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

Growing evidence suggests that cardiac nonmyocyte cells may play an important regulatory role in the response to myocardial overload and injury via altered expression of paracrine products, such as cytokines and growth factors, but information concerning the cell-specific changes in the expression of these substances in heart-failure models is limited. Therefore, cardiac nonmyocytes were isolated from rats 1 day and 1 and 6 wk after left coronary artery ligation with resulting hemodynamic evidence of heart failure and in sham-operated control animals. mRNAs for tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, transforming growth factors (TGF)-beta1 and TGF-beta3, and type I and type III collagen were measured by Northern analyses. The temporal and quantitative relationships between the expression of these cytokines and collagen and myocyte hypertrophy were determined. mRNA expression of IL-1beta was increased by 1.3-fold at 1 day and 1 wk, and expression of TNF-alpha, IL-1beta, IL-6, TGF-beta1, and TGF-beta3 were increased by 1.4- to 2.1-fold at the 1-wk time point before returning toward baseline at 6 wk. There were significant correlations between the expression of these cytokines and the expression of types I and III collagen, which also peaked at 1 wk. Myocyte hypertrophy was seen first at 6 wk. These observations are consistent with a hypothesis that nonmyocyte cells play a regulatory role in the extracellular matrix changes during postinfarction remodeling and highlight the importance of examining cell-specific changes in gene expression and elucidating the role of cell-to-cell interactions within the myocardium.
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PMID:Cytokine expression increases in nonmyocytes from rats with postinfarction heart failure. 968 21

Myocardial tumor necrosis factor-alpha (TNF-alpha) is an autocrine contributor to myocardial dysfunction and cardiomyocyte death in ischemia-reperfusion injury (I/R), sepsis, chronic heart failure, and cardiac allograft rejection. Cardiac resident macrophages and cardiomyocytes themselves produce TNF-alpha. In this regard, adenosine (ADO) has been reported to reduce macrophage TNF-alpha production. Our purposes were to determine whether (1) I/R induces rat myocardial TNF-alpha production; (2) ADO decreases ischemia-induced rat myocardial TNF-alpha production; (3) ADO functionally protects human myocardium against I/R; and (4) TNF-alpha-binding protein (TNFBP; p55) confers similar protection when substituted for ADO pretreatment. To study this, human atrial trabeculae were obtained during cardiac surgery and suspended in organ baths, paced at 1 Hz, and force development was recorded during I/R (45/120 min) with or without ADO pretreatment (125 microM x 10 min), or TNFBP (1 microgram/ml) during I/R. Isolated rat hearts were perfused using the Langendorff method undergoing I/R (20/40 min) with or without ADO pretreatment (125 microM x 2 min) and rat myocardial expression of TNF-alpha was assessed by ELISA. Results demonstrated that I/R increased rat myocardial TNF-alpha levels from 324 +/- 36 to 902 +/- 77 pg/g (P < 0.05; ANOVA and Bonferroni/Dunn) and decreased human myocardial developed force (DF) to 18 +/- 2% of baseline (%BDF; P < 0.05). ADO pretreatment decreased ischemia-induced rat myocardial TNF-alpha production (356 +/- 107 pg/g; P < 0.05) and increased postischemic DF of human myocardium to 39 +/- 3% BDF (P < 0.05. Further substantiating the link between ischemia-induced TNF-alpha production and injury, TNFBP administration similarly improved post-I/R function of human myocardium (55 +/- 5% BDF; P < 0.05 vs. I/R alone). We conclude that (1) I/R induces rat myocardial TNF-alpha production; (2) ADO pretreatment decreases I/R-induced rat myocardial TNF-alpha production; (3) ADO improves human myocardial function; (4) TNFBP confers similar protection; and (5) inhibition/neutralization of TNF-alpha represents a novel strategy for protecting human myocardium against ischemia and reperfusion injury.
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PMID:Adenosine reduces cardiac TNF-alpha production and human myocardial injury following ischemia-reperfusion. 969 10

