Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An increase in circulating levels of proinflammatory cytokines has been proposed as an important pathogenic factor contributing to cardiac injury during chronic heart failure. To determine whether plasma levels of the cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) increase during pacing-induced heart failure, we paced the hearts of seven dogs at 210 beats/min for 3 weeks and at 240 beats/min for an additional week to induce severe clinical signs of cardiac decompensation. Hemodynamic measurements and blood samples from the aorta and coronary sinus (CS) were taken at control, at 3 weeks, and in end-stage failure. Decompensated heart failure occurred at 29 +/- 1.8 days, when left ventricular (LV) end-diastolic pressure was 25 +/- 1.3 mmHg, LV systolic pressure was 92 +/- 4 mmHg, mean arterial pressure was 77 +/- 3 mmHg, and dP/dtmax was 1219 +/- 73 (all P < 0.05 vs control). Arterial concentration of IL-6 was 12 +/- 4.0 U/ml at control, 11 +/- 2.7 U/ml at 3 weeks, and 10 +/- 1.7 U/ml in end-stage failure (NS). At the same time points, IL-6 in CS plasma was 12 +/- 3.5, 13 +/- 2.8 and 11 +/- 2.4 U/ml, respectively (NS vs control and vs arterial concentrations). TNF-alpha did not reach detectable concentrations in arterial or CS blood at any time. TNF-alpha and IL-6 concentrations did not increase in arterial blood, were not released in the CS from the heart during the development of pacing-induced heart failure, and can not universally be implicated in the pathogenesis of all forms of cardiac dysfunction. Our findings are consistent with other data from patients in which severe heart failure was not associated with increased levels of circulating cytokines.
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PMID:Cytokines are not a requisite part of the pathophysiology leading to cardiac decompensation. 1063 60

To study the changes of tumor necrosis factor-alpha (TNF-alpha) produced by peripheral blood mononuclear cells (PBMC) of patients with congestive heart failure (CHF), we determined the TNF-alpha concentrations of plasma and culture supernatant of PBMCs in 113 patients with various heart diseases. The results showed that plasma levels of TNF-alpha were significantly higher in CHF patients (n=50, 13.36+/-6.09 pg/ml) and in cachetic CHF patients (n=26, 19.20+/-10.42 pg/ml) than in the controls (n=37, 6.73+/-3.91 ng/ml). The supernatant levels of TNF-alpha in cultured PBMC (PBMC-TNF-alpha) were also significantly elevated in CHF patients (5.77+/-2.11 ng/ml), and even higher in cachetic CHF patients (7.01+/-5.11 ng/ml), as compared with the controls (2.27+/-2.24 ng/ml). There was a significant correlation between levels of PBMC-TNF-alpha and severity of heart failure (r=0.48, P<0.01). But no correlation between PBMC-TNF-alpha and plasma TNF-alpha was observed. These results demonstrate that the expression of TNF-alpha in PBMC is increased in patients with CHF, especially in patients with CHF accompanied by cachexia, suggesting that PBMC-TNF-alpha may be a potential biochemical indicator to evaluate the patients with CHF.
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PMID:Elevated tumor necrosis factor alpha of blood mononuclear cells in patients with congestive heart failure. 1063 33

Recent studies have focused their attention on the role of the proinflammatory cytokine tumor necrosis factor (TNF) in the development of heart failure. First recognized as an endotoxin-induced serum factor that caused necrosis of tumors and cachexia, it is now recognized that TNF participates in the pathophysiology of a group of inflammatory diseases including rheumatoid arthritis and Crohn's disease. The normal heart does not express TNF; however, the failing heart produces robust quantities. Furthermore, there is a direct relationship between the level of TNF expression and the severity of disease. In addition, both in vivo and in vitro studies demonstrate that TNF effects cellular and biochemical changes that mirror those seen in patients with congestive heart failure. Furthermore, in animal models, the development of the heart failure phenotype can be abrogated at least in part by anticytokine therapy. Based on information from experimental studies, investigators are now evaluating the clinical efficacy of novel anticytokine and anti-TNF strategies in patients with heart failure; one such strategy is the use of a recombinantly produced chimeric TNF alpha soluble receptor. Thus, in view of the emerging importance of proinflammatory cytokines in the pathogenesis of heart disease, we review the biology of TNF, its role in inflammatory diseases, the effects of TNF on the physiology of the heart and the development of clinical strategies that target the cytokine pathways.
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PMID:The role of tumor necrosis factor in the pathophysiology of heart failure. 1071 53

