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 observed increased susceptibility of patients with fulminant hepatic failure for local and systemic infections has been hypothesized to be due to a failure for the hepatic clearance function and subsequent leaking of endogenous endotoxins into the systemic circulation. However, experimental evidence for such a systemic inflammation during liver failure due to endogenous endotoxemia is lacking. Therefore, we designed a study to clarify whether circulating endotoxins due to liver failure could lead to the development of systemic inflammations. In a rat model for liver failure induced by a two-thirds partial hepatectomy, we evaluated the course of circulating tumor necrosis factor and interleukin-6, changes in blood chemistry and hemodynamics, and histopathological changes in the lungs. Partially hepatectomized animals, but not sham-operated animals, demonstrated cardiac failure, increased levels of creatinin and urea, metabolic acidosis, high plasma levels of tumor necrosis factor and interleukin-6, and an influx of PMNs in the lungs-together indicating the development of a systemic inflammatory response. Continuous infusion of recombinant N-terminal bactericidal/permeability-increasing protein (rBPI23), a well described endotoxin-neutralizing protein, prevented these inflammatory reactions. Ex vivo experiments with rat plasma samples confirmed the presence of circulating endotoxins in partially hepatectomized rats as opposed to those treated with rBPI23. Thus, our results indicate that the early phase of liver failure induces a systemic inflammatory response triggered by circulating endotoxins, which can be prevented by perioperative infusion of rBPI23.
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PMID:Liver failure induces a systemic inflammatory response. Prevention by recombinant N-terminal bactericidal/permeability-increasing protein. 748 5

Hypertrophy of the overloaded heart, characterized by an increased number of sarcomeres, provides an adaptive, short-term response. However, when cardiac overload is long-standing, the hypertrophic response appears to cause shortened myocyte survival. The mechanisms responsible for the deleterious effects of chronic myocardial hypertrophy may include a maladaptive growth response of the mature heart. Because terminally differentiated adult cardiac myocytes have little or no capacity to divide, stimuli that promote growth in the overloaded adult heart cannot lead to normal cell division. Instead, overload initiates an unnatural growth response that appears to shorten cardiac myocyte survival, possibly because the same growth factors that mediate the hypertrophic response of the adult heart can also induce programmed cell death (apoptosis). The converting enzyme inhibitors and nitrates, which have growth-inhibitory as well as vasodilator effects, may improve prognosis in heart failure by inhibiting the production of transcription factors. These transcription factors stimulate both the unnatural growth response to overload and stimuli that lead to apoptosis. Since both beta-adrenergic agonists and cytokines, such as tumor necrosis factor-alpha, can stimulate production of similar transcription factors, evidence suggests that beta blockers and vesnarinone improve the prognosis in patients with heart failure possibly because of their ability to inhibit maladaptive growth.
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PMID:Cell death in the failing heart: role of an unnatural growth response to overload. 748 19

Cytokines play a pathogenetic role in a variety of infective and inflammatory diseases. In the present study, we had two objectives: (a) to define the kinetics of tumor necrosis factor (TNF) in plasma after acute myocardial infarction (AMI) in patients treated with early thrombolysis, and (b) to measure other cytokines, interleukin-1 (IL-1) and TNF receptor antagonists, in plasma. TNF-alpha, but not IL-1 beta or IL-8, was present in plasma of 6 of 7 patients with severe AMI (Killip class 3 or 4). No TNF (< 50 pg/ml) was detected in a group of 11 patients with uncomplicated myocardial infarction (Killip class 1) or in control patients without AMI. Soluble TNF receptor type I and IL-1 receptor antagonist (IL-1Ra) were also significantly increased in the group with severe AMI compared with those with uncomplicated AMI. Circulating TNF is increased only in AMI complicated by heart failure at hospital admission. This finding may have diagnostic and therapeutic relevance.
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PMID:Cytokines in acute myocardial infarction: selective increase in circulating tumor necrosis factor, its soluble receptor, and interleukin-1 receptor antagonist. 751 19

Controversy still exists concerning the therapy for viral myocarditis which manifests a wide variety of clinical symptoms. Vesnarinone, a quinolinone derivative that was developed as a positive inotropic agent with complex actions, including phosphodiesterase inhibition and cation channel modification, has recently been confirmed to improve the prognosis of patients with chronic heart failure. However, the precise mechanism of this beneficial effect is not yet clearly understood. In this study, using a murine model of acute viral myocarditis resulting from encephalomyocarditis virus infection, survival and myocardial damage were markedly improved by treatment with vesnarinone. In contrast, survival was not improved by treatment with amrinone, a phosphodiesterase inhibitor. Although vesnarinone did not inhibit viral replication or protect myocytes from viral direct cell injury, it did inhibit the increase in natural killer cell activity after viral infection. On the other hand, amrinone failed to inhibit natural killer cell activity. Both vesnarinone and amrinone suppressed the production of tumor necrosis factor-alpha. Therefore, we postulate that vesnarinone exerted its beneficial effects through an inhibition of natural killer cell activity, and that it serves as an immunomodulator providing new therapeutic possibilities for the treatment of viral myocarditis and/or immunological disorders.
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PMID:Treatment of virus-induced myocardial injury with a novel immunomodulating agent, vesnarinone. Suppression of natural killer cell activity and tumor necrosis factor-alpha production. 808 62

