Single dose recombinant human erythropoietin reduces transforming growth factor beta in patients on chronic haemodialysis.

Short-term effects of recombinant human erythropoietin on serum levels of transforming growth factor beta-1, interleukin 1-alpha, interleukin 3, interferon gamma, and tumour necrosis factor alpha in patients with chronic renal failure on chronic haemodialysis were investigated. Recombinant human erythropoietin was applied subcutaneously in a dose of 75 IU/kg on 19 patients. Serum levels of transforming growth factor beta-1, interleukin 1-alpha, interleukin 3, interferon gamma, tumour necrosis factor alpha and erythropoietin, red blood cell parameters: red blood cell count, haemoglobin, haematocrit, and erythrocyte indices were determined before and after recombinant human erythropoietin single application. Transforming growth factor beta-1 serum levels were decreased after recombinant human erythropoietin (22.70 +/- 1.51 ng/ml versus 18.77 +/- 1.70 ng/ml (p < 0.01). None of the other investigated parameters was influenced significantly by recombinant human erythropoietin. Recombinant human erythropoietin in patients with chronic renal failure on chronic haemodialysis may influence anaemia not only through its stimulating effect on erythropoiesis, but also by direct oxygen-independent decrease of at least one of the negative regulators of erythropoiesis--the transforming growth factor beta.     

Dynamic changes of erythropoietin and tumor necrosis factor-alpha levels in peripheral blood and their correlation with erythropoiesis changes in posttransfusion polycythemia in animals

Posttransfusion polyglobulia reveals elevated level of the tumor necrosis factor-alpha in peripheral blood, suppresses erythropoiesis in bone marrow erythroblastic islands by diminishing the newly forming erythroblastic islands, and suppresses erythropoietin production in rats.     

The inducibility of TNF-alpha production is different in the granulocytic and monocytic differentiated forms of wild type and CGD-mutant PLB-985 cells

Chronic granulomatous disease is an inherited disorder associated with a defect in phagocytic cell oxidative metabolism resulting in ineffective microbicidal activity. Consequently, patients with chronic granulomatous disease suffer from recurrent infections. Published data show that besides the failure to produce superoxide and its derivatives, other functional problems can also be found in chronic granulomatous disease-mutant cells. Since in innate immune responses other mediators, such as cytokines, also play an important role, we hypothesized that there may be a disturbance in cytokine production by chronic granulomatous disease-mutant cells as well. To prove this hypothesis, the production of tumour necrosis factor-alpha, an important proinflammatory cytokine, was determined by enzyme-linked immunosorbent assay in wild-type and chronic granulomatous disease-mutant myelomonoblastic PLB-985 cells in their immature, granulocytic and monocytic/macrophage differentiated forms. Tumour necrosis factor-alpha production was induced with N-formyl-L-methionyl-L-leucyl-L-phenylalanine (100 nmol/L), lipopolysaccharide (10 micro g/mL), opsonized zymosan (100 micro g/mL) or phorbol 12-myristate 13-acetate (100 nmol/L) for 24 h. We could demonstrate that: (i) there were marked differences in tumour necrosis factor-alpha production only in the differentiated forms of both wild-type and chronic granulomatous disease-mutant cells, while there were no differences in the case of their immature counterparts; (ii) only chronic granulomatous disease-mutant cells retained sensitivity to phorbol 12-myristate 13-acetate both in their granulocytic and monocytic forms, although phorbol 12-myristate 13-acetate responsiveness was a characteristic of both types of immature cells; (iii) the granulocytic form of wild-type cells produced tumour necrosis factor-alpha after opsonized zymosan stimulation, but such a response was not observed in cells originating from the chronic granulomatous disease-mutant cell line; (iv) with the monocytic forms, significantly higher tumour necrosis factor-alpha production could be induced by lipopolysaccharide in the wild-type cells than in the chronic granulomatous disease-mutant cells, although there was no difference in their lipopolysaccharide receptor CD14 expression. In summary, these data show an altered inducibility of tumour necrosis factor-alpha production by chronic granulomatous disease-mutant cells. Our observations suggest a further defect in differentiated chronic granulomatous disease-mutant cells in addition to the known defect in reduced nicotinamide adenine dinucleotide phosphate oxidase, which may contribute to the development of susceptibility to infections in people with chronic granulomatous disease.     

