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)

In summary, over a decade of investigation has demonstrated the pathophysiologic importance of TNF in the development and progression of cardiac dilatation and heart failure. Although the signaling pathways that regulate the cardiac production of TNF have not yet been identified and the potential benefits of TNF expression to the heart are not understood, the benefits of anticytokine therapy in animal models is marked. Unfortunately, these salutary effects in the laboratory have not transitioned to the bedside. To accomplish the translational portion of the cytokine story, we must identify the point in time during the transition from compensated to decompensated heart failure in which TNF is expressed. In addition, we must better understand the role that other down-stream and non-TNF-dependent cytokines play in the development of heart failure. Not all patients are the same; therefore, we must pursue clinical trials that will allow us to elucidate the optimal degree of TNF inhibition, identify the patients who are most likely to respond to TNF inhibition, and determine what the true, long-term effects of TNF inhibition may be. Finally, we must recognize that inflammatory activities can exist in tissues and organs in the absence of TNF. Thus, anticytokine strategies alone might not be effective in ameliorating the signs and symptoms of heart failure. It is hoped that the failure of recent studies to demonstrate salutary benefits in patients with class II to IV heart failure will not diminish enthusiasm for the long-term potential of anticytokine therapy.
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PMID:The role of anticytokine therapy in heart failure: recent lessons from preclinical and clinical trials? 1269 32

Experimental studies have shown that cytokine production by the heart may be regulated by sympathetic nervous system stimulation of cardiac beta-adrenergic receptors. Proinflammatory cytokine levels are increased in heart failure, whereas cardiac fixation of 123-I-metaiodobenzylguanidine (MIBG) has been used to study myocardial adrenergic innervation. This study was designed to assess the relation between cardiac MIBG uptake and circulating levels of proinflammatory cytokines in patients with idiopathic dilated cardiomyopathy (IDC). Forty-seven patients (12 women; mean age 56.5 +/- 9 years) with angiographically proved IDC, in New York Heart Association functional classes II to III, and who had left ventricular ejection fraction 30.6 +/- 9.5%, and 20 healthy controls were studied with planar MIBG. The early (10 minutes) and late (4 hours) heart to mediastinum uptake ratio and washout were calculated. Circulating plasma levels of interleukins (IL)-1 and IL-6, tumor necrosis factor-alpha, and solube receptors of TNF (sTNFR) I and II were measured. The patient group had significantly lower values of MIBG uptake at 10 minutes (p <0.001) and 4 hours (p <0.001) and higher washout (p <0.001) than the controls. Late MIBG uptake was significantly correlated with New York Heart Association class (r = -0.42, p = 0.02), left ventricular ejection fraction (r = 0.34, p = 0.01), left ventricular systolic wall stress (r = -0.40, p = 0.05), oxygen consumption at peak exercise (r = 0.32, p = 0.03), IL-1 (r = -0.55, p <0.001), TNF (r = -0.33, p = 0.02), and sTNFRII (r = -0.44, p = 0.001). Multivariate linear regression analysis revealed that MIBG at 4 hours was independently associated with IL-1 levels (p <0.001). Thus, reduced cardiac sympathetic innervation in heart failure is associated with elevated levels of inflammatory cytokines, suggesting that it has a potential inflammatory effect via modulation of the cardiac production of these cytokines.
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PMID:Relation of cardiac sympathetic innervation to proinflammatory cytokine levels in patients with heart failure secondary to idiopathic dilated cardiomyopathy. 1274 1