We tested the hypothesis that the inflammatory cytokines can regulate fibroblast extracellular matrix metabolism. Neonatal and adult rat cardiac fibroblasts cultures in vitro were exposed to interleukin (IL)-1beta (4 ng/mL), tumor necrosis factor-alpha (TNF-alpha; 100 ng/mL), IL-6 (10 ng/mL), or interferon-gamma (IFN-gamma; 500 U/mL) for 24 hours. IL-1beta, and to a lesser extent TNF-alpha, decreased collagen synthesis, which was measured as collagenase-sensitive [(3)H]proline incorporation, but had no effect on cell number or total protein synthesis. IL-1beta decreased the expression of procollagen alpha(1)(I), alpha(2)(I), and alpha1(III) mRNA, but increased the expression of procollagen alpha(1)(IV), alpha(2)(IV), and fibronectin mRNA, indicating a selective transcriptional downregulation of fibrillar collagen synthesis. IL-1beta and TNF-alpha each increased total matrix metalloproteinase (MMP) activity as measured by in-gel zymography, causing specific increases in the bands corresponding to MMP-13, MMP-2, and MMP-9. IL-1beta increased the expression of proMMP-2 and proMMP-3 mRNA, suggesting that increased metalloproteinase activity is due, at least in part, to increased transcription. The effects of IL-1beta were not dependent on NO production. Thus, IL-1beta and TNF-alpha decrease collagen synthesis and activate MMPs that degrade collagen. These observations suggest that IL-1beta and TNF-alpha may contribute to ventricular dilation and myocardial failure by promoting the remodeling of interstitial collagen.
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PMID:Interleukin-1beta and tumor necrosis factor-alpha decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro. 1086 17

BACKGROUND-Myocardial failure is an important problem after heart transplantation. Right ventricular (RV) failure is most common, although its mechanisms remain poorly understood. Inflammatory cytokines play an important role in heart failure. We studied the expression of tumor necrosis factor (TNF)-alpha and other cytokines in donor myocardium and their relationship to the subsequent development of RV failure early after transplantation. METHODS AND RESULTS-Clinical details were obtained, and ventricular function was assessed by transesophageal echocardiography in 26 donors before heart retrieval. A donor RV biopsy was obtained immediately before transplantation, and each recipient was followed for the development of RV failure. Reverse transcriptase-polymerase chain reaction was performed to detect TNF-alpha, interleukin-2, interferon-gamma, and inducible nitric oxide synthase expression. Eight of 26 recipients (30.8%) developed RV failure. Seven of these 8 (87.5%) expressed TNF-alpha, but only 4 of the 18 (22.2%) who did not develop RV failure expressed TNF-alpha (P<0.005). As a predictor of RV failure, TNF-alpha mRNA had a sensitivity of 87.5%, a specificity of 83.3%, a positive predictive value of 70%, and a negative predictive value of 93.7%. Western blotting demonstrated more TNF-alpha protein in the myocardium of donor hearts that developed RV failure (658+/-60 versus 470+/-57 optical density units, P<0.05). Immunocytochemistry localized TNF-alpha expression to cardiac myocytes. Reverse transcriptase-polymerase chain reaction detected interferon-gamma in 2 (7.7%), interleukin-2 in 1 (3.8%), and inducible nitric oxide synthase mRNA in 1 (3.8%) of the 26 donor hearts, none of which developed RV failure. CONCLUSIONS-TNF-alpha expression in donor heart cardiac myocytes seems to predict the development of RV failure in patients early after heart transplantation.
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PMID:Tumor necrosis factor-alpha is expressed in donor heart and predicts right ventricular failure after human heart transplantation. 1089 97

Our understanding of the pathophysiology of chronic heart failure is rapidly expanding. recent investigations suggest a role for various proinflammatory and vasoconstrictive cytokines in the development and progression of the disease. In particular, tumor necrosis factor-alpha, interlukin-6, and endothelin have all been implicated in heart failure desease progression. These cytokines appear to be activated in response to a remodeling, induction of programmed cell death, neurohormonal activation, and hemodynamics, these agents cause a variety of deleterious effects in the setting of ventricular dysfunction. Investigational inhibitors and antagonists of these substances show promise for the future treatment of heart failure.
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PMID:Insights into pathogenesis and treatment of cytokines in cardiomyopathy. 1098 Aug 82

Sphingomyelin and its metabolic products are now known to have second messenger functions in a variety of cellular signaling pathways. At the epicenter of the sphingomyelin--cell signaling pathway is a family of phospholipases called sphingomyelinases. These enzymes cleave sphingomyelin to produce ceramide and phosphocholine. Ceramide in turn serves as a lipid second messenger that induces a variety of cell regulatory phenomenon such as programmed cell death (apoptosis), cell differentiation, cell proliferation, and sterol homeostasis. Neutral sphingomyelinase (N-SMase) is a Mg2+ sensitive enzyme that can be activated by a host of physiologically relevant and structurally diverse molecules like tumor necrosis factor-alpha (TNF-alpha), oxidized human low density lipoproteins (Ox-LDL), and several growth factors. Large amounts of ceramide accumulate in human fatty streaks and plaques along with Ox-LDL, growth factors, and proinflammatory cytokines in human atherosclerosis. A further role of ceramide and N-SMase in atherosclerosis was uncovered by the finding that Ox-LDL and TNF-alpha stimulated N-SMase activity. In turn, ceramide and/or a homolog serves as an important stress signaling molecule in signal transduction, which leads to apoptosis. Interestingly, an antibody against N-SMase can abrogate Ox-LDL and TNF-alpha induced apoptosis, and therefore may be useful for additional studies of apoptosis in experimental animals. Overexpression of recombinant human N-SMase in human aortic smooth muscle cells markedly stimulate apoptosis, presumably via the multioligomerization of the 'death domain'. Since plaque stability is an integral aspect of atherosclerosis management, activation of N-SMase and subsequent apoptosis may be vital events in the onset of plaque rupture, stroke and heart failure. In contrast to these observations in human hepatocytes, TNF-alpha mediated N-SMase activation did not induce apoptosis. Rather it stimulated the maturation of sterol regulatory element (SRE) binding protein (SREBP-1). Moreover, a cell permeable ceramide was found to reconstitute the phenomenon above in a sterol-independent fashion. These findings provide alternate avenues for therapy of patients with hypercholesterolemia and atherosclerosis. The findings reported here suggests that N-SMase plays important cell regulatory roles and provide an exciting opportunity to further these findings to understand the pathophysiology of human disease states.
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PMID:Neutral sphingomyelinase: past, present and future. 1100 63

