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)

Recent experimental studies have shown that tumor necrosis factor alpha (TNF-alpha) has deleterious cardiovascular effects. Tumor necrosis factor alpha antagonists bind to TNF-a and functionally inactivate this cytokine and thereby reverse some of these effects. Various clinical studies of TNF-alpha antagonists have reported conflicting results. The present review analyses all reported clinical trials of TNF-alpha antagonists in congestive heart failure (CHF). The effect of these agents on clinical composite score, CHF hospitalizations, and mortality were compared. Early clinical studies of blocking TNF in patients with heart failure demonstrated promising results. However, recent large-scale, placebo-controlled trials have failed to show any improvement in the clinical status of heart failure. There have in fact, been some reports of worsening of heart failure with these agents. It may be concluded that TNF-alpha antagonists could adversely affect the clinical condition of patients with moderate to severe heart failure.
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PMID:Current status of TNF blocking therapy in heart failure. 1612 32

Cytokine production in idiopathic dilated cardiomyopathy (IDC) may depend on neurohumoral stimulation, haemodynamic impairment or auto-antibody production. We aimed to ascertain the impact of haemodynamic improvements with standard medical therapy and neurohumoral blockade on white cell tumour necrosis factor- alpha (TNF-alpha ) production in patients with IDC. Twenty-seven patients with IDC and NYHA class I to IV heart failure but without evidence of oedema, reduced peripheral perfusion, or elevated plasma endotoxin concentrations were evaluated for indicators of cytokine activation. Plasma TNF-alpha concentrations were raised (p < 0.001) in patients prior to commencement of medical therapy as compared to controls (n = 27). In addition, endotoxin-free cultured whole blood TNF-alpha production was enhanced (p < 0.02) in the patients. Although plasma TNF-alpha tended to decrease, excessive whole blood TNF-alpha production remained unaltered following marked improvements in haemodynamics and functional class (increase in absolute left ventricular ejection fraction = 8.7 +/- 2.6%, p < 0.01, 37% in NYHA functional class I after therapy) with six to 12 months of medical therapy (diuretic, angiotensin converting enzyme inhibitor and beta-blocker). Against a role for neurohumoral substances in promoting excessive white cell TNF-alpha synthesis the angiotensin II receptor antagonist, losartan, failed to modulate white cell TNF- alpha production in patients with IDC. We concluded that white cell TNF-alpha overproduction is sustained in patients with IDC despite haemodynamic improvement with standard medical therapy and blockade of angiotensin II receptors. These data suggest that mechanisms other than haemodynamic impairment and neurohumoral activation contribute to excess white cell TNF-alpha production in IDC.
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PMID:Sustained white cell cytokine activation in idiopathic dilated cardiomyopathy despite haemodynamic improvement with medical therapy. 1621 Nov 23

We report a case of heart failure after infusion of Remicade (infliximab) in a patient without heart insufficiency. The patient, a 25-year-old woman with inflammatory bowel disease, developed new-onset heart failure after receiving TNF antagonist therapy. After the treatment was discontinued and heart failure therapy was started, the patient improved significantly. The U.S. Food and Drug Administration has published 47 case reports of heart failure after therapy with a tumor necrosis factor antagonist, where 38 patients developed new-onset heart failure and 9 patients experienced heart failure exacerbation. There are no published reports of heart failure after TNF antagonist therapy in the Danish literature.
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PMID:[Dilated cardiomyopathy as a side effect of treatment with infliximab]. 1621 21

The pro-inflammatory cytokine, tumor necrosis factor alpha (TNF alpha), in concert with neurohormones, contributes to chronic heart failure (CHF) progression. This implies that TNF a antagonism may constitute an important target for CHF therapy. However, clinical trials in CHF patients using compounds that trap TNF alpha, comprising infliximab, an antibody directed to TNF alpha, and etanercept, a soluble recombinant receptor of TNF alpha, gave disappointing results bringing back to light the dual, short-term beneficial and long-term harmful effect of TNF alpha. This review focuses on the dual, concentration- and time-related effects of TNF alpha, the yin and yang action of TNF alpha in cardiac ischemia/reperfusion and contraction. Importantly, the harmful effects of TNF a are related to glutathione deficiency, a common hallmark to several other chronic inflammatory diseases. Recently, in rat models of CHF, oral administration of the glutathione precursor, N-acetylcysteine (NAC), was shown to hinder pathways of TNF alpha harmful signalling and to rescue cardiac structure and function. These results suggest that glutathione deficiency in association with TNF alpha activation may play a role in the pathophysiology of CHF and that NAC may represent a potential therapy in CHF.
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PMID:Tumor necrosis factor alpha and glutathione interplay in chronic heart failure. 1623 78