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

Proinflammatory cytokines are capable of modulating cardiovascular function by a variety of mechanisms. These cytokines are elevated in patients with severe heart failure, but changes in mild or moderate heart failure have not been reported. Therefore, simultaneous arterial and coronary sinus concentrations of interleukin-1alpha, soluble interleukin-2 receptor, interleukin-6, and tumor necrosis factor-alpha were measured in 78 patients with New York Heart Association functional class II to IV heart failure and compared with 17 healthy volunteers. Concentrations of interleukin-1alpha, soluble interleukin-2 receptor, and interleukin-6 were determined by a "sandwich" enzyme-linked immunosorbent assay and tumor necrosis factor-alpha by tissue culture technique. There were no statistical differences in interleukin-1alpha, soluble interleukin-2 receptor, or tumor necrosis factor-alpha concentrations in mild to moderate heart failure versus control subjects. Interleukin-6 was significantly elevated, 75 +/- 16 versus 0.4 +/- 0.4pg/ml (p = 0.002). Cytokine concentrations did not differ by heart failure etiology. Paired arterial and coronary sinus concentrations were not significantly different. Soluble interleukin-2 receptor concentrations were significantly correlated with New York Heart Association functional class (r = 0.59, p = 0.04) and negatively associated with exercise tolerance time (r = -0.59, p = 0.007). Thus, interleukin-6 is significantly elevated in mild or moderate heart failure.
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PMID:Circulating concentrations of proinflammatory cytokines in mild or moderate heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. 865 Nov 23

Myocarditis is an important cause of heart failure among adolescents and young adults. A remarkable observation is the discrepancy between the limited overt evidence of myocyte injury and the global impairment of left ventricular function. This discrepancy has stimulated suggestions that immunological mechanisms contribute to cardiac damage. We have developed two murine models of myocarditis, one elicited by cardiotropic Coxsackie B3 (CB3) virus infection and the other by cardiac myosin immunization, to better analyze the pathogenetic mechanisms responsible for immune-mediated heart-muscle disease. Both virus infection and myosin immunization produce myocardial inflammation and elicit heart-reactive antibodies which bind to the myocardium in vivo and which recognize the cardiac myosin heavy chain. Each model offers unique advantages. The virus-induced disease more closely resembles human myocarditis; myosin immunization isolates the autoimmune components of the disease since no virus infection is involved. We have also distinguished strains of mice resistant to autoimmune myocarditis (such as B10.A) from those susceptible to the autoimmune phase of disease (such as A.CA and A/J). Mice from a resistant strain to virus-or myosin-induced autoimmune heart disease develop myocardial inflammation and myosin antibodies if co-treated with tumor necrosis factor (TNF)-alpha or interleukin (IL)-1 when infected or immunized. Thus, cytokines can modulate the outcome of cardiotropic virus infection and enhance its autoimmune sequela. We also found that blocking IL-1 receptor inhibits autoimmune myocarditis in genetically susceptible mice.
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PMID:The pathogenesis of postinfectious myocarditis. 881 Oct 68

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

To study the potential role of tumor necrosis factor (TNF) in chronic heart failure, we measured the plasma levels of TNF by enzyme linked immunoabsorbent assay in 109 patients with various heart diseases grouped as 'non-heart failure' (n = 36), 'heart failure' (n = 36) and 'cachectic' (n = 37). The daily food intake was also investigated. The results showed that there was no obvious difference of daily caloric intake among the three groups of patients. Plasma levels of TNF were significantly elevated in the patients with 'heart failure' (0.51 +/- 0.26 ng/ml, mean +/- S.E.M.), and even higher in the patients with 'cachexia' (6.19 +/- 2.76 ng/ml), as compared with the patients with 'non-heart failure' (0.09 +/- 0.03 ng/ml). Twenty-five patients with 'cachexia' and 11 patients with 'heart failure' had plasma levels of TNF > or = 100 pg/ml, whereas only 5 patients with 'non-heart failure' had plasma levels of TNF above that level. The patients with high levels of TNF were more cachectic than those with normal levels of TNF (body mass index 19.5 +/- 3.4 vs. 22.3 +/- 3.6, P < 0.05). In multivariate analysis, elevated levels of TNF were associated with the level of serum total protein, presence of heart failure and cachexia. These findings indicate that plasma levels of TNF are increased in patients with heart failure, and high levels of TNF may play an important role in the pathogenesis of cardiac cachexia.
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PMID:Elevated plasma levels of tumor necrosis factor in chronic heart failure with cachexia. 907 51


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