score and by echocardiography using a wall motion index. The maximum change in serum tumour necrosis factor alpha after infarction (delta TNF) was calculated by subtracting tumour necrosis factor alpha concentration on admission from peak tumour necrosis factor alpha concentration. The average peak tumour necrosis factor alpha level was observed 84 h after admission (median: 12 pg.ml-1). Between the 72nd and the 96th h no significant changes in tumour necrosis factor alpha values were observed. Analysis of the data showed that larger delta (TNF) values were found to be associated significantly with signs of heart failure (P = 0.003), the presence of rhythm disturbances (P = 0.001), increased enzymatic infarct extent indicated by cumulative release of alpha-hydroxybutyrate-dehydrogenase (r = 0.74; P < 0.001), large myocardial perfusion defects measured with 201 thallium scintigraphy (r = 0.80; P < 0.001), and a considerable number of left ventricular wall motion abnormalities (r = 0.57; P < 0.001). In conclusion, delta (TNF) is a reliable method of assessing damage severity in the myocardium after acute myocardial infarction. As only two blood samples are necessary within 84 h, the method may be one of the more convenient for the assessment of infarct size in clinical practice.
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PMID:Assessment of myocardial injury by serum tumour necrosis factor alpha measurements in acute myocardial infarction. 896 Apr 15

The level of tumor necrosis factor alpha (TNF-alpha) is increased in patients with congestive heart failure and may play an important role in the development and progression of heart failure. Two types of TNF receptor (TNF-RI and TNF-RII) are expressed in virtually every cell and have different biologic roles. Soluble forms of the two receptors (sTNF-RI and sTNF-RII) have been identified as extracellular domain fragments. Serum levels of TNF-alpha, sTNF-RI and sTNF-RII were measured in 66 patients with heart failure and 27 control subjects using an enzyme-linked immunosorbent assay (ELISA). Hemodynamic variables, norepinephrine, atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP) were evaluated. TNF-alpha was significantly higher in patients with heart failure than in controls subjects (9.4 +/- 1.4 vs 4.8 +/- 0.8 pg/ml; p < 0.05). sTNF-RI and -RII were significantly increased in relation to the severity of heart failure (control subjects, 0.66 +/- 0.04 and 1.97 +/- 0.15 ng/ml; NYHA class II, 1.10 +/- 0.08 and 2.28 +/- 0.12 ng/ml; NYHA class III, 1.63 +/- 0.22 and 3.00 +/- 0.24 ng/ml; NYHA class IV, 2.78 +/- 0.46 and 4.52 +/- 0.62 ng/ml, respectively). In 9 patients whose clinical symptoms improved after treatment, the levels of sTNF-RI and -RII decreased by 17.3 +/- 5.7% (p < 0.05) and 22.1 +/- 6.9% (p < 0.05), respectively. There were significant positive correlations between sTNF-RI and -RII and mean pulmonary pressure (r = 0.69 and r = 0.61; p < 0.001) and mean capillary wedge pressure (r = 0.65 and r = 0.54; p < 0.001 and p < 0.01, respectively), but not with left ventricular end-diastolic volume or ejection fraction (NS). sTNF-RI and -RII were also significantly positively correlated with plasma levels of norepinephrine (r = 0.75 and r = 0.50; p < 0.001 and p < 0.05), ANP (r = 0.72 and r = 0.70; p < 0.001), and BNP (r = 0.60 and r = 0.60; p < 0.001). In conclusion, soluble TNF receptors are increased in proportion to the severity of congestive heart failure and may reflect the current status of congestive heart failure rather than the level of left ventricular dysfunction.
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PMID:Soluble tumor necrosis factor receptors are elevated in relation to severity of congestive heart failure. 927 70

The majority of patients with chronic heart failure (CHF) have a decreased exercise tolerance. It has not been well established if muscle fatigue is related to a peripheral myopathy with specific metabolic, histologic and biochemical abnormalities. CHF patients demonstrate depressed oxidative capacity and activation of anaerobic glycolysis, leading to a reduction in the energy substrates. In addition, the skeletal muscles of the lower limbs demonstrate a shift toward type IIb fibers. Many factors, such as prolonged immobilization, reduced blood flow and neuroendocrine activation, can be cited in order to explain the origin of this myopathy. Recent studies show that immobilization is not the only reason for modifications in skeletal muscle composition, since patients with disuse atrophy show an increased percentage in myosin heavy chain I, while IIb is decreased. The opposite pattern is observed in CHF. It would appear that several factors such as deconditioning, prolonged immobilization and reduced blood flow, may produce muscular atrophy. The reasons behind specific changes in fibre composition may be found in metabolic factors such as insulin resistance, TNF levels and dysfunction of the ergo-metabolo muscle receptors.
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PMID:[Skeletal musculature modifications and mechanisms of fatigue in chronic heart failure]. 928 Jul 30