Mice that overexpress the inflammatory cytokine tumor necrosis factor-alpha in the heart (TNF mice) develop heart failure characterized by atrial and ventricular dilatation, decreased ejection fraction, atrial and ventricular arrhythmias, and increased mortality (males > females). Abnormalities in Ca2+ handling, prolonged action potential duration (APD), calcium alternans, and reentrant atrial and ventricular arrhythmias were previously observed with the use of optical mapping of perfused hearts from TNF mice. We therefore tested whether altered voltage-gated outward K+ and/or inward Ca2+ currents contribute to the altered action potential characteristics and the increased vulnerability to arrhythmias. Whole cell voltage-clamp recordings of K+ currents from left ventricular myocytes of TNF mice revealed an approximately 50% decrease in the rapidly activating, rapidly inactivating transient outward K+ current Ito and in the rapidly activating, slowly inactivating delayed rectifier current IK,slow1, an approximately 25% decrease in the rapidly activating, slowly inactivating delayed rectifier current IK,slow2, and no significant change in the steady-state current Iss compared with controls. Peak amplitudes and inactivation kinetics of the L-type Ca2+ current ICa,L were not altered. Western blot analyses revealed a reduction in the proteins underlying Kv4.2, Kv4.3, and Kv1.5. Thus decreased K+ channel expression is largely responsible for the prolonged APD in the TNF mice and may, along with abnormalities in Ca2+ handling, contribute to arrhythmias.
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PMID:Electrical remodeling of cardiac myocytes from mice with heart failure due to the overexpression of tumor necrosis factor-alpha. 1633 42

Chronic Chagas' disease cardiomyopathy (CCC) is the most important clinical outcome of infection by the parasite Trypanosoma cruzi, affecting 18 million individuals in Latin America. One-third of CCC patients develop heart failure due to end-stage dilated cardiomyopathy, and their survival is reduced by 50% compared to patients with other cardiomyopathies. Genetic susceptibility may play a role in the differential survival of severe CCC patients. Given the role of TNF-alpha in the progression of heart failure, and the increased TNF-alpha plasma and heart tissue levels observed in these patients, we chose TNF as a candidate gene for increased mortality in severe CCC patients. We typed the TNFa microsatellite and the -308 TNF promoter polymorphism and then analyzed the survival curves of 42 patients with severe ventricular dysfunction (left ventricular ejection fraction<or=40%) according to the presence of the TNF2 promoter allele or the TNFa2 microsatellite allele, both previously associated with high TNF-alpha production. Multivariate regression analysis (Cox proportional hazards model) revealed the TNF genotype and age of onset of severe CCC as independent predictors of mortality in severe CCC. We showed that patients positive for TNF2 or TNFa2 alleles display a significantly shorter survival time compared to those carrying other alleles; the median survival times were 2.9 and 8 months, respectively (HR(adj)=2.28, p=0.020). We have identified for the first time a genetic factor related to reduced survival in severe Chagas' disease cardiomyopathy. The association of TNF genotype with earlier death in CCC should be taken into account when planning therapeutic intervention.
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PMID:TNF gene polymorphisms are associated with reduced survival in severe Chagas' disease cardiomyopathy patients. 1642 98

Physiological testosterone therapy increases exercise capacity and reduces symptom scores in men with chronic heart failure (CHF). Tumour necrosis factor-alpha (TNF-alpha) exerts a significant pathologic activity in CHF, and physiologic testosterone replacement therapy is associated with reduced serum levels of TNF-alpha in hypogonadal men with concomitant coronary artery disease. It is unknown whether testosterone exerts a similar immunomodulatory action in men with CHF. Testosterone therapy administered in three placebo-controlled studies, for either 6 hours (two 30-mg buccal tablets, n=12) or 3 months (fortnightly 100 mg intra muscular injection, n=20; or daily 5 mg transdermally, n=62). The effects of testosterone were also assessed on lipopolysaccharide (LPS)-induced TNF- production in whole blood obtained from 27 men with CHF. Incubation with testosterone (10 nM, 1 M, and 100 M) resulted in a reduction in LPS-induced TNF- production from 12.6 +/- 1.3 to 11.2 +/- 1.1 (P = 0.053), 10.3 +/- 1.1 (P = 0.0046), and 9.2 +/- 1.1 (P = 0.000066) ng/ml, respectively. However in men with CHF, serum levels of TNF- were similar before and after treatment with testosterone or placebo, irrespective of the length of study or route of administration. The clinically beneficial actions of testosterone in men with CHF are unlikely to be mediated by reducing TNF-alpha.
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PMID:Physiologic testosterone therapy has no effect on serum levels of tumour necrosis factor-alpha in men with chronic heart failure. 1643 47