Sphingolipids and their metabolic products are now known to have second-messenger functions in a variety of cellular signaling pathways. Lactosylceramide (LacCer), a glycosphingolipid (GSL) present in vascular cells such as endothelial cells, smooth muscle cells, macrophages, neutrophils, platelets, and monocytes, contributes to atherosclerosis. Large amounts of LacCer accumulate in fatty streaks, intimal plaque, and calcified intimal plaque, along with oxidized low density lipoproteins (Ox-LDLs), growth factors, and proinflammatory cytokines. A possible role for LacCer in vascular cell biology was suggested when this GSL was found to stimulate the proliferation in vitro of aortic smooth muscle cells (ASMCs). A further link of LacCer in atherosclerosis was uncovered by the finding that Ox-LDLs stimulated specifically the biosynthesis of LacCer. Ox-LDL-stimulated endogenous synthesis of LacCer by activation of UDP-Gal:GlcCer,beta1-4galtransferase (GalT-2) is an early step in this signaling pathway. In turn, LacCer serves as a lipid second messenger that orchestrates a signal transduction pathway, ultimately leading to cell proliferation. This signaling pathway includes LacCer-mediated activation of NADPH oxidase that produces superoxide. Such superoxide molecules stimulate the GTP loading of p21(ras). Subsequently, the kinase cascade (Raf-1, Mek2, and p44MAPK [mitogen-activated protein kinase]) is activated. The phosphorylated form of p44MAPK translocates from the cytoplasm to the nucleus and engages in c-fos expression, proliferating cell nuclear antigen (PCNA) such as cyclin activation, and cell proliferation takes place. Interestingly, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of GalT-2, can abrogate the Ox-LDL-mediated activation of GalT-2, the signal kinase cascade noted above, as well as cell proliferation. Additional studies have revealed that LacCer mediates the tumor necrosis factor-alpha (TNF-alpha)-induced nuclear factor-kappaB expression and intercellular adhesion molecule (ICAM-1) expression in vascular endothelial cells via the redox-dependent transcriptional pathway. LacCer also stimulates the expression of CD11/CD8, or Mac-1, on the surface of human neutrophils. Collectively, this phenomenon may contribute to the adhesion of neutrophils or monocytes to the endothelial cell surface and thus initiate the process of atherosclerosis. In addition, the LacCer-mediated proliferation of ASMCs may contribute to the progression of atherosclerosis. On the other hand, programmed cell death (apoptosis) by proinflammatory cytokines such as TNF-alpha, interleukin-1, and high concentrations of Ox-LDL occur via activation of a cell membrane-associated neutral sphingomyelinase (N-SMase). N-SMase hydrolyzes sphingomyelin into ceramide and phosphocholine. In turn, ceramide or a homologue serves as an important stress-signaling molecule. Interestingly, an antibody against N-SMase can abrogate Ox-LDL- and TNF-alpha-induced apoptosis and therefore may be useful for in vivo studies of apoptosis in experimental animals. Because 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, or heart failure. Interestingly, in human liver cells, N-SMase action mediates the TNF-alpha-induced maturation of the sterol regulatory-element binding protein. Moreover, a cell-permeable ceramide can reconstitute the phenomenon above in a sterol-independent fashion. Such findings may provide new avenues for therapy for patients with atherosclerosis. The findings described here indicate an important role for sphingolipids in vascular biology and provide an exciting opportunity for further research in vascular disease and atherosclerosis.
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PMID:Sphingolipids in atherosclerosis and vascular biology. 976 22

The present study investigated the secretion level and gene expression of adrenomedullin (AM), a novel vasorelaxant peptide, in cultured neonatal rat cardiac myocytes and nonmyocytes, and the effects of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF alpha) on its production and secretion in these cells. Under serum-free conditions, both myocytes and nonmyocytes secreted immunoreactive (ir-) AM into the culture medium in a time-dependent manner. The secretion rates of ir-AM from myocytes and nonmyocytes per 10(5) cells were almost equivalent. The expression of AM messenger RNA was also observed in cultured myocytes and nonmyocytes. The peptide secretion and messenger RNA level of AM in cardiac myocytes were increased after stimulation with IL-1beta. In nonmyocytes, IL-1beta and TNF alpha remarkably augmented both the release of ir-AM into the medium and AM gene expression after 24 and 48 h of incubation. These observations indicate that cardiac ventricular cells (i.e. myocytes and nonmyocytes) actively produce AM and also suggest that cytokines such as IL-1beta and TNF alpha regulate the gene expression and secretion of this peptide in the ventricles. On the basis of these results and the findings that IL-1beta and TNF alpha are involved in heart failure and cardiac hypertrophy, AM may play a role as an autocrine/paracrine modulator in some cardiac disorders.
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PMID:Production and secretion of adrenomedullin in cultured rat cardiac myocytes and nonmyocytes: stimulation by interleukin-1beta and tumor necrosis factor-alpha. 979 68