Nuclear factor-kappaB (NF-kappa B) is a pleiotropic oxidant-sensitive transcription factor that is present in the cytosol in an inactive form complexed to an inhibitory kappaB (I kappa B) monomer. Various stimuli, including ischemia, hypoxia, free radicals, cytokines, and lipopolysaccharide (LPS), activate NF-kappa B by inducing phosphorylation of I kappa B. Phosphorylation of serine residues at positions 32 and 36 is critical for ubiquitination and degradation of I kappa B alpha with consequent migration of NF-kappa B to the nucleus. Although NF-kappa B is thought to contribute to numerous pathophysiologic processes, definitive assessment of its role has been hindered by the inability to achieve specific inhibition in vivo. Pharmacologic inhibitors of NF-kappa B are available, but their utility for in vivo studies is limited by their relative lack of specificity. Targeted ablation of genes encoding NF-kappa B subunits has not been productive in this regard because of fetal lethality in the case of p65 and functional redundancy in the Rel family of proteins. To overcome these limitations, we have created a viable transgenic mouse that expresses a phosphorylation-resistant mutant of I kappa B alpha (I kappa B alpha(S32A,S36A)) under the direction of a cardiac-specific promoter. Several transgenic lines were obtained with copy numbers ranging from one to seven. The mice exhibit normal cardiac morphology and histology. Total myocardial I kappa B alpha protein level is elevated 3.5- to 6.5-fold with a concomitant 50-60% decrease in the level of I kappa B beta. Importantly, expression of I kappa B(S32A,S36A) results in complete abrogation of myocardial NF-kappa B activation in response to tumor necrosis factor- alpha (TNF-alpha) and LPS stimulation. Thus, novel transgenic mice have been created that make it possible to achieve cardiac-specific and selective inhibition of NF-kappa B in vivo. These transgenic mice should be useful in studies of various cardiac pathophysiological phenomena that involve NF-kappa B activation, including ischemic preconditioning, heart failure, septic shock, acute coronary syndromes, cardiac allograft rejection, and apoptosis.
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PMID:Cardiac-specific abrogation of NF- kappa B activation in mice by transdominant expression of a mutant I kappa B alpha. 1113 32

The development of chronic heart failure (CHF) includes phenotypic changes in a host of homeostatic systems so that, as the disease advances, CHF may be seen as a multi-system disorder with its origins in the heart but embracing many extra-cardiac manifestations. Immunological abnormalities are recognised in this context, in particular, changes in the expression of mediators of the innate immune response. Higher levels of the pro-inflammatory cytokine tumor necrosis factor (TNF) are found in the circulation and in the myocardium of patients with CHF than in controls, and TNF has been implicated in a number of pathophysiological processes that are thought important to the progression of CHF. Therapies directed against this cytokine therefore represent a novel approach to heart failure management. Anti-TNF strategies in CHF may target the mechanisms of immune activation, the intracellular pathways regulating TNF production, or the fate of TNF once it has been released into the circulation. Circulating endotoxin may be an important stimulus to TNF production by circulating monocytes, tissue macrophages and cardiac myocytes in CHF and efforts to limit this phenomenon are of interest. Several established pharmacological therapies for patients with CHF, including angiotensin converting enyzme inhibitors, beta-blockers, and phosphodiesterase inhibitors may modify cellular TNF production by their action on intracellular mechanisms, whereas TNF receptor fusion proteins have been developed that target circulating TNF itself. Patients with New York Heart Association class IV symptoms, those with cardiac cachexia and those with oedematous decompensation of their disease have the highest serum TNF levels and are most likely to benefit most from such a therapeutic approach.
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PMID:Tumour necrosis factor in chronic heart failure: a peripheral view on pathogenesis, clinical manifestations and therapeutic implications. 1115 10

Heart failure is a complex neurohumoral and inflammatory syndrome. Recent studies have shown that proinflammatory cytokines (interleukin-1, interleukin-2, interleukin-6, interleukin-10, and tumor necrosis factor) are involved in cardiac depression and in the complex syndrome of heart failure. Understanding the involvement of these cytokines may enable us to reverse cardiac depression and heart failure by the use of monoclonal antibodies directed against specific cytokines to block the downhill progression of heart failure.
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PMID:Pathophysiological role of cytokines in congestive heart failure. 1116 Jul 65


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