Despite interest in neurohormonal activation as a determinant of prognosis in chronic heart failure (CHF) and as a target for pharmacological treatments, data are lacking on the time-related effects of electrical cardiac resynchronization therapy (CRT) on a broad spectrum of neurohormones and cytokines. The aim of this study was to assess time-courses and extents of changes within the neurohormonal profile of CHF patients treated with CRT. We performed a prospective follow-up study in 32 patients with NYHA class III-IV CHF to investigate the effects of CRT on a broad panel of neurohormones proposed for characterization of CHF patients. Levels of atrial and brain natriuretic peptides (ANP, BNP), epinephrine, norepinephrine, aldosterone, plasma renin activity, IL-6, TNF, soluble receptors sTNFR1 and 2, and chromogranin A were assessed before implantation and after 3 months of CRT; when feasible, measurements were also performed at 1 week, 1 month and 12 months (clinical evaluation, echocardiography and ECG were also performed at each time-point). The results showed that at 3 months improvement in NYHA class and echographically assessed left ventricular (LV) reverse structural remodeling were accompanied by significant reductions versus baseline in ANP and BNP, but not in other neurohormones. Moreover a baseline ANP concentration < or = 150 pg/ml was a good predictor of response to CRT in terms of NYHA class reduction and reverse LV remodeling. In conclusion 3 months of CRT significantly reduce natriuretic peptides concentrations, while values of other neurohormones and inflammatory cytokines are relatively unvaried. A baseline ANP concentration < or = 150 pg/ml might be a clinically useful predictor of medium-term response to CRT.
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PMID:Neurohormones and inflammatory mediators in patients with heart failure undergoing cardiac resynchronization therapy: time courses and prediction of response. 1662 Nov 49

The goal of the treatment of chronic heart failure is improvement of patient's prognosis and QOL. To achieve this goal, new pharmacological and nonpharmacological approaches have been developed. ACE inhibitor - and beta-blocker-treatment added to the standard therapy has been established to improve the prognosis, and ICD, cardiac resynchronization treatment (CRT) with biventricular pacing and LV assist device also contribute to the advances in the therapeutic progress. However, recent clinical trials for the new drugs which antagonize the endothelin receptors and TNF receptors failed to demonstrate the benefit of these new drugs. Establishment of the therapeutic strategies for treatment of diastolic heart failure is also another problem to be solved.
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PMID:[Recent advances in treatment and the future problems to be solved]. 1668 59

Tumor necrosis factor-alpha (TNF-alpha) plays an important role in the development of heart failure. There is a direct correlation between myocardial function and myocardial TNF levels in humans. TNF may induce local inflammation to exert tissue injury. On the other hand, suppressors of cytokine signaling (SOCS) proteins have been shown to inhibit proinflammatory signaling. However, it is unknown whether TNF mediates myocardial inflammation via STAT3/SOCS3 signaling in the heart and, if so, whether this effect is through the type 1 55-kDa TNF receptor (TNFR1). We hypothesized that TNFR1 deficiency protects myocardial function and decreases myocardial IL-6 production via the STAT3/SOCS3 pathway in response to TNF. Isolated male mouse hearts (n = 4/group) from wild-type (WT) and TNFR1 knockout (TNFR1KO) were subjected to direct TNF infusion (500 pg.ml(-1).min(-1) x 30 min) while left ventricular developed pressure and maximal positive and negative values of the first derivative of pressure were continuously recorded. Heart tissue was analyzed for active forms of STAT3, p38, SOCS3 and SOCS1 (Western blot analysis), as well as IL-1beta and IL-6 (ELISA). Coronary effluent was analyzed for lactate dehydrogenase (LDH) activity. As a result, TNFR1KO had significantly better myocardial function, less myocardial LDH release, and greater expression of SOCS3 (percentage of SOCS3/GAPDH: 45 +/- 4.5% vs. WT 22 +/- 6.5%) after TNF infusion. TNFR1 deficiency decreased STAT3 activation (percentage of phospho-STAT3/STAT3: 29 +/- 6.4% vs. WT 45 +/- 8.8%). IL-6 was decreased in TNFR1KO (150.2 +/- 3.65 pg/mg protein) versus WT (211.4 +/- 26.08) mice. TNFR1 deficiency did not change expression of p38 and IL-1beta following TNF infusion. These results suggest that deficiency of TNFR1 protects myocardium through SOCS3 and IL-6 but not p38 MAPK or IL-1beta.
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PMID:Deficiency of TNFR1 protects myocardium through SOCS3 and IL-6 but not p38 MAPK or IL-1beta. 1711 46


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