Defective production of interferon-gamma and tumour necrosis factor-alpha by AIDS mononuclear cells after in vitro exposure to Rhodococcus equi

The production of interferon-gamma and tumour necrosis factor-alpha was evaluated in the peripheral blood mononuclear cells (PBMCs) from healthy donors and AIDS patients after Rhodococcus equi infection in vitro. PBMCs from healthy donors secreted elevated levels of IFN-gamma and TNF-alpha when challenged in vitro with killed R. equi, whereas the release of both cytokines was impaired in supernatant cultures from AIDS patients. We conclude that the failure of IFN-gamma generation in AIDS patients in response to R. equi is not antigen-specific but it may reflect the global impairment of T-cell function. In such patients, however, the infection with R. equi, a facultative intracellular pathogen which survives and replicates within macrophages, may be responsible for the impairment in the TNF-alpha release, possibly enhancing the HIV-induced macrophage dysftmction.     

镉负荷大鼠一氧化氮和肿瘤坏死因子-α释放在介导多器官机能活动障碍中的作用

选择健康SD雄性成年大鼠36只,随机分成对照组(C组)、镉负荷中剂量组(M组)、镉负荷高剂量组(H组).将分析纯CdCl2·2.5H2O用生理盐水稀释成含镉0.4 mg/ml浓度的注射溶液,高压灭菌.M组和H组大鼠每天分别按含镉0.5和1.0 mg/kg体重腹腔注射染毒,C组用同样方法注射与H组同等剂量的生理盐水,进行急性镉负荷实验,连续观察7 d.研究急性镉负荷对大鼠血液及几种组织中一氧化氮(NO)自由基、肿瘤坏死因子-α(TNF-a)变化的影响及作用.结果显示在整个实验期内,镉负荷大鼠体重与对照组比较明显下降;睾丸、心脏和肝脏组织中的镉含量极显著上升,并随镉负荷剂量和时间而增加;血浆NO水平M组虽高于对照组,但差异不显著,而H组极显著高于对照组,M和H组血浆TNF-α明显高于对照组;在整个实验期内,镉负荷大鼠睾丸、心脏和肝脏组织匀浆中NO较对照组高或明显高于对照组,睾丸和心脏组织匀浆中TNF-a也均高于或明显高于对照组,但肝脏中的TNF-a三组间没有差异.结果提示,镉负荷诱发NO、TNF-α大量释放在导致大鼠多种器官机能活动障碍发生过程中可能起重要作用.     

Acute and chronic influence of hemodialysis according to the membrane used on phagocytic function of neutrophils and monocytes and pro-inflammatory cytokines production in chronic renal failure patients

This work evaluated the phagocytic capacity of monocytes and neutrophils, and tumor necrosis factor-alpha, interleukin 6, 1 and 8 serum levels in chronic renal failure patients under peritoneal dialysis and hemodialysis treatment, compared with chronic renal failure patients without dialysis treatment and healthy individuals, in order to contribute to a better understanding of the action of these therapies on the evolution of chronic renal failure patients. All patients with chronic renal failure (under dialysis or not) showed decreased phagocytic capacity of neutrophils and monocytes. All those in hemodialysis (cellulose acetate or polysulfone membranes) showed a decreased phagocytic capacity. The phagocytic index for neutrophil was 13 times lower than that of the control group for both membranes, whereas for monocytes, only those using polysulfone membrane showed a significant decrease of 4.9 times in phagocytic capacity. There was an acute stimulation of the phagocytosis by neutrophils after a single session of dialysis with both types of membrane, while only cellulose acetate membrane decreased the phagocytic index of monocytes after the hemodialysis session. Patients using cellulose acetate showed a chronic increase in tumor necrosis factor-alpha serum levels, while those using polysulfone showed a chronic increase in interleukin 6. After a single hemodialysis procedure, no acute effect of the treatment on tumor necrosis factor-alpha and interleukin 6 levels was identified. The decreased phagocytic function of neutrophils and monocytes may account for the high levels of susceptibility of chronic renal failure patients to infections with pyogenic bacteria and tuberculosis. Furthermore, inflammatory activity may occur with both types of membrane studied, suggesting that it will be useful for these patients to evaluate some anti-inflammatory or anti-cytokine therapies against tumor necrosis factor-alpha and interleukin 6, in order to avoid cardiovascular complication.     