Many different diseases may lead to heart failure. Nevertheless, the symptoms and pathophysiological changes in heart failure are uniform as are the basic principles of treatment. Although significant progress has been achieved in understanding the biology of heart failure and the therapeutic options, the quality of life of heart failure patients and their survival are often poor. Since cardiac transplantation as a final therapeutic option is limited by the availability of donor organs, new strategies and technologies need to be explored to treat the failing heart effectively. Approaches to improve the medical therapy of heart failure mainly focus on strategies to escape the vicious circle of decreased contractility and neurohumoral activation. Substances with promising experimental and clinical results include neutral endopeptidase inhibitors, endothelin antagonists or cytokine inhibitors, e.g. TNF antagonists. Mechanical and electrical devices are under development such as left ventricular assist devices (LVADs), biventricular pacemakers and artificial hearts, which may become valuable alternative therapies. Gene therapy approaches aim to improve the vascularization of the heart, the Ca-homeostasis of the myocytes or the survival of cardiac cells in disease. Finally, cellular cardiomyoplasty is a relatively novel approach to replace or support the cardiomyocytes of the diseased heart by implanting new ones. Which cell type under which conditions will turn out to be the most suitable is still unknown and subject to debate. Ongoing clinical studies will only help to demonstrate the safety and feasibility of this technique but not determine its long-term efficacy. It is highly desirable that one of these new therapeutic strategies or a combination of them will have a significant impact on the future management of heart failure. Currently, our main clinical focus must be to treat as many patients as possible with drugs that are known to improve symptoms and survival, like ACE inhibitors, beta-blockers, cardiac glycosides, diuretics and spironolactone.
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PMID:[Therapeutic perspectives in heart failure]]. 1280 18

Experimental studies have suggested that TNF alpha, a pro-inflammatory cytokine, may contribute to the deterioration of cardiovascular function through various mechanisms, including the generation of reactive oxygen species. It has not yet been demonstrated whether TNF alpha has prooxidant activity in patients with heart failure, and what the mechanism eventually resulting in this effect are. We analyzed 42 patients (38 men and 4 women, aged 26 to 74 years) with heart failure, secondary to idiopathic dilated cardiomyopathy (n=21), coronary artery disease (n=15), and valve disease (n=6), and 20 controls (18 men and 2 women, aged 49 to 67 years). Ten patients were in class I, 9 in class II, 15 in class III and 8 in class IV according to NYHA Classification. Blood samples were obtained from each patient to evaluate basal and collagen-induced platelet O(2)(-) production, and plasma TNF alpha. In vivo results showed increased platelet O(2)(-) production and plasma TNF alpha levels in NYHA class III-IV compared with that in controls or in NYHA I-II (p<0,001); platelet O(2)(-) production correlated significantly (R=0,6; p<0,01) with TNF alpha plasma levels. In vitro studies showed TNF alpha dose-dependently (5-40 pg/ml) induced platelet O(2)(-) production, and that this effect was significantly inhibited by its specific inhibitor, WP9QY (1 microM); aspirin (100 microM), AACOCF(3), a specific PLA(2) inhibitor (14 microM), and DPI, an inhibitor of NADPH oxidase, significantly inhibited TNF alpha-mediated platelet O(2)(-) production. This study suggests that in patients with heart failure, enhanced platelet O(2)(-) production is mediated by TNF alpha via activation of arachidonic acid and NADPH oxidase pathways.
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PMID:Enhanced TNF alpha and oxidative stress in patients with heart failure: effect of TNF alpha on platelet O2- production. 1288 80

The natriuretic peptides, including human B-type natriuretic peptide (BNP), have been implicated in the regulation of cardiac remodeling. Because transforming growth factor-beta (TGF-beta) is associated with profibrotic processes in heart failure, we tested whether BNP could inhibit TGF-beta-induced effects on primary human cardiac fibroblasts. BNP inhibited TGF-beta-induced cell proliferation as well as the production of collagen 1 and fibronectin proteins as measured by Western blot analysis. cDNA microarray analysis was performed on RNA from cardiac fibroblasts incubated in the presence or absence of TGF-beta and BNP for 24 and 48 hours. TGF-beta, but not BNP, treatment resulted in a significant change in the RNA profile. BNP treatment resulted in a remarkable reduction in TGF-beta effects; 88% and 85% of all TGF-beta-regulated mRNAs were affected at 24 and 48 hours, respectively. BNP opposed TGF-beta-regulated genes related to fibrosis (collagen 1, fibronectin, CTGF, PAI-1, and TIMP3), myofibroblast conversion (alpha-smooth muscle actin 2 and nonmuscle myosin heavy chain), proliferation (PDGFA, IGF1, FGF18, and IGFBP10), and inflammation (COX2, IL6, TNFalpha-induced protein 6, and TNF superfamily, member 4). Lastly, BNP stimulated the extracellular signal-related kinase pathway via cyclic guanosine monophosphate-dependent protein kinase signaling, and two mitogen-activated protein kinase kinase inhibitors, U0126 and PD98059, reversed BNP inhibition of TGF-beta-induced collagen-1 expression. These findings demonstrate that BNP has a direct effect on cardiac fibroblasts to inhibit fibrotic responses via extracellular signal-related kinase signaling, suggesting that BNP functions as an antifibrotic factor in the heart to prevent cardiac remodeling in pathological conditions.
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PMID:B-type natriuretic peptide exerts broad functional opposition to transforming growth factor-beta in primary human cardiac fibroblasts: fibrosis, myofibroblast conversion, proliferation, and inflammation. 1472 74

