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)

The serum concentration of C-reactive protein was prospectively assessed in 37 patients with various degrees of heart failure. The serum concentration of C-reactive protein was higher than normal in 26 (70%) patients. The concentration was directly related to the severity of heart failure and the stage of decompensation. Hepatic cell damage is the most likely stimulus to cytokine production and hence release of C-reactive protein in heart failure. Heart failure is an additional cause of raised serum concentration of C-reactive protein but the pathological importance of this feature is not yet known.
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PMID:Study of serum C-reactive protein concentration in cardiac failure. 233 94

Tumor necrosis factor-alpha (TNF alpha) is a proinflammatory cytokine with negative inotropic effects. Recently, elevated levels of TNF alpha have been identified in patients with advanced heart failure. Although the clinical significance of this finding is unclear at present, there is increasing evidence that this cytokine may play a primary pathophysiologic role in the development and pathogenesis of heart failure in humans. Indeed, many of the clinical hallmarks of heart failure, including left ventricular dysfunction, cardiomyopathy, and pulmonary edema can be explained by the known biological effects of TNF alpha in humans. The present review will summarize recent evidence with regard to the biological role for TNF alpha in the adult mammalian heart, as well as summarize the increasing body of clinical information that implicates this cytokine in the pathophysiology of heart failure.
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PMID:Tumor necrosis factor-alpha and the failing human heart. 748 17

To investigate the role of neutrophil activation in the pathophysiology and sequelae of disseminated intravascular coagulation (DIC), we measured plasma levels of granulocyte elastase-alpha 1-proteinase inhibitor complex (GEPIC) in 41 patients with DIC and 27 patients with similar underlying conditions but without DIC. Mean GEPIC levels were significantly higher in patients with DIC (421.0 +/- 45.6 ng/ml) than in patients without DIC (246.1 +/- 41.9 ng/ml, P < 0.01). Significant differences were also noted in DIC patients with or without infection (474.7 +/- 61.2 ng/ml vs. 302.4 +/- 48.9 ng/ml, P < 0.04), with or without organ dysfunction (546.6 +/- 72.7 ng/ml vs. 305.6 +/- 42 ng/ml, P < 0.01), and with or without respiratory failure (640.0 +/- 91.2 ng/ml vs. 328.1 +/- 55.1 ng/ml, P < 0.01). No significant difference was found in mean GEPIC levels in DIC patients with or without renal failure, heart failure, hepatic failure, or gastrointestinal bleeding. The frequency of respiratory failure correlated with rising plasma levels of GEPIC. Mortality was higher in patients with GEPIC levels > 500 ng/ml (53.8%) than in patients with GEPIC levels < 500 ng/ml (28.6%). This correlation was particularly strong in patients with DIC, infection, and respiratory failure. Based on these data, we suggest that neutrophil activation, triggered by the coagulation cascade and perhaps augmented by endotoxin or cytokine release with infection, significantly contributes to respiratory failure and mortality in patients with DIC.
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PMID:Plasma levels of granulocyte elastase-alpha 1-proteinase inhibitor complex in patients with disseminated intravascular coagulation: pathophysiologic implications. 809 45