Enhancement of YD spin relaxation by the CaMn4 cluster in photosystem II detected at room temperature: a new probe for the S-cycle

One of the major conceptual advances in the understanding of the pathogenesis of heart failure has been the insight that myocardial dysfunction and heart failure may progress as the result of the sustained over-expression of nitric oxide (NO) metabolites locally and in blood modulated by inducible nitric oxide synthase (iNOS). This by virtue of their deleterious effects is sufficient to contribute to disease progression by provoking left ventricular (LV) remodeling, hypertrophy and progressive LV dysfunction. Recently, tumor necrosis factor-alpha (TNF-alpha) has also been identified in this setting of heart failure. Analogous to the situation with NO, the over-expression of TNF-alpha is sufficient to contribute to disease progression in heart failure phenotype. Although important interactions between TNF-alpha and the NO have been recognized in the cardiovascular system for over a decade, the nature and importance of the interactions between these biologically active molecules in cardiac hypertrophy has become apparent only in the recent times. Therefore, we focused on the prevailing updated evidence which suggests that there is a functionally significant cross-regulation between NO and TNF-alpha signaling in blood thus playing a part in cardiac hypertrophy and failure. The discussions presented here will have a bearing on the therapeutic potential via inhibitors of these pathways in reducing cardiomyocyte hypertrophy and the LV dysfunction.     

NO-cGMP and TNF-α counter regulatory system in blood: Understanding the mechanisms leading to myocardial dysfunction and failure

One of the major conceptual advances in the understanding of the pathogenesis of heart failure has been the insight that myocardial dysfunction and heart failure may progress as the result of the sustained over-expression of nitric oxide (NO) metabolites locally and in blood modulated by inducible nitric oxide synthase (iNOS). This by virtue of their deleterious effects is sufficient to contribute to disease progression by provoking left ventricular (LV) remodeling, hypertrophy and progressive LV dysfunction. Recently, tumor necrosis factor-alpha (TNF-α) has also been identified in this setting of heart failure. Analogous to the situation with NO, the over-expression of TNF-α is sufficient to contribute to disease progression in heart failure phenotype. Although important interactions between TNF-α and the NO have been recognized in the cardiovascular system for over a decade, the nature and importance of the interactions between these biologically active molecules in cardiac hypertrophy has become apparent only in the recent times. Therefore, we focused on the prevailing updated evidence which suggests that there is a functionally significant cross-regulation between NO and TNF-α signaling in blood thus playing a part in cardiac hypertrophy and failure. The discussions presented here will have a bearing on the therapeutic potential via inhibitors of these pathways in reducing cardiomyocyte hypertrophy and the LV dysfunction.     

Excretory/secretory products from plerocercoids of Spirometra erinaceieuropaei suppress the TNF-alpha gene expression by reducing phosphorylation of ERK1/2 and p38 MAPK in macrophages