Over the past decade, a large number of studies have demonstrated that tumor necrosis factor-alpha (TNFalpha) plays an important role in the development of heart failure. Indeed, administration of TNFalpha to experimental animals and transgenic over-expression of TNFalpha replicate the heart failure phenotype. Furthermore, attenuation of the biologic activity of TNFalpha abrogates the development of heart failure in model systems. These pre-clinical studies, suggested that anti-cytokine therapy could prove beneficial in the treatment of patients with heart failure. While early studies supported this hypothesis, anti-TNF strategies have not demonstrated salutary benefits in large, multicenter randomized and placebo-controlled clinical trials in patients with symptomatic heart failure. This finding was disappointing. However, recent studies might provide clarification of this conundrum. For example, the failure to elicit beneficial effects with anti-cytokine therapy might be explained by novel pharmacogenomic or pharmacodynamic effects, the design of the Phase III clinical trials, or discordance between animal models and the human condition. Thus, appropriately designed clinical trials and newer anticytokine agents may demonstrate benefit.
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PMID:Is there any future for tumor necrosis factor antagonists in chronic heart failure? 1496 62

TNF-alpha is a cytokine that may play a role in the pathogenesis of heart failure. In patients with heart failure, increased levels of TNF-alpha were observed that were high enough to reduce cardiac contractility in vitro. The mortality of heart failure patients increases with higher levels of TNF-alpha. For these reasons, inhibition of TNF-alpha appears to be a valid target for the improvement of heart failure therapy beyond the current practice of inhibiting neurohormonal activation with beta-blockade, angiotensin-converting enzyme (ACE) inhibition and aldosterone antagonism. However, whilst this strategy (using soluble TNF receptor or TNF antibodies) was successful in smaller short-term studies, larger longer-term studies have not revealed any beneficial effect of this therapy (RENAISSANCE, RECOVER, RENEWAL, ATTACH). In contrast, the mortality tended to be higher in the treated groups giving rise to questions about the overall strategy. The reasons for this failure of the clinical studies to show a longer-term benefit from TNF-alpha inhibitors are unclear, but they may include an error of the general concept, individual adverse effects of the agents used for the studies, incorrect dosage and the fact that the current therapy of heart failure with beta-blockade, ACE inhibitors and aldosterone antagonists cannot be further improved by additional blockade of neurohormones or cytokines.
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PMID:TNF and congestive heart failure: therapeutic possibilities. 1516 27

Beyond regulation of sexual function, male steroids play an important role in many physiological homeostasis systems, including the cardiovascular system. Via a specific androgen receptor, testosterone mediates cardiomyocyte trophicity both in physiological situations and in hypertrophy-related cardiac diseases. Androgens also regulate pathological levels of inflammatory cytokines such as Il-6 or TNF in advanced heart failure. They also mediate vascular resistance since coronary vasodilatation has been proven both in vitro and in vivo. Reduced free testosterone serum levels (age-mediated or premature coronary artery disease) promote a pro-atherogenic lipid profile expressed as lower serum HDL-cholesterol and up-regulation of triglyceride levels. This observation has relevant clinical implications for the evaluation and treatment of coronary artery disease. As most of normal and diseased cardiovascular system functions are influenced by androgens, further evaluation of their physiological implications should be undertaken as well as large-scale rigorous studies of the therapeutic implications in two disabling diseases, coronary heart disease and heart failure.
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PMID:[The heart and androgens]. 1524 76