The cytokine modulating effects of inotropic agents on human umbilical vein endothelial cells (HUVEC) were investigated. Confluent HUVEC in 24-well plates were treated with inotropic agents and then stimulated with 10 ng/ml of human interleukin (IL)-1 beta. After 24 h of incubation, the cytokine levels in the culture supernatants were determined by specific enzyme-linked immunosorbent assay (ELISA) kits. Vesnarinone [OPC-8212; 3,4-dihydro-6-(4-(3,4-dimethoxybenzoil)-1-piperazinyl)-2(1H)- quinolinone] at 26 mumol/l significantly suppressed the production of IL-6, granulocyte macrophage colony stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF) induced by IL-1 beta. Although 8 bromoadenosine 3'5' cyclic monophosphate (8Br-cAMP) at 100 mumol/l also inhibited the production of these cytokines, the inhibitory effect was less marked than that of vesnarinone. Amrinone at 26 mumol/l and NKH477 at 10 nmol/l also had a less marked inhibitory effect against the production of IL-6. Next, the inhibitory effect of inotropic agents against the expression of the adhesion molecules of HUVEC was measured by a cell ELISA method. Vesnarinone at 26 mumol/l and NKH477 at 10 mumol/l, a water soluble forskolin derivative used as a positive control, both significantly inhibited the expression of E-selectin induced by 10 ng/ml of human tumor necrosis factor (TNF)-alpha. Amrinone at 26 mumol/l did not inhibit the expression of E-selectin. The level of HUVEC cAMP induced by vesnarinone at 26 mumol/l was much lower than that induced by NKH477 at 10 mumol/l. Moreover, according to a 3-(4,5-dimethyl-thiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) cell viability assay, vesnarinone did not affect the viability of HUVEC. The immunosuppressive effects of vesnarinone described above are not derived from either a cAMP elevating effect or a cytotoxic effect against HUVEC. Although the cytokine network in heart failure has not yet been elucidated, patients with congestive heart failure might benefit from the immunomodulating effects of inotropic agents.
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PMID:Inotropic agent vesnarinone inhibits cytokine production and E-selectin expression in human umbilical vein endothelial cells. 857 41

In both cell culture based model systems and in the failing human heart, beta-adrenergic receptors ( beta-AR) undergo agonist-mediated down-regulation. This decrease correlates closely with down-regulation of its mRNA, an effect regulated in part by changes in mRNA stability. Regulation of mRNA stability has been associated with mRNA-binding proteins that recognize A + U-rich elements within the 3'-untranslated regions of many mRNAs encoding proto-oncogene and cytokine mRNAs. We demonstrate here that the mRNA-binding protein, AUF1, is present in both human heart and in hamster DDT1-MF2 smooth muscle cells and that its abundance is regulated by beta-AR agonist stimulation. In human heart, AUF1 mRNA and protein was significantly increased in individuals with myocardial failure, a condition associated with increases in the beta-adrenergic receptor agonist norepinephrine. In the same hearts, there was a significant decrease (approximately 50%) in the abundance of beta1-AR mRNA and protein. In DDT1-MF2 cells, where agonist-mediated destabilization of beta2-AR mRNA was first described, exposure to beta-AR agonist resulted in a significant increase in AUF1 mRNA and protein (approximately 100%). Conversely, agonist exposure significantly decreased (approximately 40%) beta2-adrenergic receptor mRNA abundance. Last, we demonstrate that AUF1 can be immunoprecipitated from polysome-derived proteins following UV cross-linking to the 3'-untranslated region of the human beta1-AR mRNA and that purified, recombinant p37AUF1 protein also binds to beta1-AR 3'-untranslated region mRNA.
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PMID:Regulation of the mRNA-binding protein AUF1 by activation of the beta-adrenergic receptor signal transduction pathway. 862 51

The aetiology of dilated cardiomyopathy is unknown by definition. Viral myocarditis is often viewed as an early stage in the progression of the disease leading to cardiomyopathy and heart failure in humans. The chronic inflammatory process is manifested histologically as a sparse, diffuse lymphocytic infiltration of the myocardium, classified as borderline or ongoing myocarditis according to the Dallas classification. Because of limitations of light microscopy, chronic myocarditis remains an enigmatic condition to diagnose and to treat. In contrast to routine histological staining procedures, immunohistochemical methods enable better identification and quantification of infiltrating cells and also provide further evidence that the activated immunological process within the myocardium is ongoing. In 176 patients with clinically suspected dilated cardiomyopathy, borderline myocarditis was diagnosed in only 14 cases (8%) histologically. However, using immunohistological analysis of endomyocardial biopsies, pathologically increased lymphocytic infiltration was revealed in 67 biopsy specimens (38%), and activated lymphocytes or activated macrophages in all analysed inflamed cardiac tissues. All positive biopsies showed an activated vascular endothelium, demonstrated by the enhanced expression of different adhesion molecules. Various cytokines were locally released from activated inflammatory cells. This may cause a cytokine-rich micro-environment which could be responsible for the enhanced expression of adhesion molecules and thereby contribute to the inflammatory traffic of immune cells into inflamed myocardial areas. These observations underline the hypothesis that the immune process is still active in a group of patients with clinically suspected dilated cardiomyopathy, causing progression of the disease.
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PMID:Immunohistochemistry in dilated cardiomyopathy. 868 73