We previously reported that excretory/secretory products from plerocercoids of Spirometra erinaceieuropaei suppress gene expression and production of tumour necrosis factor-alpha in murine macrophages stimulated with lipopolysaccharide. The present study investigated the suppressive mechanisms of tumour necrosis factor-alpha mRNA by excretory/secretory products in lipopolysaccharide-stimulated murine macrophages. Electrophoretic mobility shift assay and supershift assay revealed that neither nuclear translocation of nuclear factor-kappa B nor conformation of the p50/p65 nuclear factor-kappa B subunits was affected by the treatment of excretory/secretory products in lipopolysaccharide-stimulated macrophages. Inhibition of extracellular signal-regulated protein kinase 1/2 with PD98059 or p38 mitogen-activated protein kinase with SB203580 partially reduced tumour necrosis factor-alpha mRNA expression, and a combination of the two inhibitors additionally suppressed the level of tumour necrosis factor-alpha mRNA, revealing that both pathways are crucial for full induction of the gene. Northern blot analysis showed that excretory/secretory products additionally suppressed tumour necrosis factor-alpha mRNA expression in cells treated with PD98059 or SB208530 and, in turn, we found that excretory/secretory products reduced phosphorylation of extracellular signal-regulated protein kinase 1/2 and p38 mitogen-activated protein kinase in lipopolysaccharide-stimulated macrophages by Western blot analysis. This is the first report demonstrating that excretory/secretory products from parasites suppress tumour necrosis factor-alpha mRNA expression by reducing phosphorylation of extracellular signal-regulated protein kinase 1/2 and p38 mitogen-activated protein kinase without any effect on nuclear factor-kappa B activity in macrophages stimulated with lipopolysaccharide. We hypothesise that excretory/secretory products may enable this parasite to survive within the host.     

Production of biologically active recombinant human soluble CD23 and its effect on PBMCs isolated from hyper-IgE blood

A recombinant form of human soluble CD23 (sCD23), the low affinity receptor for IgE (FcepsilonRII), was produced by PCR cloning the lectin-binding domain sequence into a bacterial expression vector. After renaturation and purification, the sCD23 bound IgE and divalent metal ions, indicating its activity. The recombinant human sCD23 exhibited similar proinflammatory properties as the native protein. Although interleukin-1beta, tumour necrosis factor-alpha, and nuclear factor-kappaB appeared not to be enhanced significantly in unstimulated RPMI 8866 B-lymphoblastoid and U937 promonocytic cell lines with 24 h incubation of recombinant sCD23, they were produced in both healthy and hyper-IgE-derived peripheral blood mononuclear cells, especially tumour necrosis factor-alpha. This study concludes that while recombinant and chimeric sCD23 may be useful in blocking IgE binding to immune cells and decreasing IgE synthesis by B-lymphocytes, the production of proinflammatory cytokines, particularly tumour necrosis factor-alpha will enhance immune responses in cases of asthma, allergy, and hyper-IgE syndrome.     

促红细胞生成素治疗慢性心力衰竭156例临床观察

目的:观察EPO对慢性充血性心力衰竭(CHF)治疗效果。方法:选择CHF患者212例,随机分为非EPO治疗组(56例)和EPO治疗组(156例)。其中非EPO治疗组采用常规抗心衰治疗,EPO治疗组接受常规抗心衰治疗和EPO治疗,直至临床观察结束。治疗后观察心功能指标改变。结果:156例心衰患者经过EPO治疗后,左室射血分数,每搏输出量,每分输出量,心指数均较非EPO治疗对照组患者明显改善(P<0.05),其中尤以左室射血分数改善最为明显(P<0.01)。156例EPO治疗组患者中116例心衰伴贫血患者心功能各项指标的改善较40例心衰不伴贫血患者更为明显,具有显著统计学意义(P<0.01)。结论:EPO对CHF患者心功能的改善主要是因为EPO的促红细胞生成作用。EPO对于慢性心功能不全有独立于促红细胞生成以外的治疗作用。     

Detection of erythropoietin in exhaled breath condensate of nonhypoxic subjects using a multiplex bead array

As a noninvasive method, exhaled breath condensate (EBC) has gained importance to improve monitoring of lung diseases and to detect biomarkers. The aim of the study was to investigate, whether erythropoietin (EPO) is detectable in EBC. EBC was collected from 22 consecutive patients as well as from healthy individuals. Using a multiplex fluorescent bead immunoassay, we detected EPO in EBC, as well as tumour necrosis factor-alpha (TNF-alpha) in 13 out of 22 patients simultaneously (EPO 0.21 +/- 0.03 in U/mL and TNF-alpha 34.6 +/- 4.2 in pg/mL, mean +/- SEM). No significant differences for EPO levels or correlation between EPO and TNF-alpha were found but TNF-alpha was significantly higher in patients with chronic obstructive pulmonary disease (COPD) than in non-COPD (obstructive sleep apnoea, OSA, and lung healthy patients). This is the first report of detection of EPO in EBC. Due to the small study size more data is needed to clarify the role of EPO in EBC.     