Alterations in body composition and nutritional status are common in humans with heart failure and are related, in part, to increases in cytokine concentrations. Cytokines have not been studied previously in dogs with naturally occurring cardiac disease nor has fish oil administration been used in this population to decrease cytokine production. The purposes of this study were to characterize nutritional and cytokine alterations in dogs with heart failure and to test the ability of fish oil to reduce cytokines and improve clinical outcome. Body composition, insulinlike growth factor-1, fatty acids, and cytokines were measured in 28 dogs with heart failure and in 5 healthy controls. Dogs with heart failure then were randomized to receive either fish oil or placebo for 8 weeks. All parameters were measured again at the end of the study period. At baseline, 54% of dogs with heart failure were cachectic and the severity of cachexia correlated with circulating tumor necrosis factor-alpha concentrations (P = .05). Cytokine concentrations at baseline, however, were not significantly increased in dogs with heart failure compared to controls. Baseline plasma arachidonic acid (P = .02), eicosapentaenoic acid (P = .03), and docosahexaenoic acid (P = .004) concentrations were lower in dogs with heart failure than in controls. Fish oil supplementation decreased interleukin-1 beta (IL-1) concentrations (P = .02) and improved cachexia (P = .01) compared to the placebo group. The mean caloric intake of the heart failure dogs as a group was below the maintenance energy requirement (P < .001), but no difference was found in food intake between the fish oil and placebo groups. Insulinlike growth factor-1 concentrations (P = .01) and reductions in circulating IL-1 concentrations over the study period (P = .02) correlated with survival. These data demonstrate that canine heart failure is associated with cachexia, alterations in fatty acids, and reduced caloric intake. Fish oil supplementation decreased IL-1 concentrations and improved cachexia. In addition, reductions in IL-1 predicted survival, suggesting that anticytokine strategies may benefit patients with heart failure.
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PMID:Nutritional alterations and the effect of fish oil supplementation in dogs with heart failure. 985 37

Cardiodepressant effects of tumor necrosis factor-alpha (TNF-alpha have been documented in numerous experimental settings in vivo and in vitro. In vivo administration of TNF-alpha mimicks the cardiovascular pattern of sepsis including septic cardiomyopathy. Serum levels of TNF-alpha were found to be elevated both in sepsis and in numerous non-septic heart disorders. Although an involvement of TNF-alpha in the pathogenesis of septic cardiomyopathy seems likely, presently no definite conclusion can be drawn with regard to the role of TNF-alpha in chronic heart failure. The origin and trigger mechanisms for the release of TNF-alpha in heart failure are a matter of debate, endotoxin (LPS) from intestinal translocation in venous congestion being one possible player. The negative inotropic impact of TNF-alpha is frequently ascribed to the induction of inducible nitric oxide (NO) synthase (iNOS). Results from in vitro studies rather suggest a complex interaction of TNF-alpha with the heart, with pleiotropic effects on cardiomyocyte performance, including an induction of iNOS at higher TNF-alpha concentrations, but NO-independent cardiodepression at low, pathophysiologically more relevant concentrations. TNF-alpha effects on the heart also vary with regard to the kinetics of the process: rapidly occuring cardiodepressant effects include a release of sphingosine and a suppression of the calcium transient, while chronic administration of TNF-alpha was shown to depress the synthesis of precursors for the phosphoinositide pathway and inhibit pyruvate dehydrogenase activity and mitochondrial function. Whether secondary cytokines induced by TNF-alpha in cardiomyocytes contribute to cardiodepression or whether apoptotic signals activated by TNF-alpha are involved in the cardiodepressive pathways is presently unknown.
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PMID:Cardiodepression by tumor necrosis factor-alpha. 988 17

Despite repeated attempts to develop a unifying hypothesis that explains the clinical syndrome of heart failure, no single conceptual paradigm has withstood the test of time. In this regard, recent studies have shown that a class of biologically active molecules, generically referred to as cytokines, are overexposed in heart failure. This article will review recent clinical and experimental material that suggest proinflammatory (stress activated) cytokines such as tumor necrosis factor-alpha (TFN-alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6) may play a role in the pathogenesis of congestive heart failure. The scope of this article includes an overview of the biology of cytokines in the heart, as well as review of the clinical studies that have documented elevated levels of cytokines and cytokine receptors in patients with heart failure.
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PMID:The role of cytokines in the failing human heart. 989 94