Interleukin-2 (IL-2) is a cytokine with proven activity against metastatic renal cell carcinoma (RCC) and malignant melanoma (MM). The intravenous administration of high-dose IL-2 is limited by important cardiovascular side effects such as hypotension, fluid retention, arrhythmias, and myocardial ischemia, which often cause dose reduction and/or treatment withdrawal. The occurrence of these toxic events is not predicted by routine pretreatment examinations. The aim of the present study was to test the reliability of serial echocardiography in predicting subsequent cardiac adverse effects in patients undergoing IL-2 administration. In 19 patients (15 men, 4 women; median age: 51 years, range 27-71 years; 10 affected by metastatic RCC and 9 affected by MM) we performed two-dimensional and Doppler echocardiography before and immediately after 28 continuous intravenous infusions (CIVI) of IL-2 at the dose of 18 MIU/m2/day for 4 days. Left ventricular systolic function and the diastolic transmitral flow pattern were assessed before and after IL-2 administration. Significant changes of two indexes of left ventricular filling were noted: a decrease of the ratio of maximal flow velocity in early diastole to that in late diastole (E/A) (basal: 1.12 +/- 0.46, mean +/- SD; posttreatment: 0.83 +/- 0.27; p < 0.01) and an increase of the percentage of the atrial contribution to left ventricular filling (basal: 37.75 +/- 11.58%; posttreatment: 49.43 +/- 16.48%; p < 0.01). Eight major cardiovascular events causing IL-2 infusion withdrawal were observed (two ischemic electrocardiographic modifications, three grade III-IV hypotension, one atrial fibrillation, one pericardial effusion, one acute heart failure). These major cardiovascular events were observed more often when an abnormal basal E/A ratio < 1.0 (p < 0.05) was found. We conclude that Doppler transmitral flow pattern analysis before and subsequent to IL-2 infusion is a useful and easily available procedure for the monitoring of cardiac modifications during CIVI IL-2 administration. It might also predict a major cardiovascular event during IL-2 administration. Patients with basal E/A ratio < 1.0 should be more carefully monitored during treatment and/or should be treated with lower IL-2 doses to avoid cardiovascular toxicity.
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PMID:Isolated left ventricular filling abnormalities may predict interleukin-2-induced cardiovascular toxicity. 873 96

Cytokines are soluble peptides that mediate cell-to-cell interactions via specific cell surface receptors. There is a growing body of evidence that cytokines may play an important role in the pathogenesis of heart failure, and the intriguing possibility has been postulated that anticytokine therapy may favorably alter the clinical outcome of heart failure. As cytokines are essentially pleiotropic and redundant in nature, elimination of a single cytokine from the biologic system often fails to have major consequences. Therefore, the prospect has been raised for developing immunomodulating therapy for heart failure, enabling the simultaneous modification of the actions of multiple cytokines. The recently observed clinical benefit of vesnarinone on mortality and morbidity in patients with heart failure has been attributed to this immunomodulation. In the murine model of myocarditis and heart failure, vesnarinone enhanced the cumulative survival rate without affecting virus replication on virus-induced cytopathic effects. Vesnarinone inhibited excessive cytotoxicity of natural killer cells presumably by suppressing activation mediated by K channel inhibition. Vesnarinone also inhibited the production of cytokines. Cytokine inhibitory effects were different from those of other phosphodiesterase inhibitors or direct elevation of intracellular cyclic adenosine monophosphate, suggesting that the effects did not appear to be derived solely from a cyclic adenosine monophosphate-elevating action. Such cytokine regulation also appeared to be different in normal patients and in patients with heart failure. In conclusion, vesnarinone exerts an immunomodulating effect by suppressing natural killer cell activity and inhibiting cytokine production. These findings may hold open the hope that immunomodulation could be a new therapeutic modality. However, further studies on the long-term safety and efficacy of vesnarinone are warranted to establish the eventual status of this agent in the treatment of heart failure.
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PMID:Vesnarinone: a potential cytokine inhibitor. 889 63