Tumour necrosis factor-alpha and lipopolysaccharide enhance interferon-induced tryptophan degradation and pteridine synthesis in human cells

The capacity of recombinant interferon-alpha, -beta and -gamma, of bacterial lipopolysaccharide and of recombinant tumour necrosis factor-alpha to induce indoleamine 2,3-dioxygenase and synthesis of pteridines was studied in human peripheral blood mononuclear cells, human macrophages and normal dermal fibroblasts. The action of interferon-alpha and -beta on macrophages was supported by lymphocyte factors as indicated by the effect of these mediators in the absence or presence of lymphocytes. Tumour necrosis factor-alpha alone was ineffective in peripheral blood mononuclear cells and macrophages, but it significantly increased the action of all three interferon species on macrophages and fibroblasts. Lipopolysaccharide directly affected macrophages or dermal fibroblasts and enhanced the effect of interferon-gamma. However, in the presence of lymphocytes, the action of lipopolysaccharide was mediated via interferon-gamma.     

DNA enzyme targeting TNF-alpha mRNA improves hemodynamic performance in rats with postinfarction heart failure

Tumor necrosis factor-alpha (TNF-alpha) probably affects the pathogenesis of heart failure. Here we have investigated the therapeutic potential of a nuclease-resistant DNA enzyme that specifically cleaves TNF-alpha mRNA. A phosphorothioate-modified DNA enzyme was designed to retain similar cleavage activity as its unmodified version, and that inhibited the expression of TNF-alpha in vitro. To test its efficacy in vivo, postinfarction congestive heart failure was induced in anesthetized rats by ligation of the left coronary artery. A 4-wk treatment with the DNA enzyme induced a substantial reduction in left ventricular end-diastolic pressure and lung weight concomitant with an increase in arterial blood pressure and myocardial blood flow compared with controls. The concentration of TNF-alpha in coronary sinus blood was markedly lowered on treatment, and myocardial TNF-alpha mRNA was substantially reduced. Recovery studies showed that the DNA enzyme cleavage activity was present within the myocardium throughout the observation period and had no apparent toxic effects. Our findings indicate that DNA enzyme-based therapy may hold promise in the treatment of this debilitating disease.     

Purine modulation of cytokine release during diuretic therapy of rheumatoid arthritis

Since free radicals are implicated in rheumatoid arthritis (RA) and since uric acid is a free radical scavenger, we examined the effects of treating RA patients with with the diuretic bumetanide to try to improve their arthritic control. Seventy patients, aged 18-75 years, were randomised to receive bumetanide 4 mg/day or placebo. Uric acid levels increased, but not that of other purines, in the blood of drug-treated patients compared with placebo-treated controls. There were no significant changes in clinical measurements of disease activity or in ESR or CRP levels. There were no over all differences in the blood levels of the cytokines, nor in the basal or stimulated production of cytokines from the blood cultures. The adenosine receptor agonist 5'N-ethylcarboxamido-adenosine (NECA) used to modify cytokine release in cultures of whole blood taken from the patients, depressed the release of tumour necrosis factor-alpha (TNFalpha), but failed to depress the release of interleukin-1b (IL-1b) or interleukin-6 (IL-6), a difference from earlier studies of healthy control subjects and, thus, a difference which may contribute to the disease activity.     

The role of anemia in congestive heart failure and chronic kidney insufficiency: the cardio renal anemia syndrome

Anemia is a major problem in patients with chronic kidney insufficiency. The development of recombinant human erythropoietin has enabled physicians to correct this anemia. Although anemia has not been considered to be a common or important contributor to congestive heart failure, anemia of any cause can lead to cardiac damage and eventually congestive heart failure. Our joint renal-cardiac heart failure team found that anemia was indeed very common in congestive heart failure and was associated with severe, medication-resistant cardiac failure. Correction of the anemia with erythropoietin and intravenous iron led to a marked improvement in patients' functional status and their cardiac function, and to a marked fall in the need for hospitalization and for high-dose diuretics; renal function usually improved or at least stabilized. Subsequent investigations by others have confirmed many of our observations. We call this interrelationship between congestive heart failure, chronic kidney insufficiency, and anemia the Cardio-Renal Anemia syndrome. Treatment of the anemia in congestive heart failure may prove vital in preventing progression of both the heart failure and the associated renal disease.     