Inflammatory cytokines may play a pathogenic role in the development of congestive heart failure (CHF). Elevated circulating levels of inflammatory cytokines have been reported in CHF, but most studies have focused on only a few cytokine parameters. However, the activity of these cytokines are modulated by soluble cytokine receptors and cytokines with anti-inflammatory activities, and in the present study several of these interacting factors were examined simultaneously in 38 CHF patients with various degrees of heart failure and in 21 healthy controls. Patients with CHF had increased plasma concentrations of tumor necrosis factor (TNF)alpha, interleukin-6, soluble TNF receptors and the soluble interleukin-6 receptor, glycoprotein (gp)130. They also had elevated ratios of TNFalpha/soluble TNF receptors and interleukin-6/soluble gp130 as well as enhanced interleukin-6 bioactivity in serum, suggesting inflammatory net effects. In addition to raised circulating levels of inflammatory cytokines, CHF patients with severe heart failure also had abnormalities in the levels of anti-inflammatory cytokines, with decreased levels of transforming growth factor beta1 and inadequately raised interleukin-10 in relation to the elevated TNFalpha concentrations. This dysbalance between inflammatory and anti-inflammatory cytokines was also found in monocyte supernatants from CHF patients. The abnormalities in the cytokine network were most pronounced in patients with the most severe heart failure, and several of the immunologic parameters, in particular soluble gp130, were correlated with variables reflecting deranged hemodynamic status. The present study analyzing the complexity of the cytokine network in CHF, demonstrates profound disturbances in the levels of both inflammatory and anti-inflammatory mediators with a marked dysbalance favoring inflammatory effects.
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PMID:Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. 1007 27

The tumor necrosis factor (TNF) alpha level is elevated in patients with advanced heart failure, and the phosphorylation of contractile regulatory proteins is reduced in the human heart. We hypothesized that TNFalpha affects the phosphorylation of proteins involved in regulating contraction; phospholamban (PLB), myosin light chain 2 (MLC2) and troponin I (TnI). Spontaneously beating rat neonatal cardiac myocytes, prelabelled with [32P]orthophosphate, were treated with TNFalpha for 30 min, and stimulated with isoproterenol for 5 min. 32P-labelled myofibrillar proteins were isolated by 15% SDS-PAGE. Baseline phosphorylation levels of PLB, TnI and an unknown 23kDa phosphoprotein were decreased by TNFalpha in a dose-dependent manner. Moreover, TNFalpha attenuated the phosphorylation levels of PLB and TnI increased by a concentration of 0.01 microM isoproterenol, but not by 1 microM of isoproterenol. Although TNFalpha had no effect on the cAMP content or cAMP-dependent protein kinase activity in the presence or absence of isoproterenol, an inverse relationship was observed between the concentration of TNFalpha and the cGMP content in cardiac myocytes, and treatment with TNFalpha resulted in a concentration-dependent increase in type 2A protein phosphatase activity. The observation that TNFalpha decreases phosphorylation levels of PLB and TnI in cardiac myocytes suggests that the reduction of these protein phosphorylation levels is partially responsible for alterations of intracellular Ca2+-cycling and the force of contraction in TNF alpha-treated cardiac myocytes. Furthermore, TNFalpha reduces myocyte contraction and protein phosphorylation states possibly via cAMP-independent mechanisms, at least in part, by the activation of type 2A protein phosphatase.
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PMID:Tumor necrosis factor-alpha decreases the phosphorylation levels of phospholamban and troponin I in spontaneously beating rat neonatal cardiac myocytes. 1007 33

We studied body composition and cytokine levels in 58 patients with heart failure and 16 control patients using dual-energy x-ray absorptiometry. Bone mineral content and density, and lean and fat tissue content, were reduced in cachectic compared with noncachectic patients and control subjects, with negative relations between indexes of bone composition and tumor necrosis factor and tumor necrosis factor receptor 1.
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PMID:Loss of bone mineral in patients with cachexia due to chronic heart failure. 1007 75


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