Cytokines have been associated with the pathogenesis of acute coronary syndromes and chronic heart failure (CHF), which are both associated with cardiomyocyte loss. In CHF, increased serum concentrations of proinflammatory cytokines, including tumour necrosis factor alpha (TNF-alpha) and also soluble TNF receptor have been found. Both TNF and Fas-ligand have been able to induce programmed cell death (apoptosis) of cardiomyocytes in various experimental studies. In ischaemic conditions of the heart, increased serum levels of soluble Fas receptor have been found. The proinflammatory cytokines interleukin 1 (IL-1), IL-2 and interferon-gamma can induce TNF production from target cells, including myocytes. TNF and some other cytokines are able to induce nitric oxide production, which depresses cardiac function and can induce apoptosis. However, anti-inflammatory cytokines such as IL-10, IL-4 and IL-13, secreted by T-helper type 2 lymphocytes and other cells, inhibit the production of proinflammatory cytokines. Preliminary studies suggest that cardiotrophin-1, produced by cardiomyocytes, is able to inhibit cytokine-induced cardiomyocyte apoptosis in vitro. As growth hormone is able to inhibit the production of proinflammatory cytokines in many cell types, it may also play an important role in the regulation of apoptosis induced by these cytokines. When the cytokine-induced pathways leading to altered gene expression of cardiomyocytes are understood, this knowledge may aid in the development of drugs that prevent progressive cardiomyocyte loss, in particular by inhibiting cytokine-induced apoptosis.
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PMID:Cytokines and cardiomyocyte death. 937 93

Cardiac hypertrophy and heart failure are frequently accompanied by elevated plasma levels of tumor necrosis factor alpha (TNF alpha), the pathogenetic relevance of this finding being a matter of debate. In human acute septic cardiomyopathy, on the other hand, the negative inotropic impact of TNF alpha on the heart is well documented and frequently ascribed to the induction of inducible nitric oxide (NO) synthase (iNOS) and an enhanced production of NO in the heart. Yet the present study presents evidence that in cardiomyocytes TNF alpha in non-toxic concentrations specifically depresses contractile performance independent of NO. In spontaneously beating neonatal rat cardiomyocytes, TNF alpha in a low, pathophysiologically relevant concentration (10 U/ml, 1-3 days) does not alter basal pulsation amplitude, but blocks alpha- and beta-adrenoceptor-stimulated increase in contractility and beating irregularity and impairs the impact of high extracellular calcium on contractile performance. However, this low TNF alpha-concentration does not suffice to induce iNOS - documented by reverse transcriptase polymerase chain reaction - or enhance nitrite concentrations in the cell culture supernatants as a measure of cellular NO production, neither in the presence nor absence of dexamethasone (0.1 micro M). Only in high concentration - the specific proinflammatory action being documented by an enhanced release of interleukin-6 from cardiomyocytes - TNF alpha (1000 U/mol; 6, 24 h) weakly induces the mRNA for iNOS, with a consecutive moderate rise in cellular nitrite production. TNF alpha-incubation (10-1000 U/ml) does not alter the morphological appearance of the cells displayed by phase contrast microscopy or evoke gross cytotoxicity.
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PMID:Tumor necrosis factor alpha (TNF alpha) is cardiodepressant in pathophysiologically relevant concentrations without inducing inducible nitric oxide-(NO)-synthase (iNOS) or triggering serious cytotoxicity. 940 66

Endothelin-1 (ET-1) enhances the biosynthesis of interleukin-6 (IL-6) in endothelial cells and bone marrow-derived stromal cells of the rat. This study investigates (i) whether ET-1 stimulates the formation of tumour necrosis factor alpha (TNF alpha) or interferon-gamma (IFN gamma) in cultured macrophages or in the anaesthetized rat. Incubation of J774.2 macrophages with ET-1 (0.001-1 microM) caused a concentration- and time-dependent increase in the concentration of TNF alpha, but not of IFN gamma, in the culture medium. The increase in TNF alpha caused by stimulation of J774.2 macrophages was abolished by pretreatment of cells with (i) the protein synthesis inhibitor cycloheximide, (ii) with the selective ETA-receptor antagonists BQ-123 or BQ-485 (but not the selective ETB-receptor antagonist BQ-788), (iii) the tyrosine kinase inhibitors genistein or tyrphostin AG126, or (iv) with the glucocorticoid, dexamethasone. The inhibition by dexamethasone of the formation of TNF alpha by cells activated with ET-1 is not due to the formation of lipocortin-1 (LC1), as it was not reduced by a monoclonal antibody against LC1. Systemic administration (i.v.) of ET-1 (1 nmol.kg-1) to anaesthetized rats caused a rapid and sustained (maximum: 45 min; return to baseline: within 180 min) rise in the plasma levels of TNF alpha. This is the first demonstration that ET-1 can release proinflammatory cytokines in vitro and in vivo. The generation of TNF alpha caused by ET-1 involves (in sequence) the (i) activation of ETA-receptors, (ii) activation of tyrosine kinase resulting in the phosphorylation of intracellular proteins, (iii) the activation of, hitherto, unknown transcription factors, finally resulting in (iv) transcription and translation of the TNF alpha gene. The generation of TNF alpha by cells activated with ET-1 points to a pro-inflammatory role of ET-1 in diseases associated with local (e.g. atherosclerosis, heart failure) or systemic inflammation (circulatory shock), which are associated with high ET-1 plasma levels.
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PMID:Endothelin-1 stimulates the biosynthesis of tumour necrosis factor in macrophages: ET-receptors, signal transduction and inhibition by dexamethasone. 944 16

The cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) are increased in the circulation of patients with chronic heart failure. However, their correlation with left ventricular dysfunction has not yet been thoroughly evaluated, and their interrelation with other neurohumoral systems, such as the adrenergic system and endothelin, is unclear. Therefore TNF-alpha, its soluble receptor II, IL-6, big endothelin, and noradrenaline levels were simultaneously measured in venous blood from 65 patients with heart failure in New York Heart Association (NYHA) class II to IV during therapy with digitalis, furosemide, and enalapril. TNF-alpha plasma levels were 3.2+/-0.2 SEM pg/ml in 38 patients in NYHA function class II, 4.0+/-0.3 SEM pg/ml in 16 patients in NYHA function class III, and 5.3+/-0.9 SEM pg/ml in 11 patients in NYHA function class IV (p < 0.001 vs NYHA function class II). IL-6 plasma levels were 3.1+/-0.6 SEM pg/ml in 38 patients in NYHA function class II, 5.2+/-0.8 SEM pg/ml in 16 patients in NYHA function class III, and 13.3+/-3.9 SEM pg/ml in 11 patients in NYHA function class IV (p < 0.0001 vs NYHA function class II andp < 0.0001 vs NYHA class III). Thus both cytokines increased with increasing severity of heart failure, but only IL-6 plasma levels were different in patients in the more severe function classes. TNF-alpha correlated closely with TNF soluble receptor II (r = 0.8, p < 0.0001) and modestly with serum creatinine (r = 0.6, p < 0.0001), whereas IL-6 plasma levels were not statistically related to kidney function. Significant modest correlations were also found among TNF-alpha and IL-6 (r = 0.3, p < 0.01), big endothelin (r = 0.3, p < 0.01), and noradrenaline levels (r = 0.4, <0.001). This study supports the hypothesis that in heart failure both cytokines, TNF-alpha, and IL-6, as well as neurohumoral factors, play a role in the clinical progression of the disease. Thereby levels of TNF-alpha but not IL-6 seem to be related to concomitant kidney dysfunction.
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PMID:Circulating tumor necrosis factor-alpha levels in chronic heart failure: relation to its soluble receptor II, interleukin-6, and neurohumoral variables. 958 80

Tumour necrosis factor alpha (TNF alpha) is increased in patients with cardiac cachexia, a condition associated with reduced peripheral blood flow both at rest and after interventions causing vasodilation. By contrast, in patients with chronic heart failure (CHF), higher TNF levels are associated with a greater capacity for vasodilation in the arm. To clarify the relationship between peripheral blood flow and TNF in CHF, we studied the relation between TNF alpha and blood flow in the leg (plethysmography, post maximal exercise and 5 min ischaemia) in 34 patients (age 63 +/- 2 years, ejection fraction 29 +/- 3%, peak VO2 16.6 +/- 1.1 ml/kg/min, mean +/- SEM). Peak leg blood flow correlated significantly with total TNF alpha (r = 0.68, p < 0.0001, peak VO2 (r = 0.54), and soluble TNF receptors 1 (r = 0.56) and 2 (r = 0.52, all p < 0.002). TNF alpha, soluble TNF receptors 1 and 2 and aldosterone correlated with peak blood flow independently of age, ejection fraction, peak VO2 and functional NYHA class. TNF alpha was the only parameter that showed strong correlations for peak blood flow in all clinically relevant subgroups (severe vs. mild, ischaemic vs. dilated, cachectic vs. non-cachectic patients). This study shows a close and inverse relationship between peak leg blood flow and the plasma concentration of TNF alpha, suggesting a pathophysiological role for TNF alpha in reducing peak peripheral blood flow in CHF.
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PMID:Tumour necrosis factor alpha as a predictor of impaired peak leg blood flow in patients with chronic heart failure. 960 72


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