To ascertain whether elevated levels of circulating proinflammatory cytokines in patients with advanced heart failure are due to congestive heart failure or due to cachexia or infection complicating heart failure, we measured prospectively plasma concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), interleukin 2 (IL-2), and interleukin-6 (IL-6) in 12 patients with mitral stenosis with moderate congestive heart failure, but not with cachexia or infection. Blood samples were obtained from the peripheral vein and right and left atria of the patients during percutaneous mitral valvuloplasty. Levels of TNF-alpha, IL-1 beta, IL-2, and IL-6 in the plasma form the peripheral vein and right and left atria of these patients were not elevated compared with those from the peripheral vein of a control group of 10 normal subjects. On the other hand, plasma levels of TNF-alpha but not IL-1 beta, IL-2 or IL-6, were elevated in 4 of 9 patients with congestive heart failure complicated with cachexia and/or infection. Our results suggest that proinflammatory cytokine levels are not elevated in congestive heart failure uncomplicated with cachexia or infection.
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PMID:Plasma cytokine levels in cardiac chambers of patients with mitral stenosis with congestive heart failure. 890 73

Recently, the intriguing possibility has been raised that heart failure may be mediated by the biological effects of cytokines. Indeed, we found elevation of plasma concentrations of various cytokines in patients with myocardial disease. We also detected positive tumor necrosis factor (TNF-alpha) immunoreactivity in right atrial tissues obtained during surgery from patients with severe heart failure. Therefore, we postulated that some aspects of heart failure may be related to non-lethal down-modulation of cardiac function by immune cells and their cytokines. Testing this hypothesis in an experimental model of murine myocarditis, we found that injection of recombinant human TNF-alpha increased mortality of the animals infected with myocarditis virus. The anti-TNF-alpha monoclonal antibody improved survival and attenuated the myocardial lesions. Whereas, administration of recombinant human IL-2 in the acute viremic stage increased survival rate, and resulted in less intense pathological changes in the myocardium while in the subacute aviremic stage, the same amount of IL-2 reduced survival rate and exacerbated severity of the disease. Therefore, cytokine release may initiate a beneficial inflammatory and immune response in the acute phase of the disease process, but the continued induction of cytokines and the enhanced natural killer (NK) cell activity in the later stage are no longer protective. Vesnarinone, a recently synthesized inotropic agent which has proved to benefit patients with congestive heart failure by improving prognosis, also increased the survival of individual subjects in the above-mentioned murine model of heart failure. Cytotoxicity of NK cells obtained from the virus infected animals was substantially reduced when treated with vesnarinone. Vesnarinone also inhibited production of TNF-alpha and other cytokines from stimulated human lymphocytes and cultured murine splenocytes. We conclude, therefore, that inhibition of NK cell activity and suppression of cytokine production appear to be important immunological defense mechanisms which could contribute to the observed salutary effects of vesnarinone in the treatment of chronic heart failure. More broadly, immunomodulation could pave the way for a new frontier in the management of heart failure.
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PMID:Immunomodulation: a new horizon for medical treatment of heart failure. 895 91


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