Modulation of macrophage activation by prostaglandins

The effect of prostaglandtn E(2), iloprost and cAMP on both nitric oxide and tumour necrosis factor-alpha release in J774 macrophages has been studied. Both prostaglandin E(2) and iloprost inhibited, in a concentration-dependent fashion, the lipopolysaccharide-induced generation of nitric oxide and tumour necrosis factor-alpha. The inhibitory effect of these prostanoids seems to be mediated by an increase of the second messenger cAMP since it was mimicked by dibutyryl cAMP and potentiated by the selective type IV phosphodiesterase inhibitor RO-20-1724. Our results suggest that the inhibition of nitric oxide release by prostaglandin E(2) and iloprost in lipopolysaccharide-activated J774 macrophages may be secondary to the inhibition of tumour necrosis factor-alpha generation, which in turn is likely to be mediated by cAMP.     

Cytokines are not a requisite part of the pathophysiology leading to cardiac decompensation

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.     

In vitro endothelial cell activation and inflammatory responses in end-stage heart failure.

BACKGROUND: vascular endothelial cell activation and dysfunction are observed in patients with severe heart failure and may contribute to systemic manifestations of this syndrome. It remains unknown whether inflammatory activation of these cells occurs in these patients because of increased circulating proinflammatory mediators. Aim: to determine whether the serum from patients with heart failure possesses a net proinflammatory bioactivity to active proinflammatory pathways in cultured endothelial cells. METHODS: serum was obtained from stable patients with end-stage heart failure undergoing elective cardiac transplantation (Tx) and severely decompensated patients with heart failure requiring emergency left ventricular assist device (LVAD) implantation. Net proinflammatory bioactivity of serum was investigated by monitoring IkappaBalpha degradation and E-selectin expression in cultured human pulmonary artery endothelial cells (HPAEC) following incubation with serum samples. Serum cytokine concentrations were measured by ELISA and neutralizing antibodies were used to determine the role of specific factors in the observed bioactivity. RESULT: serum from both patient groups induced HPAEC IkappaBalpha degradation. Low basal HPAEC E-selectin expression significantly increased following treatment with Tx but not LVAD serum. Serum tumor necrosis factor-alpha (TNF-alpha) and IL-10 concentrations were higher in patients with LVAD than those with Tx, and soluble TNF-alpha receptor expression was high in both groups. Neither TNF-alpha nor IL-10 blocking experiments altered either bioassay result. CONCLUSION: activation of a specific profile of pro- and anti-inflammatory mediators is associated with heart failure resulting in HPAEC nuclear factor (NF)-kappaB activation. However, E-selectin expression is further regulated by unidentified factors. TNF-alpha is upregulated but appears to play no part in NFkappaB activation in these patients. These findings could have important therapeutic implications.     

Increased plasma levels of tumor necrosis factor-alpha in asymptomatic/"indeterminate" and Chagas disease cardiomyopathy patients

We compared plasma tumor necrosis factor-alpha (TNF-alpha) levels among asymptomatic/"indeterminate" Chagas disease patients (ASY) and patients across the clinical spectrum of chronic Chagas disease cardiomyopathy (CCC). Idiopathic dilated cardiomyopathy (DCM) patients and normal controls (NC) were included as controls. ASY Chagas disease patients had significantly higher plasma TNF-alpha levels than NC. TNF-alpha levels among severe CCC patients with significant left ventricular (LV) dysfunction were similar to those of DCM patients, showing average 2-fold higher levels than CCC patients without LV dysfunction and ASY patients, and 8-fold higher levels than NC. In Chagas disease, chronic TNF-a production prior to heart failure may play a role in CCC progression.