Beyond sexual function regulation, male steroids are operative in several physiologic homeostastic systems including the cardiovascular system. By ways of specific androgen receptors,testosterone can mediate cardiomyocyte trophycity, in physiologic states as in diseases involving cardiac hypertrophy. Androgenic hormones also regulate pathologic levels of inflammatory cytokines as 11-6 or TNF, in advanced heart failure. They also mediate vascular resistance with, in vitro and in vivo, proved coronary vasodilatation. Reduced free testosterone serum levels (age-mediated or in premature coronary artery disease patients (CAD) promote a pro-atherogenic lipid profile expressed as HDL-cholesterol decrease and up-regulation of triglycerids levels). The latter observation has relevant clinical significance for evaluation and treatment of CAD disease. As most of normal and diseased cardiovascular system functions are influenced by androgens, we can foresee an increasing interest for further evaluation of their physiologic implications as well as for large and rigourous studies of their therapeutic potential in two leading disabling pathologies, CAD and heart failure.
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PMID:[Heart and androgens]. 1549 57

Pharmaceutical agents aimed at reducing tumor necrosis factor-alpha (TNF-alpha) levels appeared to be attractive possibilities in the medical management of heart failure, as heart failure was shown to be associated with high TNF-alpha levels. However, therapies specifically targeting TNF-alpha failed to show any survival benefit. We examined whether a broad inhibition of inflammatory cytokine production secondary to macrophage inhibition would be more effective at improving cardiac function in the setting of heart failure. To this end, we studied Semapimod (formerly known as CNI-1493), a synthetic guanylhydrazone that inhibits macrophage activation and the production of several inflammatory cytokines. Left anterior descending coronary ligation surgery was performed on each animal to induce a myocardial infarction. After confirming heart failure by echocardiography, the animals were randomly assigned to one of four groups: (1) rats with myocardial infarct receiving high-dose Semapimod, 10 mg/kg/d (MI-H, N = 13); (2) rats with myocardial infarct receiving low-dose Semapimod, 3 mg/kg/d (MI-L, N = 9); (3) rats with myocardial infarct receiving vehicle treatment, 2.5% mannitol in water (MI-0, N = 9); and (4) control rats with sham operation and vehicle treatment (Sham, N = 10). Both Semapimod and vehicle treatments were administered by daily tail vein injections over a course of five days. Echoes were repeated at 2, 5, and 9 weeks following treatment. At 9 weeks, hemodynamic data were collected and the animals were euthanized. Trichrome staining was done to assess infarct, and immunohistochemistry was performed to assess TNF-alpha levels. Prior to drug administration, serum was taken from 5 random rats. No detectable level of TNF-alpha was seen (lower limit of detection for the assay used = 12.5 pg/mL). Also prior to any treatment, echocardiography confirmed significant cardiac impairment of rats undergoing LAD ligation as compared with sham. Over the course of the 9 weeks, there were 4 deaths, all in the MI-H group. There was no difference between Semapimod-treated animals and vehicle-treated MI animals in any echocardiographic or hemodynamic parameter. TNF-alpha staining in the noninfarcted region was evident only in the MI groups, not the sham group. When blindly compared on a semiquantitative scale (ie, 0 = no visible staining to 3 = marked staining), a significant difference in staining was observed between MI-0 versus MI-H (1.19 +/- 0.32 versus 0.33 +/- 0.14; P = 0.03) and between MI-0 and MI-L (1.19 +/- 0.32 versus 0.39 +/- 0.22; P = 0.05). In this setting, despite the fact that Semapimod treatment decreased tissue TNF-alpha levels, it did not improve cardiac function, and at high doses it was associated with higher mortality. These results in a rodent model confirm the results of clinical trials with etanercept and infliximab (ie, that decreasing TNF levels in plasma or tissues does not improve cardiac function and may actually increase mortality).
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PMID:Macrophage inhibitor, semapimod, reduces tumor necrosis factor-alpha in myocardium in a rat model of ischemic heart failure. 1555 Jul 85

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